Combinations of g-protein coupled hormone receptor modulators and melanocortin 4 receptor agonists and related methods of use

Abstract

The present disclosure relates to methods of treating a disease or disorder comprising administering a combination of an MC4R agonist with a GCHR modulator.

Description

[0001] COMBINATIONS OF G-PROTEIN COUPLED HORMONE RECEPTOR MODULATORS AND MELANOCORTIN 4 RECEPTOR AGONISTS AND RELATED METHODS OF USE

[0002] CLAIM OF PRIORITY

[0003] This application claims priority to U. S. Application No. 63 / 714,124, filed October 30, 2024; the entire contents of the foregoing application is incorporated herein by reference.

[0004] BACKGROUND

[0005] Melanocortin 4 receptor disorders include obesity, which is a condition defined by excessive and / or abnormal accumulation of fat or adipose tissue. It is associated with many lifethreatening diseases, such as cardiovascular disease, respiratory dysfunction, musculoskeletal disorders, obstructive sleep apnea, stroke, renal disease, hyperlipidemia, hypertension, infertility, type 2 diabetes, and certain cancers (e.g., breast, colorectal, endometrial, gallbladder, and pancreatic cancer). Many current therapies comprise administering compounds that reduce insulin resistance and / or body weight or involve bariatric surgeries, e.g., gastric bypass or sleeve gastrectomy; however, these therapies often entail serious complications and side effects and are not suitable for many patients. As such, there is a need for improved therapies.

[0006] SUMMARY

[0007] The present disclosure features combinations of a melanocortin 4 receptor (MC4R) agonist and a G-protein coupled hormone receptor (GCHR) modulator, such as a glucagon-like peptide- 1 receptor (GLP1R) agonist, as well as pharmaceutical compositions thereof and related methods of use. These combinations may be useful in providing improved treatments for obesity by, for example, improving weight loss and enhancing glycemic control and cholesterol metabolism beyond outcomes currently reported when either therapy is administered alone. In an embodiment, the GCHR modulator and MC4R agonist are provided to a subject concurrently, e g., wherein the subject is receiving both the GCHR modulator and MC4R in the same treatment window. In another embodiment, the GCHR modulator and MC4R agonist are provided to a subject in an alternating fashion, e.g., wherein the subject receives either the GCHR modulator or the MC4R agonist for a period of time, followed by the other of the GCHR modulator or the MC4R agonist for a period of time. In an embodiment, the combination of the GCHR modulator and the MC4R agonist function in an additive manner. In another embodiment, the combination of the GCHR modulator and the MC4R agonist function in a synergistic manner, resulting in tolerance of a lower dose of one or both of the GCHR modulator and the MC4R agonist to achieve efficacy, e.g., in the treatment of obesity in the subject.

[0008] In one aspect, featured herein is a method of treating obesity in a subject comprising administering to the subject: (i) a G-protein coupled hormone receptor (GCHR) modulator; and (ii) a melanocortin receptor 4 (MC4R) agonist. In an embodiment, the GCHR modulator comprises a glucagon-like peptide-1 receptor (GLP1R) agonist, a dual GLP1R, or a triple GLP1R. In an embodiment, the GCHR modulator is a GLP1R agonist. In an embodiment, the GLP1R agonist comprises semaglutide, orforglipron, albiglutide, dulaglutide, exendin-4, tirzepatide, liraglutide, exenatide, or lixisenatide. In an embodiment, the GCHR modulator comprises a dual GLP1R and gastric inhibitory peptide agonist. In an embodiment, the dual GLP1R and gastric inhibitory peptide agonist comprises survodutide, pemvidutide, or cotadutide. In an embodiment, the GCHR modulator comprises a triple GLP1R, gastric inhibitory peptide, and glucose-dependent insulinotropic polypeptide agonist. In an embodiment, the triple GLP1R, gastric inhibitory peptide, and glucose-dependent insulinotropic polypeptide agonist comprises retatrutide. In an embodiment, the MC4R agonist is a peptide. In an embodiment, the GCHR modulator is a peptide.

[0009] In an embodiment, each of the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof is independently formulated as a pharmaceutical composition. In an embodiment, each of the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof is formulated together as a single pharmaceutical composition. In an embodiment, each of the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof is administered concomitantly to the human subject. In an embodiment, the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof are administered within 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, or more of each other. In an embodiment, the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof are administered within 30 minutes of each other. In an embodiment, the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof are administered within 1 hour of each other. In an embodiment, the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof are administered within 2 hours of each other. In an embodiment, the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof are administered within 6 hours of each other. In an embodiment, the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof are administered within 12 hours of each other. In an embodiment, the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof are administered within 24 hours of each other. In an embodiment, the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof is administered sequentially to the human subject. In an embodiment, administered sequentially comprises administration of the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof within 24 hours. In an embodiment, the GCHR modulator or a pharmaceutically acceptable salt thereof is administered first to the human subject, followed by the MC4R agonist or a pharmaceutically acceptable salt thereof. In an embodiment, the MC4R agonist or a pharmaceutically acceptable salt thereof is administered first to the human subject, followed by the GCHR modulator or a pharmaceutically acceptable salt thereof. In an embodiment, the GCHR modulator or a pharmaceutically acceptable salt thereof is administered for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, or more prior to administration of the MC4R agonist or a pharmaceutically acceptable salt thereof. In an embodiment, the MC4R agonist or a pharmaceutically acceptable salt thereof is administered for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, or more prior to administration of the GCHR modulator or a pharmaceutically acceptable salt thereof.

[0010] In an embodiment of the foregoing aspect, the GCHR modulator or a pharmaceutically acceptable salt thereof is administered at a dosage of between 0.1 to 500 mg. In an embodiment, the GCHR modulator or a pharmaceutically acceptable salt thereof is administered at a dosage of 0.1 mg. In an embodiment, the GCHR modulator or a pharmaceutically acceptable salt thereof is administered at a dosage of 1 mg. In an embodiment, the GCHR modulator or a pharmaceutically acceptable salt thereof is administered at a dosage of 10 mg. In an embodiment, the GCHR modulator or a pharmaceutically acceptable salt thereof is administered at a dosage of 50 mg. In an embodiment, the GCHR modulator or a pharmaceutically acceptable salt thereof is administered at a dosage of 100 mg. In an embodiment, the GCHR modulator or a pharmaceutically acceptable salt thereof is administered at a dosage of 200 mg. In an embodiment, the GCHR modulator or a pharmaceutically acceptable salt thereof is administered at a dosage of 250 mg. In an embodiment, the GCHR modulator or a pharmaceutically acceptable salt thereof is administered at a dosage of 500 mg. In an embodiment, the MC4R agonist or a pharmaceutically acceptable salt thereof is administered at a dosage of between 0.1 to 10 mg. In an embodiment, the MC4R agonist or a pharmaceutically acceptable salt thereof is administered at a dosage of 0.1 mg. In an embodiment, the MC4R agonist or a pharmaceutically acceptable salt thereof is administered at a dosage of 0.5 mg. In an embodiment, the MC4R agonist or a pharmaceutically acceptable salt thereof is administered at a dosage of 1 mg. In an embodiment, the MC4R agonist or a pharmaceutically acceptable salt thereof is administered at a dosage of 2.5 mg. In an embodiment, the MC4R agonist or a pharmaceutically acceptable salt thereof is administered at a dosage of 5 mg. In an embodiment, the MC4R agonist or a pharmaceutically acceptable salt thereof is administered at a dosage of 10 mg. In an embodiment, the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof are administered orally. In an embodiment, the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof are administered subcutaneously. In an embodiment, the GCHR modulator or a pharmaceutically acceptable salt thereof is administered orally and the MC4R agonist or a pharmaceutically acceptable salt thereof are administered subcutaneously. In an embodiment, the GCHR modulator or a pharmaceutically acceptable salt thereof is administered subcutaneously and the MC4R agonist or a pharmaceutically acceptable salt thereof are administered orally. In an embodiment, the GCHR modulator or a pharmaceutically acceptable salt thereof is administered orally. In an embodiment, the GCHR modulator or a pharmaceutically acceptable salt thereof is administered subcutaneously. In an embodiment, the MC4R agonist or a pharmaceutically acceptable salt thereof is administered orally. In an embodiment, the MC4R agonist or a pharmaceutically acceptable salt thereof is administered subcutaneously. In an embodiment, the obesity is a genetic obesity or a non-genetic obesity. In an embodiment, the subject has been diagnosed with obesity. In an embodiment, the subject has been diagnosed with hypothalamic obesity. In an embodiment, the subject has a body mass index (BMI) greater than 30. In an embodiment, the subject has a waist circumference of greater than 40 cm. In an embodiment, the subject has a waist-to-hip circumference ratio of greater than 2. In an embodiment, the subject has a mutation in an MC4R pathway agonizable gene. In an embodiment, the MC4R pathway agonizable gene comprises ARL6, RAI1, SRC1, BBS19, BBS21, CEP290, IFT74, LZTFL1, MKS1, TRIM32, WDPCP, RPS6KA3, HTR2C, KSR2, PROK2, RAB23, MRAP2, AFF4, ADCY3, TUB, OTP, GPR101, or TBX3. In an embodiment, the subject has a mutation in POMC, LEPR, PCSK1, SRC1, or SH2B1. In an embodiment, the efficacy of the combination of the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof is at least Xi-fold greater than the efficacy of either of the GCHR modulator or the MC4R agonist alone at the molar amount used in the combination, wherein Xi is 1, 1.25, 1.5, 1.75, 2, 2.5, or greater. In an embodiment, the GCHR modulator and the MC4R agonist are administered in an alternating manner or in phases, wherein during each phase, only one of the GCHR modulator and the MC4R agonist are administered. In an embodiment, the phases comprise periods of time. In an embodiment, the phases comprise administration of different doses of the GCHR modulator and the MC4R agonist.

[0011] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In addition, the materials, methods, and examples are illustrative only and not intended to be limited.

[0012] BRIEF DESCRIPTION OF THE FIGURES FIG. 1 is a graph depicting the effect of co-administration of a GCHR modulator, e.g., a GLP1R peptide agonist, e.g., semaglutide, and a MC4R agonist, e.g., RM-493 (setmelanotide), on body weight and body composition in a mouse model of diet induced obesity (DIO). After 18 days of co-administration of semaglutide and RM-493, DIO mice lost a significant amount of body weight. FIG. 2 is a graph depicting the effect of co-administration of a GCHR modulator, e.g., a GLP1R peptide agonist, e.g., semaglutide, and a MC4R agonist, e.g., RM-493, on body weight and body composition in a mouse model of diet induced obesity (DIO). After 18 days of coadministration of semaglutide and RM-493, DIO mice lost a significant amount of body weight.

[0013] FIGs. 3A and 3B are graphs depicting the effect of co-administration of a GCHR modulator, e.g., a GCHR peptide agonist, e.g., semaglutide, and a MC4R agonist, e.g., RM-493, on body weight and body composition in a mouse model of diet induced obesity (DIO). After 3 weeks of co-administration of semaglutide and RM-493, liver weight (FIG. 3A) and body weight (FIG.3B) were significantly reduced.

[0014] FIG. 4 is a graph depicting the effect of co-administration of a GCHR modulator, e.g., a GLP1R peptide agonist, e.g., semaglutide, and a MC4R agonist, e.g., RM-493, on body weight and body composition in a mouse model of diet induced obesity (DIO). After 18 days of co-administration of semaglutide and RM-493, DIO mice lost a significant amount of body weight.

[0015] FIGs. 5A, 5B, and 5C are graphs depicting the effect of co-administration of a GCHR modulator, e.g., a GLP1R peptide agonist, e.g., liraglutide, and a MC4R agonist, e.g., RM-493, on body weight and body composition in a mouse model of diet induced obesity (DIO). Five-day treatment of DIO male mice was performed with the following treatment groups: vehicle (white), liraglutide (10 nmol / kg) (gray), RM-493 (3.6 Imol / kg) (black), or liraglutide (10 nmol / kg) and RM-493 (3.6 Imol / kg) (checkered). Compounds were administered by daily subcutaneous injections. Effects on (FIG. 5A) body weight and (FIG. 5B, FIG. 5C) body composition were measured. Data represent means + / - SEM; n = 8; *P < 0.05, **P < 0.01, ***P < 0.001.

[0016] FIGs. 6A-6G are graphs depicting the effect of co-administration of a GCHR modulator, e.g., a GLP1R peptide agonist, e.g., liraglutide, and a MC4R agonist, e.g., RM-493, on energy metabolic parameters in a mouse model of diet induced obesity (DIO). Five-day treatment of DIO male mice was performed with the following treatment groups: vehicle (white), liraglutide (10 nmol / kg) (gray), RM-493 (3.6 Imol / kg) (black), or liraglutide (10 nmol / kg) and RM-493 (3.6 Imol / kg) (checkered). Compounds were administered by daily subcutaneous injections. Effects on (FIG. 6A, FIG. 6B) energy expenditure, (FIG. 6C) respiratory exchange ratio (RER), (FIG.

[0017] 6D) locomotor activity, (FIG. 6E) cumulative food intake, (FIG. 6F) meal number, and (FIG.

[0018] 6G) meal size were measured. Data represent means + / - SEM; n = 8; *P < 0.05, **P < 0.01, ***P< 0.001. FIGs. 7A-7F are graphs depicting the effect of long-term co-administration of a GCHR modulator, e.g., a GLP1R peptide agonist, e.g., liraglutide, and a MC4R agonist, e.g., RM-493, on obesity and glucose metabolism in a mouse model of diet induced obesity (DIO). 22 days of treatment of DIO male mice were performed with the following treatment groups: vehicle (white), liraglutide (10 nmol / kg) (gray), RM-493 (3.6 nmol / kg) (black), or liraglutide (10 nmol / kg) and RM-493 (3.6 nmol / kg) (checkered). Compounds were administered by daily subcutaneous injections. Effects on (FIG. 7A) body weight, (FIG. 7B) cumulative food intake, (FIG. 7C, FIG. 7D) body composition and (FIG. 7E, FIG. 7F) glucose tolerance were measured. Data represent means + / - SEM; n = 8; *P < 0.05, **P < 0.01, ***p < 0.001.

[0019] FIG. 8 is a graph depicting body weight changes in db / db mice during 1 week of administration of a GCHR modulator, e.g., a GLP1R agonist, e.g., semaglutide, and a MC4R agonist, e.g., RM-718. Data represent means + / - SEM; n=8 / group.

[0020] FIG. 9 is a graph depicting the weekly body weight changes (represented in percentages) in db / db mice during 1 week of administration of a GCHR modulator, e.g., a GLP1R agonist, e.g., semaglutide, and a MC4R agonist, e.g., RM-718. Data represent means + / - SEM. G4: n=7, G5: n=7, others: n=8 / group.

[0021] FIG. 10 is a graph depicting the food intake in db / db mice during 1 week of administration of a GCHR modulator, e.g., a GLP1R agonist, e.g., semaglutide, and a MC4R agonist, e.g., RM-718. Data represent means + / - SEM. G4: n=7, G5: n=7 from day 6-8, others: n=8 / group.

[0022] FIG. 11 is a graph depicting the weekly food intake changes (represented in percentage change from baseline) in db / db mice during 1 week of administration of a GCHR modulator, e.g., a GLP1R agonist, e.g., semaglutide, and a MC4R agonist, e.g., RM-718. Data represent means + / - SEM. G4: n=7, G5: n=7, others: n=8 / group.

[0023] FIG. 12 is a graph depicting cumulative food intake in db / db mice during 1 week of administration of a GCHR modulator, e.g., a GLP1R agonist, e.g., semaglutide, and a MC4R agonist, e.g., RM-718. Data represent means + / - SEM. G4: n=7, G5: n=7 from day 6-8, others: n=8 / group.; Day 0 food intake used as baseline value.

[0024] FIGs. 13A-13C are graphs depicting fed blood glucose (FIG. 13A), mean fed blood glucose (represented in percent change from baseline) (FIG. 13B), and mean fed blood glucose change during administration in db / db mice during 1 week of administration of a GCHR modulator, e.g., a GLP1R agonist, e.g., semaglutide, and a MC4R agonist, e.g., RM-718. Data represent means + / - SEM. FIG. 13A: G4: n=7, G5: n=7 at day 8, others: n=8 / group. FIG 13B:

[0025] G4: n=7, others: n=8 / group. FIG. 13C: G4: n=7, others: n=8 / group.

[0026] FIGs. 14A-14C are graphs depicting changes in body composition (total mass change from control (FIG. 14A), fat mass change from control (FIG. 14B), and lean mass change from control (FIG. 14C)) in db / db mice after 1 week of administration of a GCHR modulator, e.g., a GLP1R agonist, e.g., semaglutide, and / or a MC4R agonist, e.g., RM-718. Fat mass and lean mass were measured and recorded. Data represent means + / - SEM. n=6 / group 1, 4, 5, n=7 / group 2, 3, 6, 7.

[0027] FIGs. 15A-15C are graphs depicting changes in body composition (total mass change from control represented in percentage (FIG. 15A), fat mass change from control represented in percentage (FIG. 15B), and lean mass change from control represented in percentage (FIG. 15C)) in db / db mice after 1 week of administration of a GCHR modulator, e.g., a GLP1R agonist, e.g., semaglutide, and / or a MC4R agonist, e.g., RM-718. Fat mass and lean mass were measured and recorded on Day 18. Data represent means + / - SEM. n=6 / group 1, 4, 5, n=7 / group 2, 3, 6, 7, n=5 / group 8, 9.

[0028] FIG. 16 is a graph illustrating the comparative effect of administration of an MC4R agonist, e.g., setmelanotide, on patients having acquired hypothalamic obesity (HO) who were either (i) concomitantly being administered a GCHR modulator, e g., a GLP1R agonist, e.g., liraglutide, semaglutide, or tirzepatide, or (ii) not concomitantly being administered a GCHR modulator.

[0029] DETAILED DESCRIPTION

[0030] The present patent application discloses methods of treating a disease or disorder, such as obesity, comprising administering to a subject in need thereof a melanocortin-4 receptor (MC4R) agonist and a G-protein coupled hormone receptor (GCHR) agonist, e.g., a glucagon-like peptide- 1 receptor (GLP1R) agonist. In an embodiment, administering a combination of an MC4R agonist and a GCHR modulator, e g., a GLP1R agonist, acts synergistically in a subject in treating obesity, thereby leading to weight loss, decrease in hunger, and / or increase in energy expenditure in the subject. Definitions

[0031] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. Although any methods and materials similar or equivalent to those described herein can be used in the practice for testing of the present invention, the preferred materials and methods are described herein. In describing and claiming the present invention, the following terminology will be used.

[0032] The articles “a” and “an” are used herein to refer to one or to more than one (e.g., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0033] “About” as used herein when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of ±20% or ±10%, more preferably ±5%, even more preferably ±1%, and still more preferably ±0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.

[0034] “Acquire” or “acquiring” as the terms are used herein, refer to obtaining

[0035] possession of a physical entity, or a value, e.g., a numerical value, or knowledge of (e.g., knowledge of the sequence or mutational state of) a genotype or a nucleic acid or polypeptide, by “directly acquiring” or “indirectly acquiring” the physical entity, value, or knowledge. “Directly acquiring” means performing a physical process (e.g.,

[0036] performing a synthetic or analytical method) to obtain the physical entity, value, or knowledge. “Indirectly acquiring” refers to receiving the physical entity, value, or knowledge from another party or source (e.g., a third-party laboratory that directly

[0037] acquired the physical entity, value, or knowledge). Directly acquiring a physical entity includes performing a process that includes a physical change in a physical substance, e.g., a starting material. Exemplary changes include making a physical entity from two or more starting materials, shearing or fragmenting a substance, separating or purifying a substance, combining two or more separate entities into a mixture, performing a chemical reaction that includes breaking or forming a covalent or non-covalent bond. Directly acquiring a value or knowledge includes performing a process that includes a physical change in a sample or another substance. Examples include performing an analytical process which includes a physical change in a substance, e.g., a sample, analyte, or reagent (sometimes referred to herein as “physical analysis”), performing an analytical method, e.g., a method which includes one or more of the following: separating or purifying a substance, e.g., an analyte, or a fragment or other derivative thereof, from another substance; combining an analyte, or fragment or other derivative thereof, with another substance, e.g., a buffer, solvent, or reactant; or changing the structure of an analyte, or a fragment or other derivative thereof, e.g., by breaking or forming a covalent or non-covalent bond, between a first and a second atom of the analyte; or by changing the structure of a reagent, or a fragment or other derivative thereof, e.g., by breaking or forming a covalent or non-covalent bond, between a first and a second atom of the reagent.

[0038] As used herein, the term “functional,” as applied to an allele, e.g., of a MC4R pathway agonizable gene, refers to an allele having, e.g., at least 5, 10, 20, 30, 40, 50, 70, or 80% of the activity of a reference allele, e g., a wildtype allele.

[0039] As used herein, the term “nonfunctional,” as applied to an allele, e.g., a MC4R pathway agonizable gene, refers to an allele which has less than 5, 10, 20, 30, 40, 50, 70, or 80% of the activity of a reference allele, e.g., a wildtype allele. In an embodiment, a nonfunctional allele is an allele of the gene that is other than a functional allele, as the term functional allele is defined herein. By way of example, in an embodiment, if a functional allele has at least 20% of the activity of a reference allele a nonfunctional allele is an allele with less than 20% of the activity.

[0040] As used herein, the term “MC4R pathway agonizable gene” refers to a gene associated with a phenotype which can be modulated, e.g., ameliorated or lessened, by modulating MC4R, e.g., agonizing MC4R, e.g., with an MC4R agonist, e.g., with a combination of an MC4R agonist and GCHR modulator. In an embodiment, the phenotype is hyperphagia, appetite, unwanted appetite, obesity, weight, body mass, or a metabolic syndrome (e.g., diabetes) and the phenotype is, e.g., modulated, e.g., reduced or ameliorated.

[0041] In an embodiment, the term “MC4R pathway agonizable gene” does not include the melanocortin-4 receptor (MC4R) gene. In an embodiment, the term “MC4R pathway agonizable gene” does not include POMC. In an embodiment, the MC4R pathway agonizable gene does not comprise any one of POMC, Proprotein Convertase Subtilisin / Kexin Type 1 (PCSK1, also called PC 1 / 3), MAGE-like-2 (MAGEL2), leptin receptor (leptin-R), leptin, 5-hydroxytryptamine (serotonin) receptor 2C, G protein-coupled (5-HT2c receptor), nescient helix loop helix 2 (NhHL2, also called NSCL2), pro-hormone convertase, carboxypeptidase E (CPE), and single- minded 1 (Siml). In an embodiment, the MC4R pathway agonizable gene does not comprise any gene disclosed in W02013 / 102047 or WO 2017 / 059076, the full contents of each of which is incorporated herein by reference in its entirety.

[0042] In an embodiment, at least one of the MC4R alleles is functional, e.g., it has at least 5, 10, 20, 30, 40, 50, 70, or 80% of the activity of a reference allele, e.g., a wildtype allele, e.g., as measured by a functional assay. In an embodiment, one of the MC4R

[0043] alleles is functional. In an embodiment, both MC4R alleles are functional. In an embodiment, the subject is heterozygous at the MC4R gene and both alleles are

[0044] functional. In an embodiment, the subject is homozygous at the MC4R gene for a functional allele.

[0045] In an embodiment, both MC4R alleles are nonfunctional. (A nonfunctional allele is an allele which is not functional, as functional is defined herein.) In an embodiment, the subject is heterozygous at the MC4R gene and both alleles are nonfunctional. In an embodiment the subject is homozygous at the MC4R gene for a nonfunctional allele.

[0046] In an embodiment, at least one allele of an MC4R pathway agonizable gene other than MC4R is functional, e.g., it has at least 5, 10, 20, 30, 40, 50, 70, or 80% of the activity of a reference allele, e.g., a wildtype allele, e.g., as measured by a functional assay. In an embodiment one allele of an MC4R pathway agonizable gene other than MC4R is functional. In an embodiment both alleles of an MC4R pathway agonizable gene other than MC4R are functional. In an embodiment the subject is heterozygous at an MC4R pathway agonizable gene other than MC4R and both alleles are functional. In an embodiment the subject is homozygous at an MC4R pathway agonizable gene other than MC4R for a functional allele.

[0047] In an embodiment, both MC4R alleles are nonfunctional. (A nonfunctional allele is an allele which is not functional, as functional is defined herein.) In an embodiment the subject is heterozygous at the MC4R gene and both alleles are nonfunctional. In an embodiment the subject is homozygous at the MC4R gene for a nonfunctional allele.

[0048] As used herein, the term “metabolic syndrome” refers to a group of symptoms that occur together and increase the risk for coronary artery disease, stroke, and type 2 diabetes. According to the American Heart Association and the National Heart, Lung, and Blood Institute, metabolic syndrome also referred to as Syndrome X) is present if a subject has three or more of the following signs: 1) Blood pressure equal to or higher than 130 / 85 mmHg; 2) Fasting blood sugar (glucose) equal to or higher than 100 mg / dL; 3) Large waist circumference (length around the waist): - Men - 40 inches or more; - Women - 35 inches or more; 4) Low HDL cholesterol: - Men - under 40 mg / dL; - Women - under 50 mg / dL; 5) Triglycerides equal to or higher than 150 mg / dL. Metabolic syndrome can be diagnosed by testing subject’s blood pressure, blood glucose level, HDL cholesterol level, LDL cholesterol level, total cholesterol level, and triglyceride level.

[0049] As used herein, the term “agonist” refers to any chemical compound, either naturally occurring or synthetic, that, upon interacting with (e.., binding to) its target, e.g., MC4R, raises the signaling activity of MC4R above its basal level, or e.g., a GCHR, which raises the signaling activity of GCHR above its basal level. An agonist can be a superagonist (i.e. a compound that is capable of producing a greater maximal response than the endogenous agonist for the target receptor, and thus has an efficacy of more than 100%), a full agonist (i.e. a compound that elicits a maximal response following receptor occupation and activation) or a partial agonist (i.e. a compounds that can activate receptors but are unable to elicit the maximal response of the receptor system).

[0050] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of one or more of a symptom, manifestation, or underlying cause of a disease, disorder, or condition (e.g., as described herein), e.g., by administering a therapy, e.g., administering a compound described herein (e.g., an MC4R agonist of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII) (e.g., as described herein) or a G-protein coupled hormone receptor (GCHR) agonist, e.g., a GCHR modulator, e.g., a GLP1R agonist as described herein. In an embodiment, treating comprises reducing, reversing, alleviating, delaying the onset of, or inhibiting the progress of a symptom of a disease, disorder, or condition. In an embodiment, treating comprises reducing, reversing, alleviating, delaying the onset of, or inhibiting the progress of a manifestation of a disease, disorder, or condition. In an embodiment, treating comprises reducing, reversing, alleviating, reducing, or delaying the onset of, an underlying cause of a disease, disorder, or condition. In some embodiments, “treatment,” “treat,” and “treating” require that signs or symptoms of the disease, disorder, or condition have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease or condition, e.g., in preventive treatment. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence. Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence. In some embodiments, treatment comprises prevention and in other embodiments it does not. The term “treating” includes achieving one or more of the following results: reducing the body weight (as measured, for example, by a body mass index (BMI) and / or body weight), e.g., compared to a control (e.g., body weight before treatment or a predetermined body weight); reducing the waist circumference, e.g., compared to a control (e.g., waist circumference before treatment or a predetermined waist circumference); reducing the hunger level, e.g., compared to a control (e.g., hunger level before treatment or a predetermined hunger level); increasing the resting energy expenditure (REE), e.g., compared to a control (e g., REE before treatment or a predetermined REE); decreasing the food intake, e.g., compared to a control level (e.g., before treatment or a predetermined food intake); ameliorating or improving a clinical symptom or indicators associated with a disorder described herein such as obesity (e.g., obesity), Prader Willi Syndrome, Smith-Magenis syndrome, type-II diabetes, a prediabetic condition, blood level of hemoglobin A1C (HblAc) above 6%, hyperinsulimenia, hyperlipidemia, insulin insensitivity, or glucose intolerance; delaying, inhibiting or preventing the progression of obesity and / or obesity related indications; or partially or totally delaying, inhibiting or preventing the onset or development of obesity or an obesity related indication. Delaying, inhibiting or preventing the progression of the obesity includes for example, delaying, inhibiting or preventing the progression of a subject having normal weight to obesity. In embodiments, a control is a value of a parameter measured before treatment by a MC4R agonist described herein or a predetermined value. The term “treating” further includes partially or totally reducing the risk for coronary artery disease, stroke, and type 2 diabetes associated with the metabolic syndrome as well as ameliorating or improving a clinical symptom or signs of metabolic syndrome associated with metabolic syndrome, such as any one or more of the five indicators listed above. For example, the term “treating” includes delaying, inhibiting or preventing the progression of parameters associated with the metabolic syndrome, including insulin resistance, glucose clearance and parameters of cardiovascular disease including heart rate and blood pressure.

[0051] As used herein “inhibition” or “inhibits” can include a reduction in a certain parameter, such as a parameter described herein. For example, inhibition of a parameter, e.g., activity, can be at least 5%, 10%, 20%, 30%, 40%, or more is included by this term. Thus, inhibition need not be 100%.

[0052] As used herein, the term “subject” refers to a mammal, e.g., a human. Subject can also refer to an animal in need of veterinary treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like). In an embodiment, the subject is a pediatric subject (e.g., a subject under 21 or 18 years of age). In an embodiment, the subject is an adult subject (e.g., a subject over 18 or 21 years of age).

[0053] As used herein, the term “mutation” can refer to an altered nucleic acid sequence of a gene or fragment thereof compared to a wild-type sequence. For example, a mutation can include a point mutation, frame-shift mutation, missense mutation, inversion, deletion, insertion, truncation, chromosomal translocation. In embodiments, a mutation can result in the gene or fragment thereof coding for a non-functional protein, a protein with reduced activity (or a partially functional protein), or a protein with altered activity. For example, a “loss of function” mutation refers to a mutation that results in the gene or fragment thereof coding for a nonfunctional protein, which has substantially reduced activity compared to its wild-type counterpart (e.g., a non-functional protein has less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less activity than its wild-type counterpart). For example, “partial loss of function” mutation refers to a mutation that results in the gene or fragment thereof coding for a partially functional protein, which has reduced activity compared to its wild-type counterpart (e.g., a partially functional protein has less than 50% and greater than 10% of the acti vity of its wild-type counterpart).

[0054] As used herein “heterozygous” refers to the presence of two different alleles (having different nucleic acid sequences) for a given gene in a subject. In some embodiments, “heterozygous mutation” can refer to the presence of a mutation on one allele for a given gene and the lack of a mutation on the other allele of the same gene in a subject (e.g., one mutant allele and one wild type allele for a given gene). In other embodiments, a “heterozygous mutation” can be a “compound heterozygous” mutation, which refers to the presence of a mutation (e.g., loss of function mutation or partial loss of function mutation) on one allele for a given gene and a different (e.g., loss of function mutation or partial loss of function mutation) on the other allele for the same gene (e.g., two different alleles that are both mutated, e.g., non-functional or partially functional). In embodiments, where a compound heterozygous mutation includes two non-functional alleles, the genotype can be a null genotype or functionally deficient genotype.

[0055] As used herein “homozygous” refers to the presence of two identical alleles for a given gene. In some embodiments, a “homozygous mutation” refers to the presence of two mutant alleles for a given gene, where the two mutant alleles are identical

[0056] As used herein, “unit dosage form” refers to a physically discrete unit suited as unitary doses for a subject to be treated. Each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.

[0057] As used herein “dosage” refers to a quantity or amount of a therapeutic agent. In some embodiments, a dosage is the amount administered to the subject in a single administration, e.g., in a single injection, a single infusion, or single administration of one or more unit dosages. In embodiments, a dosage is the amount administered to the subject in multiple administrations, e.g., multiple injections, multiple infusions, or multiple administrations of one or more unit dosages. In other embodiments, a dosage can refer to the total amount administered to the subject in a certain time period, e.g., per day. In such examples, the dosage is typically referred to as “daily dosage” or dosage in terms of quantity per day.

[0058] As used herein “hunger” or “hunger level” refers to a subject’s appetite, desire to consume food, or perceived need for food. In embodiments, the hunger or hunger level of a subject can be quantified by using a scale to obtain a hunger score. In embodiments, the scale for hunger assigns a higher score for a subject that more frequently (e.g., often or always) feels unbearable hunger and a lower score for a subject that less frequently (e.g., sometimes or never) feels unbearable hunger. See, e.g., Sibilia. Psychological Topics 19 (2010), 2, 341-354. For example, a Likert scale for hunger can be used that assigns scores from 0 to 10 points (0=no hunger; 10=severe hunger). In other examples, a Likert scale for hunger can be used that assigns scores from 1 to 4 points, where a subject who never feels unbearable hunger is assigned a score of 1, where a subject who sometimes feels unbearable hunger is assigned a score of 2, where a subject who often feels unbearable hunger is assigned a score of 3, and where a subject who always feels unbearable hunger is assigned a score of 4.

[0059] “Combination,” as used herein refers to a selection of two or more elements or ingredients, e.g., a composition of a combination of agonists, e.g., an MC4R agonist as described herein and a G-protein coupled hormone receptor (GCHR) agonist, e.g., a GLP1R agonist, as described herein for use as a medicament or as a pharmaceutical composition for treating a disease. For example, methods of treating a disease or a method of administering to a subject in need thereof may comprise a combination, e.g., an MC4R agonist as described herein and a GCHR modulator, e.g., a GLP1R agonist, as described herein. For example, a “combination therapy” as used herein may refer to a therapy comprising a plurality of active agents, e.g., an MC4R agonist as described herein and a GLP1R agonist as described herein.

[0060] “Co-administration,” as used herein, refers to administration of unit dosages of the agonists and / or compounds disclosed herein, e.g., an MC4R agonist as described herein and a GCHR modulator, e.g., a GLP1R agonist, as described herein, before or after administration of unit dosages of one or more additional therapeutic agents, for example, administration of the compound disclosed herein within seconds, minutes, or hours of the administration of one or more additional therapeutic agents. For example, in some embodiments, a unit dose of a compound of the present disclosure is administered first, followed within seconds or minutes by administration of a unit dose of one or more additional therapeutic agents. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of a compound of the present disclosure within seconds or minutes. In some embodiments, a unit dose of a compound of the present disclosure is administered first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of one or more additional therapeutic agents. In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of a compound of the present disclosure. Coadministration of a compound disclosed herein with one or more additional therapeutic agents generally refers to simultaneous or sequential administration of a compound disclosed herein and one or more additional therapeutic agents, such that therapeutically effective amounts of each agent are present in the body of the subject.

[0061] As used herein, the term "peptide" is any peptide comprising two or more amino acids. The term peptide includes short peptides (e.g., peptides comprising between 2 - 14 amino acids), medium-length peptides (15-50) or long-chain peptides (e.g., proteins). The terms peptide and protein may be used interchangeably herein. As used herein, "peptide" is interpreted to mean a polymer composed of amino acid residues, related naturally occurring structural variants, and synthetic non-naturally occurring analogs thereof linked via peptide bonds, related naturally occurring structural variants, and synthetic non-naturally occurring analogs thereof. Synthetic peptides can be synthesized, for example, using an automated peptide synthesizer. Peptides may contain amino acids other than the 20 gene-encoded amino acids. "Peptide(s)" include those modified either by natural processes, such as processing and other post-translational modifications, but also by chemical modification techniques. Such modifications are well described in basic texts and in more detailed monographs, and are well known to those of skill in the art. It will be appreciated that in some embodiments, the same type of modification is present in the same or varying degree at several sites in a given peptide. Also, a given peptide, in some embodiments, contains more than one type of modifications. Modifications occur anywhere in a peptide, including the peptide backbone, the amino acid side chains, and the amino or carboxyl termini.

[0062] A “therapeutically effective amount” or “effective amount,” as used herein, refers to an amount that is effective to elicit the desired biological or medical response, including the amount of a compound that, when administered to a subject for treating a disease, is sufficient to affect such treatment for the disease. The effective amount will vary depending on the compound, the disease, and its severity and the age, weight, etc., of the subject to be treated. The effective amount can include a range of amounts. As is understood in the art, an effective amount may be in one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired treatment endpoint. An effective amount may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved. Suitable doses of any co-administered compounds may optionally be lowered due to the combined action (e.g., additive or synergistic effects) of the compounds. As used herein, the term "variant" is interpreted to mean a peptide that differs from a reference peptide but retains essential properties. Atypical variant of a peptide differs in amino acid sequence from another, e.g., reference, peptide. Generally, differences are limited so that the sequences of the reference peptide and the variant are closely similar overall and, in many regions, identical. A variant and reference peptide may differ in amino acid sequence by one or more substitutions, additions, deletions in any combination. A substituted or inserted amino acid residue may or may not be one encoded by the genetic code. Non-naturally occurring variants of peptides may be made by mutagenesis techniques, by direct synthesis, and by other suitable recombinant methods.

[0063] Selected Chemical Definitions

[0064] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March ’s Advanced Organic Chemistry, 5thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0065] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts. Also, all publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety.

[0066] The nomenclature used to define the peptides is that typically used in the art wherein the amino group at the N-terminus appears to the left and the carboxyl group at the C-terminus appears to the right. Where the amino acid has D and L isomeric forms, it is the L form of the amino acid that is represented unless otherwise explicitly indicated. When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, “Ci-Ce alkyl” is intended to encompass, Ci, C2, C3, C4, C5, Ce, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and Cs-Ce alkyl.

[0067] The compounds useful for practicing the methods described herein may possess one or more chiral centers and so exist in a number of stereoisomeric forms. All stereoisomers and mixtures thereof are included in the scope of the present disclosure. Racemic compounds may either be separated using preparative HPLC and a column with a chiral stationary phase or resolved to yield individual enantiomers utilizing methods known to those skilled in the art. In addition, chiral intermediate compounds may be resolved and used to prepare chiral compounds of the disclosure.

[0068] The compounds useful for practicing the methods described herein may also comprise one or more isotopic substitutions. For example, H may be in any isotopic form, including 'H,2H (D or deuterium), and3H (T or tritium); C may be in any isotopic form, including12C,13C, and14C; O may be in any isotopic form, including16O and18O; N may be in any isotopic form, including14N and15N; F may be in any isotopic form, including18F,19F; and the like.

[0069] The term "pharmaceutically acceptable salt" as used herein is meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds used in the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds used in the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolyl sulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galacturonic acids and the like (see, e.g., Berge et al, Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds used in the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. These salts may be prepared by methods known to those skilled in the art. Other pharmaceutically acceptable carriers known to those of skill in the art are suitable for use in the present disclosure.

[0070] In addition to salt forms, the present disclosure provides compounds in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

[0071] The compounds useful for practicing the methods described herein can also exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure. The compounds useful for practicing the methods described herein may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.

[0072] The term “solvate” refers to forms of the compound that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding.

[0073] Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein may be prepared, e.g., in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid. “Solvate” encompasses both solution phase and i solable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0074] The term “hydrate” refers to a compound which is associated with water. Typically, the number of the water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, a hydrate of a compound may be represented, for example, by the general formula R-x H2O, wherein R is the compound and wherein x is a number greater than 0. A given compound may form more than one type of hydrates, including, e.g., monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R-0.5 H2O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R-2 H2O) and hexahydrates (R-6 H2O)).

[0075] The term “tautomer” as used herein refers to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of 7t electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane that are likewise formed by treatment with acid or base. Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.

[0076] Symbol Meaning

[0077] Abu a-aminobutyric acid

[0078] Ac acyl group

[0079] Acc 1 -amino- l-cyclo(C3-C9)alkyl carboxylic acid

[0080] A3c 1 -amino- 1 cyclopropanecarboxylic acid

[0081] A5c 1 -amino- 1 -cyclopentanecarboxylic acid

[0082] A6c 1 -amino- 1 -cyclohexanecarboxylic acid

[0083] Aha 7-aminoheptanoic acid

[0084] Ahx 6-aminohexanoic acid

[0085] Aib a-aminoisobutyric acid

[0086] Aic 2-aminoindan-2-carboxylic acid

[0087] Ala or A Alanine P-Ala 0-alanine

[0088] Ape denotes the structure:

[0089]

[0090] Apn 5-aminopentanoic acid (HN — (CH2)4 — C(O) Arg or R Arginine

[0091] hArg Homoarginine

[0092] Asn or N Asparagine

[0093] Asp or D aspartic acid

[0094] Ate 4-amino(methyl)-l,3-thiazole-5-caroobxylic acid Bal 3-benzothienylalanine

[0095] Bip 4,4’-biphenylalanine, represented by the structure

[0096]

[0097] Bpa 4-benzoylphenylalanine

[0098] 4-Br-Phe 4-bromo-phenylalanine

[0099] Cha P -cyclohexylalanine

[0100] hCha homo-cyclohexylalanine

[0101] Chg Cyclohexylglycine

[0102] sChp

[0103] Cya a-amino acid cysteic acid

[0104] Cys or C Cysteine

[0105] hCys Homocysteine

[0106] Dab 2,4-diaminobutyric acid Dap 2,3-diaminopropionic acid

[0107] Dip P, P-diphenylalanine

[0108] Doc 8-amino-3,6-dioxaoctanoic acid with the structure of:

[0109]

[0110] Dpr 2,3-Diaminopropionic acid

[0111] Gaba 4-aminobutyric acid

[0112] Gin or Q Glutamine

[0113] Glu or E glutamic acid

[0114] Gly or G Glycine

[0115] His or H Histidine

[0116] 3-Hyp trans-3-hydroxy-L -proline, i.e., (2S,3S)-3-hydroxy-pyrrolidine-2- carboxylic acid

[0117] 4-Hyp 4-hydroxyproline, i.e., (2S,4R)-4-hydorxypyrrolidine-2-carboxylic acid

[0118] He or 1 Isoleucine

[0119] Leu or L Leucine

[0120] hLeu Homoleucine

[0121] Lys or K Lysine

[0122] Met or M Methionine

[0123] P-hMet P-homomethionine

[0124] 1-Nal P-(l-naphthyl)alanine

[0125] 2-Nal P-(2-naphthyl)alanine

[0126] Nip nipecotic acid

[0127] Nle Norleucine

[0128] Oic Octahydroindole-2-carboxylic Acid

[0129] Om Ornithine

[0130] 2-Pal P-(2-pyridiyl)alanine

[0131] 3-Pal P-(3-pyridiyl)alanine

[0132] 4-Pal P-(4-pyridiyl)alanine Pen Penicillamine

[0133] Pff (S)-pentafluorophenylalanine

[0134] Phe or F Phenylalanine

[0135] hPhe Homophenyl al anine

[0136] Pro or P Proline

[0137] hPro Homoproline

[0138] Sar Sarcosine (N-methylglycine)

[0139] Ser or S Serine

[0140] Tie tert-Leucine

[0141] Taz P-(4-thiazolyl)alanine

[0142] 2-Thi -(2-thienyl)al anine

[0143] 3-Thi P-(3-thienyl)al anine

[0144] Thr or T Threonine

[0145] Trp or W Tryptopham

[0146] Tyr or Y Tyrosine

[0147] D-(Et) Tyr has a structure of

[0148]

[0149] Vai or V Valine

[0150] Certain other abbreviations used herein are defined as follows:

[0151] Boc: tert-butyloxycarbonyl

[0152] OtBu oxy-tert-butyl

[0153] tBu: tert-butyl

[0154] Unless otherwise indicated, with the exception of the N-terminal amino acid, all abbreviations (e.g. Ala) of amino acids in this disclosure stand for the structure of -NH-C(R)(R')-CO-, wherein R and R' each is, independently, hydrogen or the side chain of an amino acid (e.g., R=CHa and R — H for Ala), or R and R' may be joined to form a ring system.

[0155] For the N-terminal amino acid, the abbreviation stands for the structure of:

[0156]

[0157] The designation “NH2” in e.g., as in Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2 (SEQ ID NO: 13), indicates that the C-terminus of the peptide is amidated. Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys) (SEQ ID NO: 107), or alternatively Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH (SEQ ID NO: 107), indicates that the C-terminus is the free acid.

[0158] “-c(Cys-Cys)-” or “-cyclo(Cys-Cys)-” denotes the structure:

[0159]

[0160] “-c(Cys-Pen)-” or “-cyclo(Cys-Pen)-” denotes the structure:

[0161]

[0162] “-c(Asp-Lys)-” or “-cyclo(Asp-Lys)-” denotes the structure:

[0163]

[0164] The following abbreviations are used throughout the disclosure:

[0165] “Hydantoin-(C(O)-(Aa-Ab))” denotes the structure:

[0166]

[0167] , wherein amino acid “Aa” has the structure:

[0168]

[0169] and amino acid “Ab” the structure:

[0170] For example, “Hydantoin-(C(O)-Arg-Ab))” would have the following structure:

[0171]

[0172] For example, a compound represented as “c[Hydantoin(C(O)-(Cys-Ab))-A1-A2-A3-A4-Cys]-” would have the following the structure:

[0173]

[0174] whereas a compound represented as “c[Hydantoin(C(O)-(Ab-Cys))-A1-A2-A3-A4-Cys]-” would have the structure:

[0175]

[0176] For further guidance, “c[Hydantoin(C(O)-(Asp-Ab))-A1-A2-A3-A4-Lys]-” represents the following compound:

[0177]

[0178] “Acyl” refers to R"-C(O)-, where R" is H, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, alkenyl, substituted alkenyl, aryl, alkylaryl, or substituted alklyaryl, and is indicated in the general formula of a particular embodiment as “Ac”. Exemplary substituted acyl groups include, without limitation, acetyl, trifluoroacetyl, hydroxyacetyl, methoxyacetyl, ethoxyacetyl, propionyl, ethoxypropionyl, isobutyryl, cyanoisobutyryl, hydroxyisobutyryl, carbamoylisobutyryl, 3, 3 -dimethylbutanoyl, pivaloyl, fluoropivaloyl, difluoropivaloyl, hydroxypivaloyl, mercaptopivaloyl, dihydroxypivaloyl, methoxypivaloyl, ethoxypivaloyl, aminopivaloyl, dimethylaminopivaloyl, hydroxyiminopivaloyl, acetylisobutyryl, -C(O)C(CH3)2CH(CH3)OH, -C(O)C(CH3)2C(CH3)2OH, acryloyl, methacryloyl, cyclopentanecarbonyl, cyclohexylenecarbonyl, carbamoyl, dimethylcarbamoyl, methanesulfonylcarbonyl, benzoyl, thiophenecarbonyl, furoyl, oxazolecarbonyl, thiazolecarbonyl, imidazolecarbonyl, pyrazolecarbonyl, tetrahydrofuroyl, dihydrofuroyl, tetrahy dropy rancarb ony 1, morpholi necarb ony 1, “Alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group containing one or more carbon atoms, where multiple carbon atoms if present are joined by single bonds. The alkyl hydrocarbon group may be straight-chain or contain one or more branches. In some embodiments, an alkyl group has 1 to 40 carbon atoms (“C1-C40 alkyl”). In some embodiments, an alkyl group has 1 to 24 carbon atoms (“C1-C24 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C1-C12 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“Ci-Cs alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-C6 alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-C6 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”). Examples of Ci-Cealkyl groups include methyl (Ci), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (Cs), amyl (Cs), neopentyl (C5), 3-methyl-2-butanyl (Cs), tertiary amyl (C5), and n-hexyl (Cs). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (Cs) and the like. Each instance of an alkyl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkyl group is unsubstituted C1-C10 alkyl (e.g., -CH3). In certain embodiments, the alkyl group is substituted C1-C6 alkyl.

[0179] “Hydroxyalkyl” refers to an alkyl group wherein one or more hydrogen atoms of the hydrocarbon group are substituted with one or more hydroxy radicals, such as hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl and the like.

[0180] “Substituted alkyl” refers to an alkyl wherein one or more hydrogen atoms of the hydrocarbon group are replaced with one or more substituents selected from the group consisting of halogen, (i.e., fluorine, chlorine, bromine, and iodine), -OH, -CN, -SH, amine

[0181] (e.g., -NH2, -NHCH3), -NO2, guanidine, urea, amidine, and -(C1-C20) alkyl, wherein said -(Ci-C20) alkyl optionally may be substituted with one or more substituents selected, independently for each occurrence, from the group consisting of halogens, — CF3, — OCH3, — OCF3, and -(CH2)o-2o-COOH. In different embodiments 1, 2, 3 or 4 substituents are present. The presence of -(CH2)o-2o-COOH results in the production of an alkyl acid. Non-limiting examples of alkyl acids containing, or consisting of, -(CH2)o-2o-COOH include 2-norbornane acetic acid, tert-butyric acid, 3-cyclopentyl propionic acid, and the like. As used herein, the term “halogen” or “halo” encompasses fluoro, chloro, bromo and iodo.

[0182] As used herein, the term “hydroxy” refers to -OH.

[0183] Guanidines are a group of organic compounds that share a common functional group with the general structure (R1R2N)(R3R4N)C=N-R5. The central bond within this group is an imine, and the group is related structurally to amidines and ureas.

[0184] “Heteroalkyl” refers to a non-cyclic stable straight or branched chain alkyl, or combination thereof, wherein one of more of the carbon atoms in the hydrocarbon group is replaced with one or more of the following groups: amino, amido, — O —, — S — or carbonyl. The heteroatom(s) O, N, P, S, and Si may be placed at any position of the heteroalkyl group, and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. In different embodiments 1 or 2 heteroatoms are present.

[0185] Exemplary heteroalkyl groups include, but are not limited to: -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -0-CH3, and -O-CH2-CH3. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. Where "heteroalkyl" is recited, followed by recitations of specific heteroalkyl groups, such as -CH2O, -NRCRD, or the like, it will be understood that the terms heteroalkyl and -CH2O or -NRCRDare not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term "heteroalkyl" should not be interpreted herein as excluding specific heteroalkyl groups, such as -CH2O, -NRCRD, or the like.

[0186] “Substituted heteroalkyl” refers to a heteroalkyl wherein one or more hydrogen atoms of the hydrocarbon group are replaced with one or more substituents selected from the group consisting of halogen, (i.e., fluorine, chlorine, bromine, and iodine), -OH, — CN, — SH, — NH2, — NHCH3, — NO2, and -(C1-C20) alkyl, wherein said -(C1-C20) alkyl optionally may be substituted with one or more substituents selected, independently for each occurrence, from the group consisting of halogens, — CF3, -OCH3, -OCF3, and -(CH2)o-20-COOH. In different embodiments 1, 2, 3 or 4 substituents are present.

[0187] “Alkenyl” refers to a hydrocarbon group made up of two or more carbons where one or more carbon-carbon double bonds are present (“C2-C24 alkenyl”). The alkenyl hydrocarbon group may be straight-chain or contain one or more branches or cyclic groups. In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C2-C10 alkenyl”). Tn some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-C8 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-C6 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2 alkenyl”). The one or more carboncarbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C2-C4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-C6 alkenyl groups include the aforementioned C2 4 alkenyl groups as well as pentenyl (Cs), pentadienyl (Cs), hexenyl (Ce), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (Cs), octatrienyl (Cs), and the like.

[0188] “Substituted alkenyl” refers to an alkenyl wherein one or more hydrogens are replaced with one or more substituents selected from the group consisting of halogen (i.e., fluorine, chlorine, bromine, and iodine), — OH, — CN, — SH, — NH2, — NHCH3, — NO2, and -(C1-C20) alkyl, wherein said — C 1-20 alkyl optionally may be substituted with one or more substituents selected, independently for each occurrence, from the group consisting of halogens, — CF3, — OCH3, — OCF3, and — (CH2)O-2O — COOH. In different embodiments 1, 2, 3 or 4 substituents are present.

[0189] As used herein, the term “alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 24 carbon atoms, one or more carbon-carbon triple bonds (“C2-C24 alkynyl”). In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C2-C10 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-C8 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-C6 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C2 alkynyl”). The one or more carboncarbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C2-C4 alkynyl groups include ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Each instance of an alkynyl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkynyl group is unsubstituted C2-10 alkynyl. In certain embodiments, the alkynyl group is substituted C2-6 alkynyl. “Aryl” refers to an optionally substituted aromatic group with at least one ring having a conjugated pi-electron system (e.g., having 6, 10, or 14 n electrons shared in a cyclic array), containing up to three conjugated or fused ring systems, having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“Ce-Ci4 aryl”). In some embodiments, an aryl group has six ring carbon atoms (“Ce aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“Cio aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“Cuaryl”; e.g., anthracyl). An aryl group may be described as, e.g., a Ce-Cio-membered aryl, wherein the term “membered” refers to the non-hydrogen ring atoms within the moiety. Aryl includes carbocyclic aryl, heterocyclic aryl and biaryl groups. Preferably, the aryl is a 5- or 6-membered ring. Preferred atoms for a heterocyclic aryl are one or more sulfur, oxygen, and / or nitrogen. Non-limiting examples of aryl include phenyl, 1-naphthyl, 2-naphthyl, indole, quinoline, 2-imidazole, 9-anthracene, indenyl, tetrahydronaphthyl and the like. Aryl substituents are selected from the group consisting of -(C1-C20) alkyl, -(C1-C20) alkoxy, halogen (i.e., fluorine, chlorine, bromine, and iodine), — OH, — CN, — SH, — NH2, -NO2, -(C1-C20) alkyl substituted with halogens, — CF3, — OCF3, and — (CH2)O-2O — COOH. In different embodiments the aryl contains 0, 1, 2, 3, or 4 substituents.

[0190] As used herein, “heteroaryl” refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 it electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-10 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl / heteroaryl) ring system. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not bear a heteroatom (e.g., 5-indolyl). A heteroaryl group may be described as, e.g., a 6-10-membered heteroaryl, wherein the term “membered” refers to the non-hydrogen ring atoms within the moiety. Each instance of a heteroaryl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0191] Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotri azolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadi azolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Other exemplary heteroaryl groups include heme and heme derivatives.

[0192] “Alkylaryl” refers to an “alkyl” joined to an “aryl”.

[0193] The term “(Ci-i2)hydrocarbon moiety” encompasses alkyl, alkenyl and alkynyl and in the case of alkenyl and alkynyl there is C2-C12.

[0194] As used herein, “cycloalkyl” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C3-C10 cycloalkyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-C8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-C6 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-C6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-C10 cycloalkyl”). A cycloalkyl group may be described as, e.g., a C4-C?-membered cycloalkyl, wherein the term “membered” refers to the non-hydrogen ring atoms within the moiety. Exemplary C3-C6 cycloalkyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (Cs), cyclopentenyl (Cs), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), and the like. Exemplary C3-C8 cycloalkyl groups include, without limitation, the aforementioned C3-C6 cycloalkyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), cubanyl (Cs), bicyclo[l.l.l]pentanyl (Cs), bicyclo[2.2.2]octanyl (Cs), bicyclo[2.1.1]hexanyl (Ce), bicyclo[3.1.1]heptanyl (C7), and the like. Exemplary C3-C10 cycloalkyl groups include, without limitation, the aforementioned C3-C8 cycloalkyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-l / Z-indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. As the foregoing examples illustrate, in certain embodiments, the cycloalkyl group is either monocyclic (“monocyclic cycloalkyl”) or contain a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic cycloalkyl”) and can be saturated or can be partially unsaturated. “Cycloalkyl” also includes ring systems wherein the cycloalkyl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is on the cycloalkyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the cycloalkyl ring system. Each instance of a cycloalkyl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is unsubstituted C3-C10 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-C10 cycloalkyl.

[0195] “Heterocyclyl” as used herein refers to a radical of a 3- to 16-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-16 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more cycloalkyl groups wherein the point of attachment is either on the cycloalkyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. A heterocyclyl group may be described as, e.g., a 3-7-membered heterocyclyl, wherein the term “membered” refers to the nonhydrogen ring atoms, i.e., carbon, nitrogen, oxygen, sulfur, boron, phosphorus, and silicon, within the moiety. Each instance of heterocyclyl may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is unsubstituted 3-16 membered heterocyclyl. In certain embodiments, the heterocyclyl group is substituted 3-16 membered heterocyclyl.

[0196] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2, 5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl (e.g., 2,2,6,6-tetramethylpiperidinyl), tetrahydropyranyl, dihydropyridinyl, tetrahydrothiopyranyl, pyridinonyl (e.g., l-methylpyridin2-onyl), andthianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, pyridazinonyl (2-methylpyridazin-3-onyl), pyrimidinonyl (e.g., 1-methylpyrimidin-2-onyl, 3-methylpyrimidin-4-onyl), dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a Ce aryl ring (also referred to herein as a 5,6-bicyclic heterocyclyl ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 5-membered heterocyclyl groups fused to a heterocyclyl ring (also referred to herein as a 5,5-bicyclic heterocyclyl ring) include, without limitation, octahydropyrrolopyrrolyl (e.g., octahydropyrrolo[3,4-c]pyrrolyl), and the like. Exemplary 6-membered heterocyclyl groups fused to a heterocyclyl ring (also referred to as a 4,6-membered heterocyclyl ring) include, without limitation, diazaspirononanyl (e.g., 2,7-diazaspiro[3.5]nonanyl). Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclyl ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. Exemplary 6-membered heterocyclyl groups fused to a cycloalkyl ring (also referred to herein as a 6,7-bicyclic heterocyclyl ring) include, without limitation, azabicyclooctanyl (e.g., (l,5)-8-azabicyclo[3.2.1]octanyl). Exemplary 6-membered heterocyclyl groups fused to a cycloalkyl ring (also referred to herein as a 6,8-bicyclic heterocyclyl ring) include, without limitation, azabicyclononanyl (e.g., 9-azabicyclo[3.3.1]nonanyl).

[0197] As used herein, the terms “cyano” or “-CN” refer to a substituent having a carbon atom joined to a nitrogen atom by a triple bond, e.g., ON.

[0198] As used herein, the term “nitro” refers to a substituent having two oxygen atoms bound to a nitrogen atom, e.g., -NO2.

[0199] As used herein, “oxo” refers to a carbonyl, i.e., -C(O)-.

[0200] The symbol

[0201]

[0202] as used herein in relation to a compound of Formula (I) or (II) refers to an attachment point to another moiety or functional group within the compound.

[0203] Alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups, as defined herein, are optionally substituted. For the avoidance of doubt, unless otherwise indicated, the term “substituted”, whether preceded by the term “optionally” or not, means substituted by one or more defined groups, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. In the case where groups may be selected from a number of alternative groups, the selected groups may be the same or different. For the avoidance of doubt, the term “independently” means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different.

[0204] Designation “(amino acid)n” means that an amino acid is repeated n times. For example, designation “(Pro)2” or “(Arg)3” mean that proline or arginine residues are repeated, respectively, two or three times.

[0205] Melanocortin-4 Receptor (MC4R)

[0206] Hmc4R is a protein encoded by a genomic sequence having GenBank accession number CH471077.2. Mutations in the MC4R receptor are an associated cause of severe childhood obesity. The carrier prevalence for MC4R mutations in a juvenile-onset obese population has been noted to be around 2.5% with a highest prevalence of 6% among severely obese children. Humans with MC4R mutations show a more or less similar phenotype as has been described for mice with mutations in the MC4R gene. MC4R deficient patients show hyperphagia, hyperinsulinaemia, increased fat mass, accompanied by lean body mass, bone mineral density and linear growth rate increases, with no changes in cortisol levels, gonadotropin, thyroid and sex steroid levels. In contrast to MC4R deletion, hyperphagia and hyperinsulinaemia tends to subside with age in human subjects. Similar to the MC4R knockout mice, the phenotype in heterozygote carriers is intermediate in comparison to homozygote carriers. The exhibited hyperphagia observed upon a test meal is less severe than that observed in people with a leptin deficiency. The severity of MC4R dysfunction seen in assays in vitro can predict the amount of food ingested at a test meal by the subject harboring that particular mutation and correlates with the onset and severity of the obese phenotype. At least 90 different MC4R mutations have been associated with obesity and additional mutations in the MC4R are likely to be discovered, leading to a similar obesity phenotype.

[0207] Examples of the MC4R mutations that cause obesity in humans are described, e.g., in Farooqi et al., The Journal of Clinical Investigation, July 2000, vol. 106 (2), pp. 271-279 and Vaisse et al., The Journal of Clinical Investigation, July 2000, vol. 106(2), pp. 253-262, the relevant portions of which are incorporated herein by reference).

[0208] Additional mutations that potentially cause obesity in humans include, R18H, R18L, S36Y, P48S, V50M, F51L, E61K, I69T, D90N, S94R, G98R, I121T, A154D, Y157S, W174C, G181D, F202L, A219 V, I226T, G231S, G238D, N240S, C271R, S295P, P299L, E308K, 1317V, L325F, and 750DelGA, as described in Xiang et al., “Pharmacological characterization of 30 human melanocortin-4 receptor polymorphisms with the endogenous proopiomelanocortin-derived agonists, synthetic agonists, and the endogenous agouti-related protein antagonist.” Biochemistry, 2010 Jun 8; 49(22):4583-600, the relevant portions of which are incorporated herein by reference.

[0209] Further examples of mutations that potentially cause obesity in humans are those listed in Online Mendelian Inheritance in Man (OMIM), a database of human genes and genetic disorders, under the accession number 155541 (MC4R) (more precisely, accession nos. 155541.0001-155541.0023) at the URL http: / / omim.org / entry / 155541. Representative examples include 4-BPDEL, NT631; 4-BP INS, NT732; TYR35TER; ASP37VAL; SER58CYS; ILE102SER; ASN274SER; 1 -BP INS, 112A; 4-BPDEL, 211CTCT; ILE125LYS; ALA175THR; ILE316SER; TYR287TER; ASN97ASP; 15-BP DEL (delta88-92 codons); and SER127LEU. The relevant portions of the OMIM database are incorporated herein by reference. Additional exemplary mutations in MC4R are described in Lee. Annals Acad. Med. 38.1(2009):34-44.

[0210] In example embodiments, the MC4R mutation results in retention of the MC4R signaling activity. Mutations in the genomic sequence encoding MC4R can be detected by the methods that are known to a person of ordinary skill in the art. For example, the genomic sequence can be cloned using nucleotide primers, such as e.g., the primers described in Farooqi et al., The Journal of Clinical Investigation, July 2000, vol. 106 (2), pp. 271-279 and Vaisse etal., The Journal of Clinical Investigation, July 2000, vol. 106(2), pp. 253-262, and the cloned sequence analyzed using commercially available sequencers and software.

[0211] Activity of MC4R can be measured by the methods known to a person of ordinary skill in the art. For example, cells can be transiently transfected with the cloned MC4R DNA, the transfected cells contacted by an agonist of MC4R (e.g. a-MSH), and the intracellular level of Camp, the secondary messenger of MC4R, measured by an electrochemiluminescence assay described, e.g., in Roubert et al., Journal of Endocrinology (2010) 207, pp. 177-183. Areduction in MC4R signaling can be ascertained by comparing the intracellular level of Camp produced in response to a given agonist by a wild type MC4R to that produced by a mutant MC4R.

[0212] The MC4R agonist may bind to the MC4R directly or indirectly. In an embodiment, the MC4R agonist binds to the MC4R in or near the ligand-binding pocket. In an embodiment, the MC4R agonist binds to the MC4R in or near the G-protein binding cavity. In an embodiment, the MC4R agonist binds to the MC4R binds in or near a transmembrane domain or extracellular loop, for example, TM2, TM3, TM5, TM7, EL2, and / or EL3. Additional interactions of the MC4R agonist and the MC4R may be exemplified in Nat Cell Research (2021) 31:1176-1189, which is incorporated herein by reference in its entirety.

[0213] Melanocortin-4 Receptor (MC4R) Pathway Genes

[0214] The melanocortin system, which includes melanocortins (MCs), agouti, agouti-related proteins, and their receptors, integrate hormonal, metabolic, and neural signals in order to control energy homeostasis and regulate appetite, energy expenditure, and body weight. The MCs, which include alpha-melanocyte-stimulating hormone (a-MSH), P-MSH, y-MSH, and ACTH, are a family of peptide hormones that are derived from a precursor protein called proopiomelanocortin (POMC). Activation of MC4 receptor (MC4R) in the POMC-MC4R pathway increases energy expenditure and decreases food intake. See, e.g., Fan et al. Nature 1997;385:165-68. The POMC-MC4R pathway includes a number of proteins, such as melanocortins (MCs), MC4 receptor (MC4R), POMC, Proprotein Convertase Subtilisin / Kexin Type 1 (PCSK1, also called PC1 / 3), MAGE-like-2 (MAGEL2), leptin receptor (leptin-R), leptin, 5-hydroxytryptamine (serotonin) receptor 2C, G protein-coupled (5-HT2c receptor), nescient helix loop helix 2 (NhHL2, also called NSCL2), pro-hormone convertase, carboxypeptidase E (CPE), and single-minded 1 (Siml), that together contribute to the regulation of energy homeostasis, e.g., by regulating appetite and energy expenditure. MC4R and other components of the POMC-MC4R pathway have a significant role in weight regulation. A mutation of the MC4R gene was reported to result in early-onset and severe obesity. It is believed that other genetic defects in the POMC-MC4R pathway likely also lead to early-onset and severe obesity. These genes are collectively termed “MC4R pathway agonizable genes” and examples are provided below. In an embodiment, the MC4R pathway agonizable gene does not comprise any one of POMC, Proprotein Convertase Subtilisin / Kexin Type 1 (PCSK1, also called PC1 / 3), MAGE-like-2 (MAGEL2), leptin receptor (leptin-R), leptin, 5-hydroxytryptamine (serotonin) receptor 2C, G protein-coupled (5-HT2c receptor), nescient helix loop helix 2 (NhHL2, also called NSCL2), pro-hormone convertase, carboxypeptidase E (CPE), and single-minded 1 (Siml). In an embodiment, the MC4R pathway agonizable gene does not comprise MC4R. In an embodiment, the MC4R pathway agonizable gene does not comprise any gene disclosed in W02013 / 102047 or WO 2017 / 059076, the full contents of each of which is incorporated herein by reference in its entirety. In an embodiment, an MC4R agonist, e.g., an MC4R agonist of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII), or a pharmaceutically acceptable salt, is used, e.g., to treat a disease, disorder, or condition caused by a mutation, deletion, or other aberration in an MC4R pathway agonizable gene. In an embodiment, a combination of an MC4R agonist, e.g., an MC4R agonist of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII), or a pharmaceutically acceptable salt, and a GCHR modulator, e.g., a GLP1R agonist as described herein, is used, e.g., to treat a disease, disorder, or condition caused by a mutation, deletion, or other aberration in an MC4R pathway agonizable gene.

[0215] In embodiments of any method described herein, the method comprises treating a subject having a mutation in a gene listed in Table 1 below. In embodiments, a method described herein comprises use of a MC4R agonist described herein to treat a subject having a mutation in an MC4R pathway agonizable gene, e g., as listed in Table 1. Table 1 describes exemplary genes, alleles, transcripts, and proteins, though other genes, alleles, transcripts, and proteins may be included.

[0216] Table 1: Exemplary MC4R pathway agonizable genes, alleles, and transcripts

[0217]

[0218]

[0219] Melanocortin-4 Receptor (MC4R) Agonists

[0220] In some embodiments, the MC4R agonist is a peptide, e.g., a compound comprising amide bonds containing naturally occurring or non-naturally occurring amino acids. In an embodiment, the MC4R agonist is a compound of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), or a pharmaceutically acceptable salt thereof, as described herein.

[0221] In some embodiments, the MC4R agonist is a compound of Formula (I):

[0222] (R2R3)-A1-c(A2-A3-A4-A5-A6-A7-A8-A9)-A10-R1(I)

[0223] or a pharmaceutically acceptable salt thereof, wherein A1is Acc, HN — (Clh)™ — C(O), L- or D-amino acid, or deleted; A2is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Asp, or Glu; A3is Gly, Ala, P-Ala, Gaba, Aib, D-amino acid, or deleted; A4is His, 2-Pal, 3-Pal, 4-Pal, Taz, 2-Thi, 3-Thi, or (X1, X2, X3, X4, X3)Phe, L-Phe o

[0224]

[0225] R5))-C(O); A7is Trp, 1-Nal, 2-Nal, Bal, Bip, D-Trp, D-2-Nal, D-Bal or D-Bip; A8is Gly, D-Ala, Acc, Ala, 13-Ala, Gaba, Apn, Ahx, Aha, HN-(CH2 )s-C(O), or deleted; A9is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Dab, Dap, Orn, or Lys; A10is Acc, HN-(CH2)f-C(O), L- or D-amino acid, or deleted; R1is OH or NH2; each of R2and R3is, independently for each occurrence, selected from the group consisting of H, (Ci-C3o)alkyl, (Ci-Cso)heteroalkyl, (Ci-C3o)acyl, (C2-C3o)alkenyl, (C2- C3o)alkynyl, aryl(Ci-C3o)alkyl, aryl(Ci-C3o)acyl, substituted (Ci-C3o)alkyl, substituted (Ci-C3o)heteroalkyl, substituted (Ci-C3o)acyl, substituted (C2-C3o)alkenyl, substituted (C2-C3o)alkynyl, substituted aryl(Ci-C3o)alkyl, and substituted aryl(Ci-C3o)acyl; each of R4and R’is, independently for each occurrence, H, (Ci-C4o)alkyl, (Ci-C4o)heteroalkyl, (Ci-C4o)acyl, (C2-C4o)alkenyl, (C2-C4o)alkynyl, aryl(Ci-C4o)alkyl, aryl(Ci-C4o)acyl, substituted (Ci-C4o)alkyl, substituted (Ci-C4o)heteroalkyl, substituted (Ci-C4o)acyl, substituted (C2-C4o)alkenyl, substituted (C2-C4o)alkynyl, substituted aryl(Ci-C4o)alkyl, substituted aryl(Ci-C4o)acyl, (Ci- C4o)alkylsulfonyl, or -C(NH)-NH2; m is, independently for each occurrence, 1, 2, 3, 4, 5, 6 or 7; n is, independently for each occurrence, 1, 2, 3, 4 or 5; s is, independently for each occurrence, 1, 2, 3, 4, 5, 6, or 7; t is, independently for each occurrence, 1, 2, 3, 4, 5, 6, or 7; X', X2, X3, X4, and X5each is, independently for each occurrence, H, F, Cl, Br, I, -(C1-C10) alkyl, substituted (Ci-C10) alkyl, (C2-C10) alkenyl, substituted (C2-C10) alkenyl, (C2-C10) alkynyl, substituted (C2-C10) alkynyl, aryl, substituted aryl, OH, NH2, NO2, or CN.

[0226] In some embodiments, for Formula (I), when R4is (Ci-C4o)acyl, aryl(Ci-C4o)acyl, substituted (Ci-C4o)acyl, substituted aryl(Ci-C4o)acyl, (Ci-C4o)alkylsulfonyl, or -C(NH)-NH2, then Rsis H or (Ci-C4o)alkyl, (Ci-C4o)heteroalkyl, (C2-C4o)alkenyl, (C2-C4o)alkynyl, aryl(Ci-C4o)alkyl, substituted (Ci-C4o)alkyl, substituted (Ci-C4o)heteroalkyl, substituted (C2-C4o)alkenyl, substituted (C2-C4o)alkynyl, or substituted aryl(Ci-C4o)alkyl.

[0227] In some embodiments, for Formula (I), when R2is (Ci-C3o)acyl, aryl(Ci-C3o)acyl, substituted (Ci-C3o)acyl, or substituted aryl(Ci-C3o)acyl, then R3is H, (Ci-C3o)alkyl, (Ci-C3o)heteroalkyl, (C2-C3o)alkenyl, (C2-C3o)alkynyl, aryl(Ci-C3o)alkyl, substituted (Ci-C3o)alkyl, substituted (Ci-C3o)heteroalkyl, substituted (C2-C3o)alkenyl, substituted (C2-C3o)alkynyl, or substituted aryl(Ci-C3o)alkyl;

[0228] In some embodiments, for Formula (I), either A3or A8or both must be present in said compound.

[0229] In some embodiments, for Formula (I) when A2is Cys, D-Cys, hCys, D-hCys, Pen, or D-Pen, then A9is Cys, D-Cys, hCys, D-hCys, Pen, or D-Pen.

[0230] In some embodiments, for Formula (I), when A2is Asp or Glu, then A9is Dab, Dap, Orn, or Lys.

[0231] In some embodiments, for Formula (I), when A8is Ala or Gly, then A1is not NIe. In some embodiments, for Formula (I), when A1is deleted, then R2and R3cannot both be H.

[0232] In some embodiments, for Formula (I): A1is A6c, Arg, D-Arg, Cha, D-Cha, hCha, Chg, D-Chg, Gaba, He, Leu, hLeu, Met, P-hMet, 2-Nal, D-2-Nal, Nip, Nle, Oic, Phe, D-Phe, hPhe, hPro, Vai, or deleted; A2is Asp, Cys, D-Cys, hCys, D-hCys, Glu, Pen, or D-Pen; A3is D-Abu, Aib, Ala, P-Ala, D-Ala, D-Cha, Gaba, D-Glu, Gly, D-Ile, D-Leu, D-Tle, D-Val, or deleted; A4is His or 3-Pal; A3is D-Bal, D-1-Nal, D-2-Nal, D-Phe, D-Trp, or D-(Et)Tyr; A6is Arg, or hArg; A7is Bal, Bip, 1-Nal, 2-Nal, Trp, D-Trp; A8is A6c, D-Ala, Aha, Ahx, Ala, -Ala, Apn, Gaba, Gly or deleted; A9is Cys, D-Cys, hCys, D-hCys, Lys, Pen, or D-Pen; and A10is Thr, or deleted, wherein at least one of A3or A8is deleted, but not both.

[0233] In some embodiments, the compound of Formula (I) is a compound disclosed in International Patent Application Publication Number WO 2007 / 008704, which is incorporated herein by reference in its entirety.

[0234] In some embodiments, the compound of Formula (I) is selected from:

[0235] (SEQ ID NO: 1) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp- -Ala-Lys)-NH2;

[0236] (SEQ ID NO: 2) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-A6c-Lys)-NH2;

[0237] (SEQ ID NO: 3) Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Ahx-Cys)-NH2;

[0238] (SEQ ID NO: 4) D-Phe-c(Cys-His-D-Phe-Arg-Trp-Ala-D-Cys)-Thr-NH2;

[0239] (SEQ ID NO: 5) D-Phe-c(Cys-His-D-Phe-Arg-Trp-P-Ala-D-Cys)-Thr-NH2;

[0240] (SEQ ID NO: 6) D-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-D-Cys)-Thr-NH2;

[0241] (SEQ ID NO: 7) Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH2;

[0242] (SEQ ID NO: 8) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Apn-Lys)-NH2;

[0243] (SEQ ID NO: 9) Ac-A6c-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2;

[0244] (SEQ ID NO: 10) Ac-D-2-Nal-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2;

[0245] (SEQ ID NO: 11) Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2;

[0246] (SEQ ID NO: 12 ) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2;

[0247] (SEQ ID NO: 13) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2;

[0248] (SEQ ID NO: 14) Ac-Nle-c(Cys-P-Ala-His-D-Phe-Arg-Trp-Cys)-NH2;

[0249] (SEQ ID NO: 15) Ac-Nle-c(Cys-Gaba-His-D-Phe-Arg-Trp-Cys)-NH2;

[0250] (SEQ ID NO: 16) Ac-Nle-c(Cys-Aib-His-D-Phe-Arg-Trp-Cys)-NH2;

[0251] (SEQ ID NO: 17) Ac-Nle-c(Cys-Gly-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 18) Ac-Nle-c(D-Cys-Ala-His-D-Phe-Arg-Trp-Cys)-NH2;

[0252] (SEQ ID NO: 19) Ac-Nle-c(D-Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 20) Ac-Nle-c(D-Cys-P-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 21) Ac-Nle-c(D-Cys-Gaba-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 22) Ac-Nle-c(D-Cys-Aib-His-D-Phe-Arg-Trp-Cys)-NH2;

[0253] (SEQ ID NO: 23) Ac-Nle-c(D-Cys-Gly-His-D-Phe-Arg-Trp-Cys)-NH2;

[0254] (SEQ ID NO: 24) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2; (SEQ ID NO: 25) Ac-Nle-c(Cys-P-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2; (SEQ ID NO: 26) Ac-Nle-c(Cys-Gaba-His-D-Phe-Arg-Trp-D-Cys)-NH2; (SEQ ID NO: 27) Ac-Nle-c(Cys-Aib-His-D-Phe-Arg-Trp-D-Cys)-NH2;

[0255] (SEQ ID NO: 28) Ac-Nle-c(Cys-Gly-His-D-Phe-Arg-Trp-D-Cys)-NH2;

[0256] (SEQ ID NO: 29) Ac-Nle-c(D-Cys-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2; (SEQ ID NO: 30) Ac-Nle-c(D-Cys-D-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2; (SEQ ID NO: 31) Ac-Nle-c(D-Cys-P-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2; (SEQ ID NO: 32) Ac-Nle-c(D-Cys-Gaba-His-D-Phe-Arg-Trp-D-Cys)-NH2; (SEQ ID NO: 33) Ac-Nle-c(D-Cys-Aib-His-D-Phe-Arg-Trp-D-Cys)-NH2; (SEQ ID NO: 34) Ac-Oic-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2;

[0257] (SEQ ID NO: 35) Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2;

[0258] (SEQ ID NO: 36) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2;

[0259] (SEQ ID NO: 37) Ac-D-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; (SEQ ID NO: 38) Ac-D-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; (SEQ ID NO: 39) Ac-Nip-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2;

[0260] (SEQ ID NO: 40) Ac-hPro-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2;

[0261] (SEQ ID NO: 41) Ac-hLeu-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2;

[0262] (SEQ ID NO: 42) Ac-Phe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2;

[0263] (SEQ ID NO: 43) Ac-D-Phe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; (SEQ ID NO: 44) Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; (SEQ ID NO: 45) n-butanoyl-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; (SEQ ID NO: 46) n-butyryl-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; (SEQ ID NO: 47) Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2;

[0264] (SEQ ID NO: 48) Ac-P-hMet-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; (SEQ ID NO: 49) Ac-Gaba-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2;

[0265] (SEQ ID NO: 50) Ac-Cha-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2;

[0266] (SEQ ID NO: 51) Ac-hCha-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2;

[0267] (SEQ ID NO: 52) Ac-Leu-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2;

[0268] (SEQ ID NO: 53) Ac-hLeu-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2;

[0269] (SEQ ID NO: 54) Ac-Phe-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2;

[0270] (SEQ ID NO: 55) Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-D-Ala-Lys)-NH2;

[0271] (SEQ ID NO: 56) Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-P-Ala-Lys)-NH2;

[0272] (SEQ ID NO: 57) Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Gaba-Lys)-NH2;

[0273] (SEQ ID NO: 58) Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Aha-Lys)-NH2;

[0274] (SEQ ID NO: 59) Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Apn-Lys)-NH2;

[0275] (SEQ ID NO: 60) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Apn-Cys)-NH2;

[0276] (SEQ ID NO: 61) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Gaba-Cys)-NH2;

[0277] (SEQ ID NO: 62) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Ahx-Cys)-NH2;

[0278] (SEQ ID NO: 63) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-P-Ala-Cys)-NH2;

[0279] (SEQ ID NO: 64) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-D-Ala-Cys)-NH2;

[0280] (SEQ ID NO: 65) Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2;

[0281] (SEQ ID NO: 66) Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-2-Nal-Cys)-NH2; (SEQ ID NO: 67) Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-l-Nal-Cys)-NH2; (SEQ ID NO: 68) n-butanoyl-Nle-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Cys)-NH2; (SEQ ID NO: 69) n-butanoyl-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 70) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Cys)-NH2;

[0282] (SEQ ID NO: 71) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-l-Nal-Cys)-NH2;

[0283] (SEQ ID NO: 72) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Bal-Cys)-NH2;

[0284] (SEQ ID NO: 73) Ac-Nle-c(Cys-D-Glu-His-D-Phe-Arg-Trp-Cys)-NH2;

[0285] (SEQ ID NO: 74) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-D-Ala-Lys)-NH2;

[0286] (SEQ ID NO: 75) Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Bal-Cys)-NH2;

[0287] (SEQ ID NO: 76) Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2;

[0288] (SEQ ID NO: 77) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2;

[0289] (SEQ ID NO: 78) Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2;

[0290] (SEQ ID NO: 79) D-Phe-c(Cys-His-D-Phe-hArg-Trp-P-Ala-D-Cys)-Thr-NH2; (SEQ ID NO: 80) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-P-Ala-D-Cys)-Thr-NH2; (SEQ ID NO: 81) D-Phe-c(Cys-His-D-Phe-Arg-Bip-P-Ala-D-Cys)-Thr-NH2; (SEQ ID NO: 82) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-P-Ala-D-Cys)-Thr-NH2; (SEQ ID NO: 83) D-Phe-c(Cys-His-D-Phe-hArg-Bip-p-Ala-D-Cys)-Thr-NH2; (SEQ ID NO: 84) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-P-Ala-D-Cys)-Thr-NH2; (SEQ ID NO: 85) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH2;

[0291] (SEQ ID NO: 86) Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Trp-Lys)-NH2;

[0292] (SEQ ID NO: 87) Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal-Lys)-NH2;

[0293] (SEQ ID NO: 88) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-OH;

[0294] (SEQ ID NO: 89) Ac-Nle-c(Cys-D-Abu-His-D-Phe-Arg-Trp-Cys)-NH2;

[0295] (SEQ ID NO: 90) Ac-Nle-c(Cys-D-Val-His-D-Phe-Arg-Trp-Cys)- NH2;

[0296] (SEQ ID NO: 91) Ac-Nle-c(Cys-D-Ile-His-D-Phe-Arg-Trp-Cys)-NH2;

[0297] (SEQ ID NO: 92) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-NH2;

[0298] (SEQ ID NO: 93) Ac-Nle-c(Cys-D-Tle-His-D-Phe-Arg-Trp-Cys)-NH2;

[0299] (SEQ ID NO: 94) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-NH2;

[0300] (SEQ ID NO: 95) Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2;

[0301] (SEQ ID NO: 96) Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2;

[0302] (SEQ ID NO: 97) Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2;

[0303] (SEQ ID NO: 98) Ac-Leu-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2;

[0304] (SEQ ID NO: 99) Ac-Cha-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2;

[0305] (SEQ ID NO: 100) Ac-Ile-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2;

[0306] (SEQ ID NO: 101) Ac-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2;

[0307] (SEQ ID NO: 102) Ac-Val-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2;

[0308] (SEQ ID NO: 103) Ac-2-Nal-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2;

[0309] (SEQ ID NO: 104) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2;

[0310] (SEQ ID NO: 105) Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2;

[0311] (SEQ ID NO: 106) Ac-Nle-c(Cys-3-Pal-D-Phe-Arg-Trp-Gaba-Cys)-NH2;

[0312] (SEQ ID NO: 107) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH;

[0313] (SEQ ID NO: 108) Ac-Nle-c(Cys-His-Phe-Arg-D-Trp-Gaba-Cys)- NH2;

[0314] (SEQ ID NO: 109) Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Ala-Lys)-NH2;

[0315] (SEQ ID NO: 110) Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-P-Ala-Lys)-NH2; (SEQ ID NO: 111) Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Gaba-Cys)-NH2; (SEQ ID NO: 112) Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Ahx-Cys)-NH2; (SEQ ID NO: 113) Ac-hPhe-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH2; (SEQ ID NO: 114) Ac-Cha-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH2; (SEQ ID NO: 115) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-P-Ala-Lys)-OH;

[0316] (SEQ ID NO: 116) Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Ahx-Cys)-OH;

[0317] (SEQ ID NO: 117) D-Phe-c(Cys-His-D-Phe-Arg-Trp-Ala-D-Cys)-Thr-OH; (SEQ ID NO: 118) D-Phe-c(Cys-His-D-Phe-Arg-Trp-P-Ala-D-Cys)-Thr-OH; (SEQ ID NO: 119) D-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-D-Cys)-Thr-OH; (SEQ ID NO: 120) Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-OH;

[0318] (SEQ ID NO: 121) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Apn-Lys)-OH;

[0319] (SEQ ID NO: 122) Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH;

[0320] (SEQ ID NO: 123) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH;

[0321] (SEQ ID NO: 124) Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; (SEQ ID NO: 125) Ac-D-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; (SEQ ID NO: 126) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; (SEQ ID NO: 127) Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; (SEQ ID NO: 128) Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; (SEQ ID NO: 129) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Gaba-Cys)-OH; (SEQ ID NO: 130) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Ahx-Cys)-OH; (SEQ ID NO: 131) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-P-Ala-Cys)-OH; (SEQ ID NO: 132) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-D-Ala-Cys)-OH; (SEQ ID NO: 133) Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-OH; (SEQ ID NO: 134) Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-2-Nal-Cys)-OH; (SEQ ID NO: 135) Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-l-Nal-Cys)-OH; (SEQ ID NO: 136) Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Bal-Cys)-OH; (SEQ ID NO: 137) Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH; (SEQ ID NO: 138) Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-OH;

[0322] (SEQ ID NO: 139) Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2; (SEQ ID NO: 140) Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 141) Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 142) Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2;

[0323] (SEQ ID NO: 143) Ac-D-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2;

[0324] (SEQ ID NO: 144) Ac-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2;

[0325] (SEQ ID NO: 145) Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2;

[0326] (SEQ ID NO: 146) Ac-D-Arg-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-NH2; and

[0327] (SEQ ID NO: 147) Ac-Arg-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-NH2,

[0328] or a pharmaceutically acceptable salt thereof. In embodiments, the compound of Formula (I) is Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2(SEQ ID NO: 140) or a pharmaceutically acceptable salt thereof. Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2(SEQ ID NO: 140), also known as RM-493 and setmelanotide, is a peptide that retains the specificity and functionality of the naturally occurring hormone that activates MC4R and has not been shown to adversely affect blood pressure in clinical trials (see, e g., Chen et al. J. Clin. Endocrinol. Metab. 2015;100(4):1639-45. The structure of Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2(SEQ ID NO: 140) is shown below:

[0329]

[0330] In some embodiments, the MC4R agonist is a compound of Formula (I-a):

[0331] H-A1-c(A2-A3-A4-A5-A6-A7-A8-A9)-A10-NH2(I-a)

[0332] or a pharmaceutically acceptable salt thereof, wherein:

[0333] A1is Phe, D-Phe, orNle;

[0334] A2is Cys;

[0335] A3is deleted;

[0336] A4is His;

[0337] A5is D-Phe or D-(Et)Tyr;

[0338] A6is Arg or hArg; A7is Trp or Bip;

[0339] A8is Ala, P-Ala, Gaba, or Apn;

[0340] A9is D-Cys; and

[0341] A10is Thr or deleted.

[0342] In some embodiments, the compound of Formula (I-a) is selected from:

[0343] (SEQ ID NO: 4) D-Phe-c(Cys-His-D-Phe-Arg-Trp-Ala-D-Cys)-Thr-NH2;

[0344] (SEQ ID NO: 5) D-Phe-c(Cys-His-D-Phe-Arg-Trp-P-Ala-D-Cys)-Thr-NH2;

[0345] (SEQ ID NO: 6) D-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-D-Cys)-Thr-NH2;

[0346] (SEQ ID NO: 79) D-Phe-c(Cys-His-D-Phe-hArg-Trp-p-Ala-D-Cys)-Thr-NH2;

[0347] (SEQ ID NO: 80) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-P-Ala-D-Cys)-Thr-NH2;

[0348] (SEQ ID NO: 81) D-Phe-c(Cys-His-D-Phe-Arg-Bip-P-Ala-D-Cys)-Thr-NH2;

[0349] (SEQ ID NO: 82) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-p-Ala-D-Cys)-Thr-NH2;

[0350] (SEQ ID NO: 83) D-Phe-c(Cys-His-D-Phe-hArg-Bip-P-Ala-D-Cys)-Thr-NH2;

[0351] (SEQ ID NO: 84) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-P-Ala-D-Cys)-Thr-NH2;

[0352] (SEQ ID NO: 85) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH2; and

[0353] (SEQ ID NO: 105) Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2.

[0354] In some embodiments, the MC4R agonist is a compound of Formula (I-b):

[0355] Ac-A1-c(A2-A3-A4-A5-A6-A7-A8-A9)-A10-NH2(I-b)

[0356] or a pharmaceutically acceptable salt thereof, wherein:

[0357] A1is Nle, A6c, D-2-Nal, Cha, Oic, Chg, hCha, D-Cha, D-hCha, Nip, hPro, hLeu, Phe, D-Phe, D-Chg, hPhe, P-hMet, Gaba, Leu, He, Vai, 2-Nal, Arg or D-Arg;

[0358] A2is Asp, Cys, D-Cys, or Pen;

[0359] A3is D-Ala, P-Ala, Gaba, Aib, Gly, Ala, D-Glu, D-Abu, D-Val, D-Ile, D-Leu, D-Tle, D-Cha, deleted;

[0360] A4His or 3 -Pal;

[0361] A5is Phe, D-Phe, or D-2-Nal;

[0362] A6is Arg;

[0363] A7is Trp, 1-Nal, 2-Nal, Bal, or D-Trp;

[0364] A8is P-Ala, A6c, Ahx, Apn, Gaba, Ala, Aha, D-Ala or deleted;

[0365] A9is Lys, Cys, D-Cys, or Pen;

[0366] A10is deleted. wherein A2and A9are pairwise selected to form a disulfide or lactam bridge. In some embodiments, the compound of Formula (I-b) is selected from: (SEQ ID NO: 1) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-P-Ala-Lys)-NH2;

[0367] (SEQ ID NO: 2) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-A6c-Lys)-NH2;

[0368] (SEQ ID NO: 3) Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Ahx-Cys)-NH2;

[0369] (SEQ ID NO: 7) Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH2;

[0370] (SEQ ID NO: 8) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Apn-Lys)-NH2;

[0371] (SEQ ID NO: 9) Ac-A6c-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2;

[0372] (SEQ ID NO: 10) Ac-D-2-Nal-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; (SEQ ID NO: 11) Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2;

[0373] (SEQ ID NO: 12 ) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2;

[0374] (SEQ ID NO: 13) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2;

[0375] (SEQ ID NO: 14) Ac-Nle-c(Cys-P-Ala-His-D-Phe-Arg-Trp-Cys)-NH2;

[0376] (SEQ ID NO: 15) Ac-Nle-c(Cys-Gaba-His-D-Phe-Arg-Trp-Cys)-NH2;

[0377] (SEQ ID NO: 16) Ac-Nle-c(Cys-Aib-His-D-Phe-Arg-Trp-Cys)-NH2;

[0378] (SEQ ID NO: 17) Ac-Nle-c(Cys-Gly-His-D-Phe-Arg-Trp-Cys)-NH2;

[0379] (SEQ ID NO: 18) Ac-Nle-c(D-Cys-Ala-His-D-Phe-Arg-Trp-Cys)-NH2;

[0380] (SEQ ID NO: 19) Ac-Nle-c(D-Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 20) Ac-Nle-c(D-Cys-P-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 21) Ac-Nle-c(D-Cys-Gaba-His-D-Phe-Arg-Trp-Cys)-NH2;

[0381] (SEQ ID NO: 22) Ac-Nle-c(D-Cys-Aib-His-D-Phe-Arg-Trp-Cys)-NH2;

[0382] (SEQ ID NO: 23) Ac-Nle-c(D-Cys-Gly-His-D-Phe-Arg-Trp-Cys)-NH2;

[0383] (SEQ ID NO: 24) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2; (SEQ ID NO: 25) Ac-Nle-c(Cys-P-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2; (SEQ ID NO: 26) Ac-Nle-c(Cys-Gaba-His-D-Phe-Arg-Trp-D-Cys)-NH2;

[0384] (SEQ ID NO: 27) Ac-Nle-c(Cys-Aib-His-D-Phe-Arg-Trp-D-Cys)-NH2;

[0385] (SEQ ID NO: 28) Ac-Nle-c(Cys-Gly-His-D-Phe-Arg-Trp-D-Cys)-NH2;

[0386] (SEQ ID NO: 29) Ac-Nle-c(D-Cys-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2; (SEQ ID NO: 30) Ac-Nle-c(D-Cys-D-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2; (SEQ ID NO: 31) Ac-Nle-c(D-Cys-P-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2; (SEQ ID NO: 32) Ac-Nle-c(D-Cys-Gaba-His-D-Phe-Arg-Trp-D-Cys)-NH2; (SEQ ID NO: 33) Ac-Nle-c(D-Cys-Aib-His-D-Phe-Arg-Trp-D-Cys)-NH2; (SEQ ID NO: 34) Ac-Oic-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; (SEQ ID NO: 35) Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; (SEQ ID NO: 36) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; (SEQ ID NO: 37) Ac-D-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; (SEQ ID NO: 38) Ac-D-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; (SEQ ID NO: 39) Ac-Nip-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; (SEQ ID NO: 40) Ac-hPro-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; (SEQ ID NO: 41) Ac-hLeu-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; (SEQ ID NO: 42) Ac-Phe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; (SEQ ID NO: 43) Ac-D-Phe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; (SEQ ID NO: 44) Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; (SEQ ID NO: 47) Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; (SEQ ID NO: 48) Ac-P-hMet-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; (SEQ ID NO: 49) Ac-Gaba-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; (SEQ ID NO: 50) Ac-Cha-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2; (SEQ ID NO: 51) Ac-hCha-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2; (SEQ ID NO: 52) Ac-Leu-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2; (SEQ ID NO: 53) Ac-hLeu-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2; (SEQ ID NO: 54) Ac-Phe-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2; (SEQ ID NO: 55) Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-D-Ala-Lys)-NH2; (SEQ ID NO: 56) Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-P-Ala-Lys)-NH2; (SEQ ID NO: 57) Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Gaba-Lys)-NH2; (SEQ ID NO: 58) Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Aha-Lys)-NH2; (SEQ ID NO: 59) Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Apn-Lys)-NH2; (SEQ ID NO: 60) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Apn-Cys)-NH2; (SEQ ID NO: 61) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Gaba-Cys)-NH2; (SEQ ID NO: 62) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Ahx-Cys)-NH2; (SEQ ID NO: 63) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-P-Ala-Cys)-NH2; (SEQ ID NO: 64) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-D-Ala-Cys)-NH2; (SEQ ID NO: 65) Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2; (SEQ ID NO: 66) Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-2-Nal-Cys)-NH2; (SEQ ID NO: 67) Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-l-Nal-Cys)-NH2; (SEQ ID NO: 70) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Cys)-NH2; (SEQ ID NO: 71) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-l-Nal-Cys)-NH2; (SEQ ID NO: 72) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Bal-Cys)-NH2; (SEQ ID NO: 73) Ac-Nle-c(Cys-D-Glu-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 74) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-D-Ala-Lys)-NH2; (SEQ ID NO: 75) Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Bal-Cys)-NH2; (SEQ ID NO: 76) Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 77) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 78) Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 86) Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Trp-Lys)-NH2; (SEQ ID NO: 87) Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal-Lys)-NH2; (SEQ ID NO: 89) Ac-Nle-c(Cys-D-Abu-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 90) Ac-Nle-c(Cys-D-Val-His-D-Phe-Arg-Trp-Cys)- NH2; (SEQ ID NO: 91) Ac-Nle-c(Cys-D-Ile-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 92) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 93) Ac-Nle-c(Cys-D-Tle-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 94) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 95) Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; (SEQ ID NO: 96) Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2; (SEQ ID NO: 97) Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2; (SEQ ID NO: 98) Ac-Leu-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; (SEQ ID NO: 99) Ac-Cha-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; (SEQ ID NO: 100) Ac-Ile-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; (SEQ ID NO: 101) Ac-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; (SEQ ID NO: 102) Ac-Val-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; (SEQ ID NO: 103) Ac-2-Nal-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; (SEQ ID NO: 106) Ac-Nle-c(Cys-3-Pal-D-Phe-Arg-Trp-Gaba-Cys)-NH2; (SEQ ID NO: 108) Ac-Nle-c(Cys-His-Phe-Arg-D-Trp-Gaba-Cys)- NH2; (SEQ ID NO: 109) Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Ala-Lys)-NH2; (SEQ ID NO: 110) Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-P-Ala-Lys)-NH2;

[0387] (SEQ ID NO: 111) Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Gaba-Cys)-NH2;

[0388] (SEQ ID NO: 112) Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Ahx-Cys)-NH2;

[0389] (SEQ ID NO: 113) Ac-hPhe-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH2;

[0390] (SEQ ID NO: 114) Ac-Cha-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH2;

[0391] (SEQ ID NO: 139) Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2;

[0392] (SEQ ID NO: 140) Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2;

[0393] (SEQ ID NO: 141) Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2;

[0394] (SEQ ID NO: 142) Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2;

[0395] (SEQ ID NO: 143) Ac-D-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2;

[0396] (SEQ ID NO: 144) Ac-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2;

[0397] (SEQ ID NO: 145) Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2;

[0398] (SEQ ID NO: 146) Ac-D-Arg-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-NH2; and

[0399] (SEQ ID NO: 147) Ac-Arg-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-NH2.

[0400] In some embodiments, the MC4R agonist is a compound of Formula (I-c):

[0401] Ac-Nle-c(A2-A3-A4-A5-A6-A7-A8-A9)-A10-NH2(I-c)

[0402] or a pharmaceutically acceptable salt thereof, wherein:

[0403] A2is Asp, Cys, D-Cys, or Pen;

[0404] A3is D-Ala, P-Ala, Gaba, Aib, Gly, Ala, Aib, Dl-Glu, D-Abu, D-Val, D-Ile, D-Leu, D-Tle, D-Cha, or deleted;

[0405] A4is His or 3-Pal;

[0406] A3is D-Phe, D-2-Nal, or Phe;

[0407] A6is Arg;

[0408] A7is Trp, D-Trp, 2-Nal, 1-Nal, Bal;

[0409] A8is P-Ala, A6c, Ahx, Apn, Gaba, D-Ala, Aha, Ala or deleted;

[0410] A9is Lys, Cys, D-Cys or Pen; and

[0411] A10is deleted,

[0412] wherein A2and A9are pairwise selected to form a disulfide or lactam bridge.

[0413] In some embodiments, the compound of Formula (I-c) is selected from:

[0414] (SEQ ID NO: 1) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-P-Ala-Lys)-NH2;

[0415] (SEQ ID NO: 2) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-A6c-Lys)-NH2; (SEQ ID NO: 3) Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Ahx-Cys)-NH2;

[0416] (SEQ ID NO: 7) Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH2;

[0417] (SEQ ID NO: 8) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Apn-Lys)-NH2;

[0418] (SEQ ID NO: 12 ) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; (SEQ ID NO: 13) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 14) Ac-Nle-c(Cys-P-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 15) Ac-Nle-c(Cys-Gaba-His-D-Phe-Arg-Trp-Cys)-NH2;

[0419] (SEQ ID NO: 16) Ac-Nle-c(Cys-Aib-His-D-Phe-Arg-Trp-Cys)-NH2;

[0420] (SEQ ID NO: 17) Ac-Nle-c(Cys-Gly-His-D-Phe-Arg-Trp-Cys)-NH2;

[0421] (SEQ ID NO: 18) Ac-Nle-c(D-Cys-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 19) Ac-Nle-c(D-Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 20) Ac-Nle-c(D-Cys-p-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 21) Ac-Nle-c(D-Cys-Gaba-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 22) Ac-Nle-c(D-Cys-Aib-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 23) Ac-Nle-c(D-Cys-Gly-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 24) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2; (SEQ ID NO: 25) Ac-Nle-c(Cys-P-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2; (SEQ ID NO: 26) Ac-Nle-c(Cys-Gaba-His-D-Phe-Arg-Trp-D-Cys)-NH2; (SEQ ID NO: 27) Ac-Nle-c(Cys-Aib-His-D-Phe-Arg-Trp-D-Cys)-NH2; (SEQ ID NO: 28) Ac-Nle-c(Cys-Gly-His-D-Phe-Arg-Trp-D-Cys)-NH2; (SEQ ID NO: 29) Ac-Nle-c(D-Cys-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2; (SEQ ID NO: 30) Ac-Nle-c(D-Cys-D-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2; (SEQ ID NO: 31) Ac-Nle-c(D-Cys-p-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2; (SEQ ID NO: 32) Ac-Nle-c(D-Cys-Gaba-His-D-Phe-Arg-Trp-D-Cys)-NH2; (SEQ ID NO: 33) Ac-Nle-c(D-Cys-Aib-His-D-Phe-Arg-Trp-D-Cys)-NH2; (SEQ ID NO: 55) Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-D-Ala-Lys)-NH2; (SEQ ID NO: 56) Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-P-Ala-Lys)-NH2; (SEQ ID NO: 57) Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Gaba-Lys)-NH2; (SEQ ID NO: 58) Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Aha-Lys)-NH2; (SEQ ID NO: 59) Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Apn-Lys)-NH2; (SEQ ID NO: 60) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Apn-Cys)-NH2; (SEQ ID NO: 61) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Gaba-Cys)-NH2; (SEQ ID NO: 62) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Ahx-Cys)-NH2; (SEQ ID NO: 63) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-P-Ala-Cys)-NH2; (SEQ ID NO: 64) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-D-Ala-Cys)-NH2; (SEQ ID NO: 65) Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2; (SEQ ID NO: 66) Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-2-Nal-Cys)-NH2; (SEQ ID NO: 67) Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-l-Nal-Cys)-NH2; (SEQ ID NO: 70) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Cys)-NH2; (SEQ ID NO: 71) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-l-Nal-Cys)-NH2; (SEQ ID NO: 72) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Bal-Cys)-NH2; (SEQ ID NO: 73) Ac-Nle-c(Cys-D-Glu-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 74) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-D-Ala-Lys)-NH2; (SEQ ID NO: 75) Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Bal-Cys)-NH2; (SEQ ID NO: 76) Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 77) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 78) Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 86) Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Trp-Lys)-NH2; (SEQ ID NO: 87) Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal-Lys)-NH2; (SEQ ID NO: 89) Ac-Nle-c(Cys-D-Abu-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 90) Ac-Nle-c(Cys-D-Val-His-D-Phe-Arg-Trp-Cys)- NH2; (SEQ ID NO: 91) Ac-Nle-c(Cys-D-Ile-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 92) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 93) Ac-Nle-c(Cys-D-Tle-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 94) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 95) Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; (SEQ ID NO: 96) Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2; (SEQ ID NO: 97) Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2; (SEQ ID NO: 106) Ac-Nle-c(Cys-3-Pal-D-Phe-Arg-Trp-Gaba-Cys)-NH2; (SEQ ID NO: 108) Ac-Nle-c(Cys-His-Phe-Arg-D-Trp-Gaba-Cys)- NH2; (SEQ ID NO: 109) Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Ala-Lys)-NH2; (SEQ ID NO: 110) Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-P-Ala-Lys)-NH2; (SEQ ID NO: 111) Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Gaba-Cys)-NH2; and (SEQ ID NO: 112) Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Ahx-Cys)-NH2.

[0422] In some embodiments, the MC4R agonist is a compound of Formula (I-d):

[0423] H-D-Phe-c(A2-A3-A4-A5-A6-A7-A8-A9)-A10-NH2(I-d)

[0424] or a pharmaceutically acceptable salt thereof, wherein:

[0425] A2is Cys;

[0426] A3is deleted;

[0427] A4is His;

[0428] A3is D-Phe or D-(Et)Tyr;

[0429] A6is Arg or hArg;

[0430] A7is Trp or Bip;

[0431] A8is Ala, P-Ala, or Gaba;

[0432] A9is D-Cys; and

[0433] A10is Thr.

[0434] In some embodiments, the compound of Formula (I-d) is selected from:

[0435] (SEQ ID NO: 4) D-Phe-c(Cys-His-D-Phe-Arg-Trp-Ala-D-Cys)-Thr-NH2;

[0436] (SEQ ID NO: 5) D-Phe-c(Cys-His-D-Phe-Arg-Trp-p-Ala-D-Cys)-Thr-NH2;

[0437] (SEQ ID NO: 6) D-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-D-Cys)-Thr-NH2;

[0438] (SEQ ID NO: 79) D-Phe-c(Cys-His-D-Phe-hArg-Trp-P-Ala-D-Cys)-Thr-NH2;

[0439] (SEQ ID NO: 80) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-P-Ala-D-Cys)-Thr-NH2;

[0440] (SEQ ID NO: 81) D-Phc-c(Cys-His-D-Phc-Arg-Bip-p-Ala-D-Cys)-Thr-NH2;

[0441] (SEQ ID NO: 82) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-p-Ala-D-Cys)-Thr-NH2;

[0442] (SEQ ID NO: 83) D-Phe-c(Cys-His-D-Phe-hArg-Bip-p-Ala-D-Cys)-Thr-NH2; and (SEQ ID NO: 84) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-P-Ala-D-Cys)-Thr-NH2.

[0443] In some embodiments, the MC4R agonist is a compound of Formula (II):

[0444] -cyclo(A1-A2-A3-A4-A5-A6-A7)-R4

[0445]

[0446] (II), or a pharmaceutically acceptable salt thereof, wherein: X Gs

[0447]

[0448] Pen or

[0449]

[0450] Cys, D-Cys, Dab, Dap, Glu, Lys, Orn, Pen or D-Pen; R1is H, (Ci-Cio)alkyl or substituted (Ci-Cio)alkyl; R2and R3each is, independently, H, (Ci-Cio)alkyl, (Ci-Cio)heteroalkyl, aryl(Ci-Cs)alkyl, substituted (Ci-Cio)alkyl, substituted (Ci-Cio)heteroalkyl or substituted aryl(Ci-Cs)alkyl or R2and R3may be fused together form a cyclic moiety; R4is OH, NH2, CO2 H or C(O)NH2; R and R6each is, independently, H, (Ci-Cio)alkyl, (Ci-Cio)heteroalkyl, aryl(Ci-C5)alkyl, substituted (Ci-Cio)alkyl, substituted (Ci-Cio)heteroalkyl or substituted aryl(Ci-Cs)alkyl or R5and R6may be fused together form a cyclic moiety; R7and R8each is, independently, H, (Ci-Cio)alkyl, (Ci-Cio)heteroalkyl, aryl(Ci-C5)alkyl, substituted (Ci-Cio)alkyl, substituted (Ci-Cio)heteroalkyl or substituted aryl(Ci-C5)alkyl; or R7and R8may be fused together form a cyclic moiety; R9is H, (Ci-Cio)alkyl or substituted (Ci-Cio)alkyl; and n is, independently for each occurrence thereof, 0, 1, 2, 3, 4, 5, 6 or 7; or a pharmaceutically acceptable salt thereof.

[0451] In some embodiments of Formula (II), A1is Cys; A2is D-Ala, Asn, Asp, Gin, Glu or D-Phe; A3is His; A4is D-2-Nal or D-Phe; A5is Arg; A6is Trp; and A7is Cys or Pen; each of R', R2, R3, and R9is, independently, H; R4is C(O)NH2; each of R5and R6is, independently, H, (Ci-Cio)heteroalkyl, substituted (Ci-Cio)alkyl or substituted (Ci-Cio)heteroalkyl or R5and R6may be fused together form a cyclic moiety; and each of R7and R8is, independently, H, (Ci-Cio)alkyl, (Ci-Cio)heteroalkyl, substituted (Ci-Cio)alkyl or substituted (Ci-Cio)heteroalkyl; or pharmaceutically acceptable salts thereof

[0452] In some embodiments, the compound of Formula (II) is selected from:

[0453] (SEQ ID NO: 148) Hydantoin(C(O)-(Arg-Gly))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 149) Hydantoin(C(O)-(Nle-Gly))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 150) Hydantoin(C(O)-(Gly-Gly))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 151) Hydantoin(C(O)-(Nle-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 152) Hydantoin(C(O)-(Gly-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 153) Hydantoin(C(O)-(Nle-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 154) Hydantoin(C(O)-(Gly-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 155) Hydantoin(C(O)-(Ala-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 156) Hydantoin(C(O)-(D-Ala-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 157) Hydantoin(C(O)-(Aib-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 158) Hydantoin(C(O)-(Val-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 159) Hydantoin(C(O)-(Ile-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 160) Hydantoin(C(O)-(Leu-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 161) Hydantoin(C(O)-(Gly-Gly))-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Cys)-NH2; (SEQ ID NO: 162) Hydantoin(C(O)-(Nle-Gly))-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Cys)-NH2; (SEQ ID NO: 163) Hydantoin(C(O)-(D-Arg-Gly))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 164) Hydantoin(C(O)-(D-Arg-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 165) Hydantoin(C(O)-(Arg-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 166) Hydantoin(C(O)-(D-Arg-Gly))-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2;

[0454] (SEQ ID NO: 167) Hydantoin(C(O)-(Arg-Gly))-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2; (SEQ ID NO: 168) Hydantoin(C(O)-(Ala-Nle))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 169) Hydantoin(C(O)-(Val-Nle))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 170) Hydantoin(C(O)-(Gly-Nle))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 171) Hydantoin(C(O)-(A6c-Nle))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 172) Hydantoin(C(O)-(Gly-Nle))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 173) Hydantoin(C(O)-(Ala-Nle))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 174) Hydantoin(C(O)-(D-Ala-Nle))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 175) Hydantoin(C(O)-(Val-Nle))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 176) Hydantoin(C(O)-(Leu-Nle))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 177) Hydantoin(C(O)-(Cha-Nle))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 178) Hydantoin(C(O)-(Aib-Nle))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 179) Hydantoin(C(O)-(Gly-Arg))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 180) Hydantoin(C(O)-(Gly-Arg))-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Cys)-NH2; (SEQ ID NO: 181) Hydantoin(C(O)-(Gly-Arg))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 182) Hydantoin(C(O)-(Gly-Arg))-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2; (SEQ ID NO: 183) Hydantoin(C(O)-(Gly-D-Arg))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 184) Hydantoin(C(O)-(Gly-D-Arg))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 185) Hydantoin(C(O)-(Gly-D-Arg))-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2; and

[0455] (SEQ ID NO: 186) Hydantoin(C(O)-(Nle-Ala))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2, or a pharmaceutically acceptable salt thereof.

[0456] In some embodiments, the compound of Formula (II) is described in WO2008 / 147556 or International Patent Application Number PCT / US08 / 06675, each of which is incorporated herein by reference in its entirety.

[0457] In embodiments, the compound of Formula (II) is hydantoin(C(O)-(Arg-Gly))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2(SEQ ID NO: 148) or a pharmaceutically acceptable salt thereof, also known as RM-511. The structure of hydantoin(C(O)-(Arg-Gly))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2 (SEQ ID NO: 148) is shown below:

[0458]

[0459] In some embodiments, the MC4R agonist is a compound of Formula (III):

[0460]

[0461] pharmaceutically acceptable salt thereof, wherein X is selected from the group consisting of -CH2-S-S-CH2-, -C(CH3)2-S-S-CH2-, -CH2-S-S-C(CH3)2-, -C(CH3)2-S-S-C(CH3)2-, -(CH2)2-S-S-CH2-, -CH2-S-S-(CH2)2-, -(CH2)2-S-S-(CH2)2-, -C(CH3)2-S-S-(CH2)2-, -(CH2)2-S-S-C(CH3)2-, -(CH2) C(O)-NR8-(CH2>-and -(CH2 -NR8-C(O)-(CH2)t-; R2each is, independently, H, (Ci-Cio)alkyl or substituted (Ci-Cio)alkyl; R3is -OH or -NH2; R4and R5each is, independently, H, (Ci-Cio)alkyl or substituted (Ci-Cio)alkyl; X1is

[0462]

[0463] ; A1is H is, 2-Pal, 3-Pal, 4-Pal, (X he, Taz, 2-Thi, 3-Thi or is deleted; A2is D-Bal, D-1-Nal, D-2-Nal, D-Phe X4, X5)Phe; A3is Arg, hArg, Dab, Dap, Lys or Orn; A4is Bal, 1-Nal, 2-Nal,

[0464]

[0465] 5)Phe or Trp; R6and R7each is, independently for each occurrence thereof, H, (Ci-Cio)heteroalkyl, aryl(Ci-Cs)alkyl, substituted (Ci-Cio)alkyl, substituted (Ci-Cio)heteroalkyl or substituted aryl(Ci-Cs)alkyl provided thatR6and R7may be joined together to form a ring; R8is H, (Ci-Cio)alkyl or substituted (Ci-Cio)alkyl; r is, independently for each occurrence thereof, 1, 2, 3, 4 or 5; and t is, independently for each occurrence thereof, 1 or 2.

[0466] Compounds according to the foregoing formula can include compounds wherein X1is

[0467]

[0468] Compounds of Formula (III) are disclosed in International Patent Publication WO 2008 / 147556 or International Patent Application Number PCT / US08 / 06675, each of which is incorporated herein by reference in its entirety.

[0469] In some embodiments, the compound of Formula (III) is selected from:

[0470] (SEQ ID NO: 187) c[Hydantoin(C(O)-(Cys-D-Ala))-His-D-Phe-Arg-Trp-Cys]-NH2;

[0471] (SEQ ID NO: 188) c[Hydantoin(C(O)-(hCys-D-Ala))-His-D-Phe-Arg-Trp-Cys]-NH2;

[0472] (SEQ ID NO: 189) c[Hydantoin(C(O)-(Cys-D-Ala))-His-D-2-Nal-Arg-Trp-Cys]-NH2;

[0473] (SEQ ID NO: 190) c[Hydantoin(C(O)-(hCys-D-Ala))-His-D-2-Nal-Arg-Trp-Cys]-NH2;

[0474] (SEQ ID NO: 191) c[Hydantoin(C(O)-(Asp-D-Ala))-His-D-Phe-Arg-Trp-Lys]-NH2;

[0475] (SEQ ID NO: 192) c[Hydantoin(C(O)-(Asp-D-Ala))-His-D-Phe-Arg-Trp-Orn]-NH2; (SEQ ID NO: 193) c[Hydantoin(C(O)-(Asp-D-Ala))-His-D-Phe-Arg-Trp-Dab]-NH2;

[0476] (SEQ ID NO: 194) c[Hydantoin(C(O)-(Asp-D-Ala))-His-D-Phe-Arg-Trp-Dap]-NH2;

[0477] (SEQ ID NO: 195) c[Hydantoin(C(O)-(Asp-His))-D-2-Nal-Arg-Trp-Lys]-NH2;

[0478] (SEQ ID NO: 196) c[Hydantoin(C(O)-(Asp-His))-D-Phe-Arg-Trp-Lys]-NH2;

[0479] (SEQ ID NO: 197) c[Hydantoin(C(O)-(Asp-A3c))-D-Phe-Arg-Trp-Lys]-NH2;

[0480] (SEQ ID NO: 198) c[Hydantoin(C(O)-(Asp-A5c))-D-Phe-Arg-Trp-Lys]-NH2;

[0481] (SEQ ID NO: 199) c[Hydantoin(C(O)-(Asp-A6c))-D-Phe-Arg-Trp-Lys]-NH2;

[0482] (SEQ ID NO: 200) c[Hydantoin(C(O)-(Asp-A3c))-D-2-Nal-Arg-Trp-Lys]-NH2;

[0483] (SEQ ID NO: 201) c[Hydantoin(C(O)-(Asp-A5c))-D-2-Nal-Arg-Trp-Lys]-NH2;

[0484] (SEQ ID NO: 202) c[Hydantoin(C(O)-(Asp-A6c))-D-2-Nal-Arg-Trp-Lys]-NH2;

[0485] (SEQ ID NO: 203) c[Hydantoin(C(O)-(Asp-Aic))-D-Phe-Arg-Trp-Lys]-NH2;

[0486] (SEQ ID NO: 204) c[Hydantoin(C(O)-(Asp-Apc))-D-Phe-Arg-Trp-Lys]-NH2;

[0487] (SEQ ID NO: 205) c[Hydantoin(C(O)-(Asp-Aic))-D-2-Nal-Arg-Trp-Lys]-NH2;

[0488] (SEQ ID NO: 206) c[Hydantoin(C(O)-(Asp-Apc))-D-2-Nal-Arg-Trp-Lys]-NH2;

[0489] (SEQ ID NO: 207) c[Hydantoin(C(O)-(Glu-D-Ala))-His-D-Phe-Arg-Trp-Orn]-NH2;

[0490] (SEQ ID NO: 208) c[Hydantoin(C(O)-(Glu-D-Ala))-His-D-Phe-Arg-Trp-Dab]-NH2;

[0491] (SEQ ID NO: 209) c[Hydantoin(C(O)-(Glu-D-Ala))-His-D-Phe-Arg-Trp-Dap]-NH2;

[0492] (SEQ ID NO: 210) c[Hydantoin(C(O)-(Glu-D-Ala))-His-D-Phe-Arg-Trp-Lys]-NH2;

[0493] (SEQ ID NO: 211) c[Hydantoin(C(O)-(Glu-His))-D-Phe-Arg-Trp-Dap]-NH2; and

[0494] (SEQ ID NO: 212) c[Hydantoin(C(O)-(Glu-His))-D-Phe-Arg-Trp-Lys]-NH2,

[0495] or a pharmaceutically acceptable salt thereof.

[0496] In some embodiments, the MC4R agonist is a compound of Formula (IV):

[0497] (R2R3)-A1-C(A2-A3-A4-A5-A6-A7-A8-A9)-NH2(IV) or a pharmaceutically acceptable salt thereof, wherein A1is Nle or deleted; A2is Cys or Asp; A3is Glu or D-Ala; A4is His; A5is D-Phe; A6is Arg; A7is Trp, 2-Nal or Bal; A8is Gly, Ala, D-Ala, 3-Ala, Gaba or Apn; A9is Cys or Lys; each of R2and R3is independently selected from the group consisting of H or (Ci-C6)acyl.

[0498] In exemplary embodiments of Formula (IV): (I) when R2is (Ci-Ce)acyl, then R3is H; and (II) when A2is Cys, then A9is Cys. Exemplary MC4R agonists of Formula (IV) are disclosed in International Patent Application Publication Number WO 2007 / 008704, which is incorporated herein by reference in its entirety.

[0499] In some embodiments, the compound of Formula (IV) is selected from:

[0500] (SEQ ID NO: 213) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gly-Cys)-NH2;

[0501] (SEQ ID NO: 214) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-D-Ala-Cys)-NH2;

[0502] (SEQ ID NO: 215) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-P-Ala-Cys)-NH2;

[0503] (SEQ ID NO: 216) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2;

[0504] (SEQ ID NO: 217) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Apn-Cys)-NH2;

[0505] (SEQ ID NO: 218) Ac-c(Cys-Glu-His-D-Phe-Arg-Trp-Ala-Cys)-NH2;

[0506] (SEQ ID NO: 219) Ac-c(Cys-Glu-His-D-Phe-Arg-2-Nal-Ala-Cys)-NH2;

[0507] (SEQ ID NO: 220) Ac-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Ala-Cys)-NH2;

[0508] (SEQ ID NO: 221) Ac-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Ala-Cys)-NH2;

[0509] (SEQ ID NO: 222) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Ala-Cys)-NH2; and

[0510] (SEQ ID NO: 223) Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal-Ala-Lys)-NH2,

[0511] or a pharmaceutically acceptable salt thereof.

[0512] In some embodiments, the MC4R agonist is a compound of Formula (V):

[0513] (R2R3)-B1-A1-c(A2-A3-A4-A5-A6-A7-A8-A9)-A10-A11-A12-A13-B2-B3-R1(V) or a pharmaceutically acceptable salt thereof: B1is a peptide moiety which contains 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids, wherein at least 5 amino acids are independently selected from the group consisting of L- Arg, D-Arg, L-hArg and D-hArg, or B1is optionally deleted; A1is Acc, HN-(CH2)m-C(O), L- or D-amino acid or deleted; A2is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Asp or Glu; A3is Gly, Glu, Ala, P-Ala, Gaba, Aib, D-amino acid or deleted; A4is H is, 2-Pal, 3-Pal, 4-Pal, Taz, 2-Thi, 3-Thi or (X', X2, X3, X4, X5)Phe; A5is D-Phe, D-1-Nal, D-2-Nal, D-Trp, D-Bal, D-(X', X2, X3, X4, X5)Phe, D-(Et)Tyr, D-Dip, D-Bip or D-Bpa; A6is Arg, hArg, Dab, Dap, Lys, Om or HN-CH((CH2)n-N(R4R5))-C(O); A7is Trp, 1-Nal, 2-Nal, Bal, Bip, Dip, Bpa, D-Trp, D-1-Nal, D-2-Nal, D-Bal, D-Bip, D-Dip or D-Bpa; A8is Gly, D-Ala, Acc, Ala, P-Ala, Gaba, Apn, Ahx or deleted; A9is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Dab, Dap, Orn

[0514]

[0515] H2)f-C(O), Pro, hPro, 3-Hyp, 4-Hyp, Thr, an L- or D-amino acid or deleted; A11is Pro, hPro, 3-Hyp, 4-Hyp or deleted; A12is Lys, Dab, Dap, Arg, hArg or deleted; A13is Asp, Glu or deleted; B2is a peptide moiety containing 1, 2, 3, 4, or 5 amino acids or deleted, B3is a peptide moiety which contains 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acids wherein at least 5 amino acids are independently selected from the group consisting of L-Arg, D-Arg, L-hArg and D-hArg, or is deleted; R1is OH or NH2; R2and R3each is, independently for each occurrence, selected from the group consisting of H, (Ci-C3o)alkyl, (Ci-C3o)heteroalkyl, (Ci-C3o)acyl, (C2-C3o)alkenyl, (C2-C3o)alkynyl, aryl(Ci-C3o)alkyl, aryl(Ci-C3o)acyl, substituted (Ci-C3o)alkyl, substituted (Ci-C3o)heteroalkyl, substituted (Ci-C3o)acyl, substituted (C2-C3o)alkenyl, substituted (C2-C3o)alkynyl, substituted aryl(Ci-C3o)alkyl and substituted aryl(Ci-C3o)acyl; R4and R5each is, independently for each occurrence, H, (Ci-C4o)alkyl, (Ci-C4o)heteroalkyl, (Ci-C4o)acyl, (C2-C4o)alkenyl, (C2-C4o)alkynyl, aryl(Ci-C4o)alkyl, aryl(Ci-C4o)acyl, substituted (Ci-C4o)alkyl, substituted (Ci-C4o)heteroalkyl, substituted (Ci-C4o)acyl, substituted (C2-C4o)alkenyl, substituted (C2-C4o)alkynyl, substituted aryl(Ci-C4o)alkyl, substituted aryl(Ci-C4o)acyl, (Ci-C4o)alkylsulfonyl or C(NH)-NH2; n is, independently for each occurrence, 1, 2, 3, 4 or 5; m is, independently for each occurrence, 1, 2, 3, 4, 5, 6 or 7; s is, independently for each occurrence, 1, 2, 3, 4, 5, 6 or 7; t is, independently for each occurrence, 1, 2, 3, 4, 5, 6 or 7; X1, X2, X3, X4and X5each is, independently for each occurrence, H, F, Cl, Br, I, -(C1-C10) alkyl, substituted (C1-C10) alkyl, (C2-C10) alkenyl, substituted (C2-C10) alkenyl, (C2-C10) alkynyl, substituted (C2-C10) alkynyl, aryl, substituted aryl, OH, NH2, NO2 or CN.

[0516] In some embodiments of Formula (V):

[0517] (I) when R4is (Ci-C4o)acyl, aryl(Ci-C4o)acyl, substituted (Ci-C4o)acyl, substituted aryl(Ci-C4o)acyl, (Ci-C4o)alkylsulfonyl or C(NH) — NH2, then R5is H, (Ci-C4o)alkyl, (Ci-C4o)heteroalkyl, (C2-C4o)alkenyl, (C2-C4o)alkynyl, aryl(Ci-C4o)alkyl, substituted (Ci-C4o)alkyl, substituted (Ci-C4o)heteroalkyl, substituted (C2-C4o)alkenyl, substituted (C2-C4o)alkynyl or substituted aryl(Ci-C4o)alkyl;

[0518] (II) when R2is (Ci-C3o)acyl, aryl(Ci-C3o)acyl, substituted (Ci-C3o)acyl or substituted aryl (Ci-C3o)acyl, then R3is H, (Ci-C3o)alkyl, (Ci-C3o)heteroalkyl, (C2-C3o)alkenyl, (C2-C3o)alkynyl, aryl(Ci-C3o)alkyl, substituted (Ci-C3o)alkyl, substituted (Ci-C3o)heteroalkyl, substituted (C2-C3o)alkenyl, substituted (C2-C3o)alkynyl or substituted aryl(Ci-C3o)alkyl;

[0519] (III) neither B1nor B2contains one or more of the following amino acid sequences: Arg-(Lys)2-(Arg)2-Gln-(Arg)3, Tyr-Ala-Arg-Lys-Ala-(Arg)2-Gln-Ala-(Arg)2, Tyr-Ala-Arg-(Ala)2-(Arg)2-(Ala)2-(Arg)2, Tyr-Ala-(Arg)9, Tyr-(Ala)3-(Arg)7, Tyr-Ala-Arg-Ala-Pro-(Arg)2-Ala-(Arg)3 or Tyr-Ala-Arg-Ala-Pro-(Arg)2-Pro-(Arg)2; (TV) either B1or B2or both must be present in said compound;

[0520] (V) when A2is Cys, D-Cys, hCys, D-hCys, Pen or D-Pen, then A9is Cys, D-Cys, hCys, D-hCys, Pen or D-Pen; and

[0521] (VI) when A2is Asp or Glu, then A9is Dab, Dap, Om or Lys.

[0522] In some embodiments of Formula (V):

[0523] B1is Arg-Lys-Gln-Lys-(Arg)5, Arg-(Lys)2-Arg-Gln-(Arg)4, Arg-(Lys)2-(Arg)3-Gln-(Arg)2, Arg-(Lys)2-(Arg)4-Gln-Arg, Arg-(Lys)2-(Arg)5-Gln, Arg-(Lys)2-Gln-(Arg)5, Arg-Gln-(Lys)2-(Arg)5, Arg-Gln-(Arg)7, Arg-Gln-(Arg)8, (Arg)2-Gln-(Arg)6, (Arg)2-Gln-(Arg)7, (Arg)3-Gln-(Arg)s, (Arg).3-Gln-(Arg)6, (Arg)4-Gln-(Arg)4, (Arg)4-Gln-(Arg)s, (Arg)5, (Arg)5-Gln-(Arg)3, (Arg)5-Gln-(Arg)4, (Arg)6, (Arg)6-Gln-(Arg)3, (Arg)7, (Arg)7-Gln-(Arg)2, (Arg)8, (Arg)8-Gln-Arg, (Arg)9, (Arg)9-Gln, (D-Arg)5, (D-Arg)6, (D-Arg)7, (D-Arg)8, (D-Arg)9, Gln-Arg-(Lys)2-(Arg)5, Gln-(Arg)8, Gln-(Arg)9, Tyr-Gly-Arg-(Lys)2-(Arg)2-Gln-(Arg)3, Tyr-Gly-Arg-(Lys)2-(Arg)2-Gln-(Arg)3-Doc; or deleted;

[0524] B2is P-Ala, P-Ala-Gly, P-Ala-Tyr, P-Ala-Tyr-Gly, (P-Ala)2, (P-Ala)2-Gly, (P-Ala)2-Tyr, (P-Ala)2-Tyr-Gly, Doc, Doc-Gly, Doc-Tyr, Doc-Tyr-Gly, (Doc)2, (Doc)2-Gly, (Doc)2-Tyr, Doc)2-Tyr-Gly, or deleted;

[0525] B3is Arg-Lys-Gln-Lys-(Arg)5, Arg-Lys-(Arg)3-Gln-(Arg)3, Arg-(Lys)2-Arg-Gln-(Arg)4, Arg-(Lys)2-Gln-(Arg)5, Arg-(Lys)2-(Arg)2-Gln-(Arg)3, Arg-(Lys)2-(Arg)3-Gln-(Arg)2, Arg-(Lys)2-(Arg)4-Gln-Arg, Arg-(Lys)2-(Arg)5-Gln, Arg-Gln-(Lys)2-(Arg)5, Arg-Gln-(Arg)7, Arg-Gln-(Arg)8, (Arg)2-Lys-(Arg)2-Gln-(Arg)3, (Arg)2-Gln-(Arg)6, (Arg)2-Gln-(Arg)7, (Arg)3-Gln-(Arg)s, (Arg)3-Gln-(Arg)6, (Arg)4-Gln-(Arg)4, (Arg)4-Gln-(Arg)5, (Arg)5, (Arg)5-Gln-(Arg)3, (Arg)5-Gln-(Arg)4, (Arg)6, (Arg)6-Gln-(Arg)3, (Arg)7, (Arg)7-Gln-(Arg)2, (Arg)8, (Arg)8-Gln-Arg, (Arg)9, (Arg)9-Gln, (D-Arg)5, (D-Arg)6, (D-Arg)7, (D-Arg)8, (D-Arg)9, Gln-Arg-(Lys)2-(Arg)5, Gln-(Arg)8, Gln-(Arg)9, or deleted;

[0526] A1is A6c, Cha, hCha, Chg, D-Chg, hChg, Gaba, hLeu, Met, P-hMet, D-2-Nal, Nip, Nle, Oic, Phe, D-Phe, hPhe, hPro, or deleted;

[0527] A2is Cys;

[0528] A3is D-Abu, Aib, Ala, P-Ala, D-Ala, D-Cha, Gaba, Glu, Gly, D-Ile, D-Leu, D-Met, D-Nle, D-Phe, D-Tle, D-Trp, D-Tyr, D-Val, or deleted;

[0529] A4is His;

[0530] A5is D-Bal, D-1-Nal, D-2-Nal, D-Phe, D-(X1, X2, X3, X4, X5)Phe, D-Trp, or D-(Et)Tyr; A6is Arg or hArg;

[0531] A7is Bal, Bip, 1-Nal, 2-Nal, Trp, or D-Trp;

[0532] A8is A5c, A6c, Aha, Ahx, Ala, P-Ala, Apn, Gaba, Gly, or deleted;

[0533] A9is Cys, D-Cys, hCys, D-hCys, Lys, Pen, orD-Pen;

[0534] A10is Pro, Thr or deleted;

[0535] A11is Pro or deleted;

[0536] A12is Arg, Lys, or deleted;

[0537] A13is Asp or deleted;

[0538] each of R2and R3is, independently, H or acyl;

[0539] or pharmaceutically acceptable salts thereof.

[0540] In some embodiments, the compound of Formula (V) is selected from:

[0541] (SEQ ID NO: 224) Tyr-Gly-Arg-(Lys)2-(Arg)2-Gln-(Arg)3-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Lys)-NH2;

[0542] (SEQ ID NO: 225) Tyr-Gly-Arg-(Lys)2-(Arg)2-Gln-(Arg)3-Doc-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Lys)-NH2;

[0543] (SEQ ID NO: 226) Nle-c(Asp-His-D-2-Nal-Arg-Trp-Lys)-P-Ala-Tyr-Gly-Arg-(Lys)2-(Arg)2-Gln-(Arg)3-NH2;

[0544] (SEQ ID NO: 227) Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Lys)-P-Ala-Tyr-Gly-Arg-(Lys)2-(Arg)2-Gln-(Arg)3-NH2;

[0545] (SEQ ID NO: 228) Nle-c(Asp-His-D-2-Nal-Arg-Trp-Lys)-(Doc)2-Tyr-Gly-Arg-(Lys)2-(Arg)2-Gln-(Arg)3-NH2;

[0546] (SEQ ID NO: 229) Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Lys)-(Pro)2-Lys-Asp-Tyr-Gly-Arg- (Lys)2-(Arg)2-Gln-(Arg)3-NH2;

[0547] (SEQ ID NO: 230) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Gly-Cys)-(Pro)2-Lys-Asp-Tyr-Gly-Arg-(Lys)2-(Arg)2-Gln-(Arg)3-NH2;

[0548] (SEQ ID NO: 231) Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Lys)-(P-Ala)2-Tyr-Gly-Arg-(Lys)2- (Arg)2-Gln-(Arg)3-NH2;

[0549] (SEQ ID NO: 232) Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Lys)-(Pro)2-Lys-Asp-Doc-Tyr-Gly-Arg-(Lys)2-(Arg)2-Gln-(Arg)3-NH2;

[0550] (SEQ ID NO: 233) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Gly-Cys)-(Pro)2-Lys-Asp-Doc-Tyr-Gly-Arg- (Lys)2-(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO: 234) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-P-Ala-Tyr-Gly-Arg-(Lys)2-(Arg)2-Gln-(Arg)3-NH2;

[0551] (SEQ ID NO: 235) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-Doc-Tyr-Gly-Arg-(Lys)2-(Arg)2-Gln-(Arg)3- H2;

[0552] (SEQ ID NO: 236) Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Lys)-(Doc)2-Tyr-Gly-Arg-(Lys)2-(Arg)2-Gln-(Arg)3-NH2;

[0553] (SEQ ID NO: 237) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-P-Ala-Tyr-Gly-Arg-(Lys)2-(Arg)2-Gln-(Arg)3-NH2;

[0554] (SEQ ID NO: 238) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-P-Ala-(Arg)5-Gln-(Arg)3-NH2;

[0555] (SEQ ID NO: 239) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-P-Ala-Gly- (Arg)5-Gln-(Arg)3-NH2;

[0556] (SEQ ID NO: 240) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-P-Ala-Tyr- Gly-(Arg)s-Gln-(Arg)3-NH2;

[0557] (SEQ ID NO: 241) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-P-Ala-Tyr-Gly-Arg-(Lys)2-Arg-Gln-(Arg)4-NH2;

[0558] (SEQ ID NO: 242) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-P-Ala-Tyr-Gly-Arg-(Lys)2-Gln-(Arg)5-NH2;

[0559] (SEQ ID NO: 243) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-P-Ala-Tyr- Gly-Arg-Lys-Gln-Lys-(Arg)5-NH2;

[0560] (SEQ ID NO: 244) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-P-Ala-Tyr-Gly-Arg-(Lys)2-(Arg)4-Gln-Arg-NH2;

[0561] (SEQ ID NO: 245) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-P-Ala-Tyr-Aib-Arg-(Lys)2-(Arg)2-Gln-(Arg)3-NH2;

[0562] (SEQ ID NO: 246) Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Arg-Asp-P-Ala- (Arg)s -Gln-(Arg)3-NH2;

[0563] (SEQ ID NO: 247) Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Lys-Asp-P-Ala- (Arg)5-Gln-(Arg)3-NH2;

[0564] (SEQ ID NO: 248) Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Lys-Asp-P-Ala- (Arg)6-Gln-(Arg)3-NH2; (SEQ ID NO: 249) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Arg-Asp-P-Ala-(Arg)5-Gln-(Arg)3-NH2;

[0565] (SEQ ID NO: 250) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-P-Ala- (Arg)5-Gln-(Arg)3-NH2;

[0566] (SEQ ID NO: 251) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-P-Ala- (Arg)6-Gln-(Arg)3-NH2;

[0567] (SEQ ID NO: 252) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Arg-Asp-P-Ala-(Arg)6-Gln-(Arg)3-NH2;

[0568] (SEQ ID NO: 253) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Arg-Asp-P-Ala-(Arg)5-Gln-(Arg)3-NH2;

[0569] (SEQ ID NO: 254) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-P-Ala-(Arg)6-Gln-(Arg)3-NH2;

[0570] (SEQ ID NO: 255) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-P-Ala-Tyr-Gly-Arg-(Lys)2-(Arg)3-Gln-(Arg)2-NH2;

[0571] (SEQ ID NO: 256) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-P-Ala-Tyr-Gly-Arg-Gln-(Lys)2-(Arg)5-NH2;

[0572] (SEQ ID NO: 257) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-P-Ala-Tyr-Gly-Arg-(Lys)2-(Arg)5-Gln-NH2;

[0573] (SEQ ID NO: 258) Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Lys-Asp-P-Ala-Tyr-Gly-Arg-(Lys)2-(Arg)2-Gln-(Arg)3-NH2;

[0574] (SEQ ID NO: 259) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-P-Ala-Tyr-Gly-Arg-(Lys)2-(Arg)2-Gln-(Arg)3-NH2;

[0575] (SEQ ID NO: 260) Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Lys-Asp-P-Ala- (Arg)2-Lys-(Arg)2-Gln-(Arg)3-NH2;

[0576] (SEQ ID NO: 261) Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Lys-Asp-P-Ala-Arg-Lys-(Arg)3-Gln-(Arg)3- H2;

[0577] (SEQ ID NO: 262) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-P-Ala- (Arg)2-Lys-(Arg)2-Gln-(Arg)3-NH2;

[0578] (SEQ ID NO: 263) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-P-Ala-Tyr-Gly-(Arg)2-Lys-(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO: 264) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-P-Ala-Gly-(Arg)2-Lys-(Arg)2-Gln-(Arg)3-NH2;

[0579] (SEQ ID NO: 265) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-P-Ala-Gly-Arg-Lys-(Arg)3-Gln-(Arg)3-NH2;

[0580] (SEQ ID NO: 266) Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Lys-Asp-P-Ala-Tyr-Gly-(Arg)2-Lys-(Arg)2-Gln-(Arg)3-NH2;

[0581] (SEQ ID NO: 267) Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Lys-Asp-P-Ala-Tyr-Gly-Arg-Lys-(Arg)3-Gln-(Arg)3-NH2;

[0582] (SEQ ID NO: 268) Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Lys-Asp-P-Ala-Gly-(Arg)2-Lys-(Arg)2-Gln-(Arg)3-NH2;

[0583] (SEQ ID NO: 269) Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Lys-Asp-P-Ala-Gly-Arg-Lys-(Arg)3-Gln-(Arg)3-NH2;

[0584] (SEQ ID NO: 270) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-P-Ala-(Arg)2-Lys-(Arg)2-Gln-(Arg)3-NH2;

[0585] (SEQ ID NO: 271) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-P-Ala-Arg-Lys-(Arg)3-Gln-(Arg)3-NH2;

[0586] (SEQ ID NO: 272) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-P-Ala-Tyr-Gly-Arg-Lys-(Arg)3-Gln-(Arg)3-NH2;

[0587] (SEQ ID NO: 273) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-P-Ala-(Arg)2-Lys-(Arg)2-Gln-(Arg)3-NH2;

[0588] (SEQ ID NO: 274) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-P-Ala-Arg-Lys-(Arg)3-Gln-(Arg)3-NH2;

[0589] (SEQ ID NO: 275) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-P-Ala-Tyr-Gly-(Arg)2-Lys-(Arg)2-Gln-(Arg)3-NH2;

[0590] (SEQ ID NO: 276) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-P-Ala-Tyr-Gly-Arg-Lys-(Arg)3-Gln-(Arg)3-NH2;

[0591] (SEQ ID NO: 277) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-P-Ala-Gly-(Arg)2-Lys-(Arg)2-Gln-(Arg)3-NH2;

[0592] (SEQ ID NO: 278) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-P-Ala-Gly-Arg-Lys-(Arg)3-Gln-(Arg)3-NH2; (SEQ ID NO: 279) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-P-Ala-(Arg)s-Gln-(Arg)3-NH2;

[0593] (SEQ ID NO: 280) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Arg-Asp-P-Ala-(Arg)s-Gln-(Arg)3-NH2;

[0594] (SEQ ID NO: 281) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-P-Ala-Tyr- Gly-(Arg)s-Gln-(Arg)3-NH2;

[0595] (SEQ ID NO: 282) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Arg-Asp-P-Ala-Tyr-Gly-(Arg)s-Gln-(Arg)3-NH2;

[0596] (SEQ ID NO: 283) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-P-Ala-(Arg)5-Gln-(Arg)4-NH2;

[0597] (SEQ ID NO: 284) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Arg-Asp-P-Ala-(Arg)5-Gln-(Arg)4-NH2;

[0598] (SEQ ID NO: 285) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-P-Ala-Tyr- Gly-(Arg)5-Gln-(Arg)4-NH2;

[0599] (SEQ ID NO: 286) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Arg-Asp-P-Ala-Tyr- Gly-(Arg)5-Gln-(Arg)4-NH2;

[0600] (SEQ ID NO: 287) Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Lys-Asp-P-Ala- (Arg)5-Gln-(Arg)4-NH2;

[0601] (SEQ ID NO: 288) Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Arg-Asp-P-Ala- (Arg)5-Gln-(Arg)4-NH2;

[0602] (SEQ ID NO: 289) Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Arg-Asp-P-Ala- (Arg)6-Gln-(Arg)3-NH2;

[0603] (SEQ ID NO: 290) Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Lys-Asp-P-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3- H2;

[0604] (SEQ ID NO: 291) Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Arg-Asp-P-Ala-Tyr-Gly-(Arg)s-Gln-(Arg)3-NH2;

[0605] (SEQ ID NO: 292) Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Lys-Asp-P-Ala-Tyr- Gly-(Arg)5-Gln-(Arg)4-NH2;

[0606] (SEQ ID NO: 293) Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Arg-Asp-P-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 294) Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Lys-Asp-P-Ala-Tyr-Gly-(Arg)6-Gln-(Arg)3-NH2;

[0607] (SEQ ID NO: 295) Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Arg-Asp-P-Ala-Tyr-Gly-(Arg)6-Gln-(Arg)3- H2;

[0608] (SEQ ID NO: 296) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Arg-Asp-P-Ala- (Arg)6-Gln-(Arg)3-NH2;

[0609] (SEQ ID NO: 297) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-P-Ala- (Arg)5-Gln-(Arg)4-NH2;

[0610] (SEQ ID NO: 298) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Arg-Asp-P-Ala- (Arg)5-Gln-(Arg)4-NH2;

[0611] (SEQ ID NO: 299) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-P-Ala-Tyr-Gly-(Arg)s-Gln-(Arg)3-NH2;

[0612] (SEQ ID NO: 300) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Arg-Asp-P-Ala-Tyr- Gly-(Arg)s-Gln-(Arg)3-NH2;

[0613] (SEQ ID NO: 301) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-P-Ala-Tyr-Gly-(Arg)6-Gln-(Arg)3-NH2;

[0614] (SEQ ID NO: 302) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Arg-Asp-P-Ala-Tyr-Gly-(Arg)6-Gln-(Arg)3-NH2;

[0615] (SEQ ID NO: 303) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-P-Ala-Tyr- Gly-(Arg)?-Gln-(Arg)4-NH2;

[0616] (SEQ ID NO: 304) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Arg-Asp-P-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2;

[0617] (SEQ ID NO: 305) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-P-Ala-(Arg)5-Gln-(Arg)4-NH2;

[0618] (SEQ ID NO: 306) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Arg-Asp-P-Ala-(Arg)5-Gln-(Arg)4-NH2;

[0619] (SEQ ID NO: 307) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Arg-Asp-P-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;

[0620] (SEQ ID NO: 308) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-P-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 309) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Arg-Asp-P-Ala-Tyr- Gly-(Arg)5-Gln-(Arg)4-NH2;

[0621] (SEQ ID NO: 310) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-P-Ala-Tyr- Gly-(Arg)6-Gln-(Arg)3- H2;

[0622] (SEQ ID NO: 311) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Arg-Asp-P-Ala-Tyr- Gly-(Arg)6-Gln-(Arg)3-NH2;

[0623] (SEQ ID NO: 312) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(Doc)2-Tyr-Gly-Arg-(Lys)2-(Arg)2-Gln-(Arg)3-NH2;

[0624] (SEQ ID NO: 313) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-P-Ala-Tyr-Gly-Arg-(Lys)2-Arg-Gln-(Arg)4-NH2;

[0625] (SEQ ID NO: 314) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-Doc-Tyr-Gly-Arg-(Lys)2 -(Arg)2-Gln-(Arg)3-NH2;

[0626] (SEQ ID NO: 315) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-P-Ala-(Arg)5-Gln-(Arg)3- NH2;

[0627] (SEQ ID NO: 316) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-P-Ala-Gly-(Arg)5-Gln-(Arg)3-NH2;

[0628] (SEQ ID NO: 317) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-P-Ala-Tyr-Gly-(Arg)5-Gln- (Arg)3-NH2;

[0629] (SEQ ID NO: 318) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-P-Ala-Gly-(Arg)5-Gln- (Arg)4-NH2;

[0630] (SEQ ID NO: 319) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-P-Ala-Tyr-Gly-(Arg)2-Lys-(Arg)2-Gln-(Arg)3-NH2;

[0631] (SEQ ID NO: 320) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-P-Ala-Tyr-Gly-Arg-Lys- (Arg)3-Gln-(Arg)3-NH2;

[0632] (SEQ ID NO: 321) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-P-Ala-Gly-(Arg)2-Lys-(Arg)2-Gln-(Arg)3-NH2;

[0633] (SEQ ID NO: 322) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-P-Ala-Gly-Arg-Lys-(Arg)3-Gln-(Arg)3-NH2;

[0634] (SEQ ID NO: 323) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-P-Ala-(Arg)2-Lys-(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO: 324) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-P-Ala-Arg-Lys-(Arg)3 -Gln-(Arg)3-NH2;

[0635] (SEQ ID NO: 325) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(P-Ala)2-(Arg)5-Gln-(Arg)3-NH2;

[0636] (SEQ ID NO: 326) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(P-Ala)2-Gly-(Arg)s -Gln-(Arg)3-NH2;

[0637] (SEQ ID NO: 327) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(P-Ala)2-Tyr-Gly-(Arg)5 -Gln-(Arg)3-NH2;

[0638] (SEQ ID NO: 328) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-Doc-(Arg)5-Gln-(Arg)3 -NH2; (SEQ ID NO: 329) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-Doc-Gly-(Arg)5-Gln-(Arg)3-NH2;

[0639] (SEQ ID NO: 330) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-Doc-Tyr-Gly-(Arg)5 -Gln-(Arg)3-NH2;

[0640] (SEQ ID NO: 331) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(Doc)2-(Arg)5-Gln-(Arg)3-NH2;

[0641] (SEQ ID NO: 332) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(Doc)2-Gly-(Arg)s -Gln-(Arg)3-NH2;

[0642] (SEQ ID NO: 333) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(Doc)2-Tyr-Gly-(Arg)s -Gln-(Arg)3-NH2;

[0643] (SEQ ID NO: 334) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-P-Ala-(Arg)5-Gln-(Arg)4- NH2;

[0644] (SEQ ID NO: 335) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-P-Ala-Tyr-Gly-(Arg)s -Gln-(Arg)4 -NH2;

[0645] (SEQ ID NO: 336) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(P-Ala)2-(Arg)5-Gln-(Arg)4-NH2;

[0646] (SEQ ID NO: 337) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(P-Ala)2-Gly-(Arg)5-Gln-(Arg)4-NH2;

[0647] (SEQ ID NO: 338) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(P-Ala)2-Tyr-Gly-(Arg)s -Gln-(Arg)4-NH2;

[0648] (SEQ ID NO: 339) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-Doc-(Arg)s -Gln-(Arg)4 -NH2; (SEQ ID NO: 340) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-Doc-Gly-(Arg)5-Gln-(Arg)4- NEE;

[0649] (SEQ ID NO: 341) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-Doc-Tyr-Gly-(Arg)s-Gln-(Arg)4-NH2;

[0650] (SEQ ID NO: 342) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(Doc)2-(Arg)s-Gln-(Arg)4- NH2;

[0651] (SEQ ID NO: 343) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(Doc)2-Gly-(Arg)5-Gln- (Arg)4 -NEE;

[0652] (SEQ ID NO: 344) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(Doc)2-Tyr-Gly-(Arg)s -Gln- (Arg)4 -NH2;

[0653] (SEQ ID NO: 345) Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-P-Ala-Tyr-Gly- (Arg)s -Gln-(Arg)3-NH2;

[0654] (SEQ ID NO: 346) Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-P-Ala-(Arg)5 -Gln-(Arg)3 -NEE;

[0655] (SEQ ID NO: 347) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-P-Ala-Tyr-Gly-(Arg)5 -Gln- (Arg)s -NEE;

[0656] (SEQ ID NO: 348) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-P-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 349) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-P-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NEE;

[0657] (SEQ ID NO: 350) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-P-Ala-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 351) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-P-Ala-(Arg)5 -Gln-(Arg)3 -NEE; (SEQ ID NO: 352) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(P-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;

[0658] (SEQ ID NO: 353) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(P-Ala)2-Gly-(Arg); -Gln-(Arg)3 - NH2;

[0659] (SEQ ID NO: 354) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(P-Ala)2-(Arg)5 -Gln-(Arg)3 -NH2; (SEQ ID NO: 355) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)3 -NEE;

[0660] (SEQ ID NO: 356) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-Doc-Gly-(Arg)5 -Gln-(Arg)3 -NEE; (SEQ ID NO: 357) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-Doc-(Arg)s -Gln-(Arg)3 -NEE; (SEQ ID NO: 358) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)3- NEE;

[0661] (SEQ ID NO: 359) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(Doc)2 -Gly-(Arg)5-Gln-(Arg)3 -NEE;

[0662] (SEQ ID NO: 360) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(Doc) 2 -(Arg)s -Gln-(Arg)3 -NEE; (SEQ ID NO: 361) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-P-Ala-Tyr-Gly-(Arg)s -Gln-(Arg)4 -NH2;

[0663] (SEQ ID NO: 362) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-P-Ala-Gly-(Arg)5-Gln-(Arg)4 -NH2; (SEQ ID NO: 363) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-P-Ala-(Arg)5-Gln-(Arg)4-NH2;

[0664] (SEQ ID NO: 364) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(P-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2;

[0665] (SEQ ID NO: 365) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(P-Ala)2 -Gly-(Arg)5-Gln-(Arg)4-NEE;

[0666] (SEQ ID NO: 366) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(P-Ala)2-(Arg)s -Gln-(Arg)4 -NH2; (SEQ ID NO: 367) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-Doc-Tyr-Gly-(Arg)s -Gln-(Arg)4 -NEE;

[0667] (SEQ ID NO: 368) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-Doc-Gly-(Arg)5-Gln-(Arg)4 -NH2; (SEQ ID NO: 369) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-Doc-(Arg)s -Gln-(Arg)4-NH2;

[0668] (SEQ ID NO: 370) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)4-NEE;

[0669] (SEQ ID NO: 371) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(Doc)2-Gly-(Arg)s -Gln-(Arg)4 -NEE;

[0670] (SEQ ID NO: 372) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(Doc)2-(Arg)s -Gln-(Arg)4 -NEE; (SEQ ID NO: 373) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-P-Ala-Lys)-P-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NEE;

[0671] (SEQ ID NO: 374) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-P-Ala-Lys)-P-Ala-(Arg)s -Gln-(Arg)3 -NEE;

[0672] (SEQ ID NO: 375) Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Ahx-Cys)-P-Ala-Tyr-Gly-(Arg)5-Gln-(Ar )3 -NEE;

[0673] (SEQ ID NO: 376) Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Ahx-Cys)-P-Ala-(Arg)s -Gln-(Arg)3 -NEE; (SEQ ID NO: 377) D-Phe-c(Cys-His-D-Phe-Arg-Trp-p-Ala-D-Cys)-Thr-P-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3 - NEE;

[0674] (SEQ ID NO: 378) D-Phe-c(Cys-His-D-Phe-Arg-Trp-P-Ala-D-Cys)-Thr-P-Ala-(Arg)5-Gln-(Arg)3-NH2;

[0675] (SEQ ID NO: 379) Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-P-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)s -NEE;

[0676] (SEQ ID NO: 380) Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-P-Ala-(Arg)5 -Gln-(Arg)3 -NEE; (SEQ ID NO: 381) Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-P-Ala-Tyr-Gly- (Arg)s -Gln-(Arg) -NEE;

[0677] (SEQ ID NO: 382) Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-P-Ala-(Arg)5 -Gln-(Arg)3 -NH2;

[0678] (SEQ ID NO: 383) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-P-Ala-Tyr-Gly-(Arg)5 -Gln-(Arg)3-NH2;

[0679] (SEQ ID NO: 384) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-P-Ala-(Arg)5 -Gln-(Arg)3 -NH2;

[0680] (SEQ ID NO: 385) Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-P-Ala-Tyr-Gly-(Arg)5 -Gln-(Arg)3 -NH2;

[0681] (SEQ ID NO: 386) Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-P-Ala-(Arg)5 -Gln-(Arg)3 -NH2;

[0682] (SEQ ID NO: 387) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-P-Ala-Tyr-Gly-(Arg)s -Gln-(Arg)3- NH2;

[0683] (SEQ ID NO: 388) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-P-Ala-(Arg)5 -Gln-(Arg)3 -NH2;

[0684] (SEQ ID NO: 389) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-(P-Ala)2-Tyr-Gly-(Arg)s -Gln-(Arg)3 - NH2;

[0685] (SEQ ID NO: 390) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-(P-Ala)2-(Arg)5-Gln-(Arg)3-NH2;

[0686] (SEQ ID NO: 391) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;

[0687] (SEQ ID NO: 392) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-Doc-(Arg)5-Gln-(Arg)3 -NH2; (SEQ ID NO: 393) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-(Doc)2 -Tyr-Gly-(Arg)5 -Gln-(Arg)3-NH2;

[0688] (SEQ ID NO: 394) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-(Doc)2 -(Arg)s -Gln-(Arg)3 -NH2;

[0689] (SEQ ID NO: 395) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-P-Ala-Tyr-Gly-(Arg)5 -Gln-(Arg)4-NH2;

[0690] (SEQ ID NO: 396) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-P-Ala-(Arg)5 -Gln-(Arg)4 -NH2;

[0691] (SEQ ID NO: 397) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-(P-Ala)2-Tyr-Gly-(Arg)s -Gln-(Arg)4 - NH2;

[0692] (SEQ ID NO: 398) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-(P-Ala)2-(Arg)5-Gln-(Arg)4-NH2;

[0693] (SEQ ID NO: 399) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-Doc-Tyr-Gly-(Arg)5 -Gln-(Arg)4 -NH2;

[0694] (SEQ ID NO: 400) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-Doc-(Arg)5 -Gln-(Arg)4 -NH2;

[0695] (SEQ ID NO: 401) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-(Doc)2-Tyr-Gly-(Arg)s -Gln-(Arg)4-NH2;

[0696] (SEQ ID NO: 402) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-(Doc)2-(Arg)5-Gln-(Arg)4-NH2;

[0697] (SEQ ID NO: 403) Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-P-Ala-Tyr-Gly-(Arg)5 -Gln-(Arg)3-NH2;

[0698] (SEQ ID NO: 404) Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-P-Ala-(Arg)5-Gln-(Arg)3-NH2;

[0699] (SEQ ID NO: 405) Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-P-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;

[0700] (SEQ ID NO: 406) Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-P-Ala-(Arg)5-Gln-(Arg)3-NH2;

[0701] (SEQ ID NO: 407) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Apn-Cys)-P-Ala-Tyr-Gly-(Arg)5 -Gln-(Arg)3-NH2; (SEQ ID NO: 408) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Apn-Cys)-P-Ala-(Arg)5-Gln-(Arg)3- NH2;

[0702] (SEQ ID NO: 409) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Ahx-Cys)-P-Ala-Tyr-Gly-(Arg)5-Gln- (Arg)3-NH2;

[0703] (SEQ ID NO: 410) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Ahx-Cys)-P-Ala-(Arg)s -Gln-(Arg)3- NH2;

[0704] (SEQ ID NO: 411) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-P-Ala-Cys)-P-Ala-Tyr- Gly-(Arg)s -Gln-(Arg)3-NH2;

[0705] (SEQ ID NO: 412) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-P-Ala-Cys)-P-Ala-(Arg)5-Gln-(Arg)3- NH2;

[0706] (SEQ ID NO: 413) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-P-Ala-Tyr-Gly -(Arg)s -Gln-(Arg)3-NH2;

[0707] (SEQ ID NO: 414) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-P-Ala-Gly-(Arg)5-Gln-(Arg)3-NH2;

[0708] (SEQ ID NO: 415) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-P-Ala-(Arg)5-Gln-(Arg)3- NH2;

[0709] (SEQ ID NO: 416) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-(P-Ala)2-Tyr-Gly-(Arg)s-Gln-(Arg)3-NH2;

[0710] (SEQ ID NO: 417) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-(P-Ala)2-Gly-(Arg)s -Gln- (Arg)3-NH2;

[0711] (SEQ ID NO: 418) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-(P-Ala)2-(Arg)5-Gln-(Arg)3- NH2;

[0712] (SEQ ID NO: 419) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-Doc-Tyr-Gly-(Arg)5 -Gln-(Arg)3-NH2;

[0713] (SEQ ID NO: 420) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-Doc-Gly-(Arg)5-Gln-(Arg)3- NH2;

[0714] (SEQ ID NO: 421) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-Doc-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 422) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;

[0715] (SEQ ID NO: 423) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-(Doc)2-Gly-(Arg)5-Gln- (Arg)3-NH2; (SEQ ID NO: 424) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-(Doc)2-(Arg)5-Gln-(Arg)3- NH2;

[0716] (SEQ ID NO: 425) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-P-Ala-D-Cys)-P-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;

[0717] (SEQ ID NO: 426) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-P-Ala-D-Cys)-P-Ala-(Arg)5 -Gln- (Arg)3-NH2;

[0718] (SEQ ID NO: 427) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-P-Ala-D-Cys)-P-Ala-Gly-(Arg)s -Gln- (Arg)3-NH2;

[0719] (SEQ ID NO: 428) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-p-Ala-D-Cys)-p-Ala-(Arg)5-Gln- (Arg)4-NH2;

[0720] (SEQ ID NO: 429) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-P-Ala-D-Cys)-(P-Ala)2-Tyr-Gly-(Arg)s -Gln-(Arg)3-NH2;

[0721] (SEQ ID NO: 430) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-P-Ala-D-Cys)-(P-Ala)2-(Arg)5 -Gln-(Arg)3-NH2;

[0722] (SEQ ID NO: 431) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-P-Ala-D-Cys)-(P-Ala)2-Gly-(Arg)5-Gln-(Arg)3-NH2;

[0723] (SEQ ID NO: 432) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-P-Ala-D-Cys)-(P-Ala)2-(Arg)5-Gln- (Arg)4-NH2;

[0724] (SEQ ID NO: 433) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-P-Ala-D-Cys)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;

[0725] (SEQ ID NO: 434) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-P-Ala-D-Cys)-Doc-(Arg)5-Gln-(Arg)3- NH2;

[0726] (SEQ ID NO: 435) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-p-Ala-D-Cys)-Doc-Gly-(Arg)5-Gln-(Arg)3-NH2;

[0727] (SEQ ID NO: 436) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-P-Ala-D-Cys)-Doc-(Arg)5-Gln-(Arg)4- NH2;

[0728] (SEQ ID NO: 437) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-P-Ala-D-Cys)-(Doc)2-Tyr-Gly-(Arg)s -Gln-(Arg)3-NH2;

[0729] (SEQ ID NO: 438) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-P-Ala-D-Cys)-(Doc)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 439) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-p-Ala-D-Cys)-(Doc)2-Gly-(Arg)5-Gln-(Arg)3-NH2;

[0730] (SEQ ID NO: 440) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-P-Ala-D-Cys)-(Doc)2-(Arg)5-Gln- (Arg)4-NH2;

[0731] (SEQ ID NO: 441) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-P-Ala-D-Cys)-Thr-P- Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;

[0732] (SEQ ID NO: 442) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-P-Ala-D-Cys)-Thr-P-Ala-(Arg)5-Gln-(Arg)3-NH2;

[0733] (SEQ ID NO: 443) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-P-Ala-D-Cys)-Thr-(P-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;

[0734] (SEQ ID NO: 444) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-P-Ala-D-Cys)-Thr-(P-Ala)2-(Arg)5-Gln-(Arg)3-NH2;

[0735] (SEQ ID NO: 445) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-P-Ala-D-Cys)-Thr-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;

[0736] (SEQ ID NO: 446) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-P-Ala-D-Cys)-Thr-Doc-(Arg)s -Gln-(Arg)3-NH2;

[0737] (SEQ ID NO: 447) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-p-Ala-D-Cys)-Thr-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;

[0738] (SEQ ID NO: 448) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-P-Ala-D-Cys)-Thr-P- Ala-Tyr-Gly-(Arg)s-Gln-(Arg)4-NH2;

[0739] (SEQ ID NO: 449) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-P-Ala-D-Cys)-Thr-P-Ala-(Arg)5-Gln-(Arg)4-NH2;

[0740] (SEQ ID NO: 450) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-P-Ala-D-Cys)-Thr-(P-Ala)2-Tyr-Gly-(Arg)s-Gln-(Arg)4-NH2;

[0741] (SEQ ID NO: 451) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-P-Ala-D-Cys)-Thr-(P-Ala)2-(Arg)s-Gln-(Arg)4-NH2;

[0742] (SEQ ID NO: 452) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-P-Ala-D-Cys)-Thr-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2;

[0743] (SEQ ID NO: 453) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-P-Ala-D-Cys)-Thr-Doc-(Arg)s-Gln-(Arg)4-NH2; (SEQ ID NO: 454) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-P-Ala-D-Cys)-Thr-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2;

[0744] (SEQ ID NO: 455) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-P-Ala-D-Cys)-Thr-(Doc)2-(Arg)5-Gln-(Arg)4-NH2;

[0745] (SEQ ID NO: 456) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-P-Ala-D-Cys)-Thr-P-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;

[0746] (SEQ ID NO: 457) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-P-Ala-D-Cys)-Thr-P-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2;

[0747] (SEQ ID NO: 458) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-P-Ala-D-Cys)-Thr-P-Ala-(Arg)5-Gln-(Arg)3-NH2;

[0748] (SEQ ID NO: 459) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-P-Ala-D-Cys)-Thr-(P-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;

[0749] (SEQ ID NO: 460) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-P-Ala-D-Cys)-Thr-(P-Ala)2-(Arg)5-Gln-(Arg)3-NH2;

[0750] (SEQ ID NO: 461) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-P-Ala-D-Cys)-Thr-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;

[0751] (SEQ ID NO: 462) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-p-Ala-D-Cys)-Thr-Doc-Tyr-Gly- (Arg)5-Gln-(Arg)4-NH2;

[0752] (SEQ ID NO: 463) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-P-Ala-D-Cys)-Thr-Doc-(Arg)5-Gln-(Arg)3-NH2;

[0753] (SEQ ID NO: 464) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-P-Ala-D-Cys)-Thr-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;

[0754] (SEQ ID NO: 465) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-P-Ala-D-Cys)-Thr-(Doc)2-(Arg)5-Gln-(Arg)3-NH2;

[0755] (SEQ ID NO: 466) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gly-Cys)-P-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;

[0756] (SEQ ID NO: 467) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gly-Cys)-P-Ala-(Arg)5-Gln-(Arg)3-NH2;

[0757] (SEQ ID NO: 468) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-P-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;

[0758] (SEQ ID NO: 469) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-P-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 470) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-(P-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;

[0759] (SEQ ID NO: 471) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-(P-Ala)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 472) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-P-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)4- NH2;

[0760] (SEQ ID NO: 473) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)- -Ala-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 474) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-(P-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2;

[0761] (SEQ ID NO: 475) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-(P-Ala)2-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 476) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;

[0762] (SEQ ID NO: 477) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-Doc-(Arg)5-Gln-(Arg)3-NH2;

[0763] (SEQ ID NO: 478) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;

[0764] (SEQ ID NO: 479) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-(Doc)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 480) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2;

[0765] (SEQ ID NO: 481) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-Doc-(Arg)5-Gln-(Arg)4-NH2;

[0766] (SEQ ID NO: 482) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-(Doc)2-Tyr-Gly-(Arg)s-Gln-(Arg)4-NH2;

[0767] (SEQ ID NO: 483) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-(Doc)2-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 484) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-P-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;

[0768] (SEQ ID NO: 485) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-P-Ala-(Arg)5-Gln-(Arg)3-NH2;

[0769] (SEQ ID NO: 486) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-(P-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;

[0770] (SEQ ID NO: 487) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-(P-Ala)2-(Arg)5-Gln-(Arg)3- NH2;

[0771] (SEQ ID NO: 488) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 489) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-Doc-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 490) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;

[0772] (SEQ ID NO: 491) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-(Doc)2-(Arg)5-Gln-(Arg)3- NH2;

[0773] (SEQ ID NO: 492) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-P-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2;

[0774] (SEQ ID NO: 493) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-P-Ala-(Arg)5-Gln-(Arg)4- NH2;

[0775] (SEQ ID NO: 494) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-(P-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2;

[0776] (SEQ ID NO: 495) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-(P-Ala)2-(Arg)5-Gln-(Arg)4- NH2;

[0777] (SEQ ID NO: 496) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-Doc-Tyr-Gly-(Arg)s-Gln-(Arg)4-NH2;

[0778] (SEQ ID NO: 497) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-Doc-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 498) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-(Doc)2-Tyr-Gly-(Arg)5-Gln- (Arg)4- NH2;

[0779] (SEQ ID NO: 499) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-(Doc)2-(Arg)5-Gln-(Arg)4- NH2;

[0780] (SEQ ID NO: 500) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-P-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;

[0781] (SEQ ID NO: 501) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-P-Ala-(Arg)5-Gln-(Arg)3- NH2;

[0782] (SEQ ID NO: 502) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-(P-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;

[0783] (SEQ ID NO: 503) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-(P-Ala)2-(Arg)5-Gln-(Arg)3-NH2;

[0784] (SEQ ID NO: 504) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;

[0785] (SEQ ID NO: 505) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-Doc-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 506) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;

[0786] (SEQ ID NO: 507) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-(Doc)2-(Arg)5-Gln-(Arg)3- NH2;

[0787] (SEQ ID NO: 508) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-P-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2;

[0788] (SEQ ID NO: 509) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-P-Ala-(Arg)5-Gln-(Arg)4-NH2;

[0789] (SEQ ID NO: 510) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-(P-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2;

[0790] (SEQ ID NO: 511) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-(P-Ala)2-(Arg)5-Gln-(Arg)4-NH2;

[0791] (SEQ ID NO: 512) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2;

[0792] (SEQ ID NO: 513) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-Doc-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 514) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2;

[0793] (SEQ ID NO: 515) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-(Doc)2-(Arg)5-Gln-(Arg)4-NH2;

[0794] (SEQ ID NO: 516) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-P-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;

[0795] (SEQ ID NO: 517) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-P-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 518) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-(P-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;

[0796] (SEQ ID NO: 519) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-(P-Ala)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 520) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-P-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2;

[0797] (SEQ ID NO: 521) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-P-Ala-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 522) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-(P-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2;

[0798] (SEQ ID NO: 523) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-(P-Ala)2-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 524) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;

[0799] (SEQ ID NO: 525) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-Doc-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 526) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;

[0800] (SEQ ID NO: 527) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-(Doc)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 528) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2;

[0801] (SEQ ID NO: 529) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-Doc-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 530) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2; and

[0802] (SEQ ID NO: 531) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-(Doc)2-(Arg)5-Gln-(Arg)4-NH2, or pharmaceutically acceptable salts thereof.

[0803] In some embodiments, a compound of Formula (V) is disclosed in International Application Publication Number WO 2007 / 008684, which is incorporated herein by reference in its entirety.

[0804] In some embodiments, the MC4R agonist is a compound of Formula (VI):

[0805] Ac-c(Cys-Glu-His-A1-Arg-A2-A3-Cys)-(Pro)2-Lys-Asp-NH2 (VI) or pharmaceutically acceptable salts thereof, wherein: A1is the D-isomer of X-Phe or 2-Nal where X is halogen; A2is Bal, 1-Nal, 2-Nal, or Trp; and A3is Aib, Ala, 0-Ala or Gly.

[0806] In some embodiments, the compound of Formula (VI) is selected from:

[0807] (SEQ ID NO: 532) Ac-c(Cys-Glu-His-D-4-Br-Phe-Arg-Trp-Gly-Cys)-(Pro)2-Lys-Asp-NH2; (SEQ ID NO: 533) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-NH2;

[0808] (SEQ ID NO: 534) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-NH2; (SEQ ID NO: 535) Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Lys-Asp-NH2; (SEQ ID NO: 536) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-NH2;

[0809] (SEQ ID NO: 537) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-P-Ala-Cys)-(Pro)2-Lys-Asp-NH2; and (SEQ ID NO: 538) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Aib-Cys)-(Pro)2-Lys-Asp-NH2, or pharmaceutically acceptable salts thereof.

[0810] In an example embodiment, the MC4R agonist is a compound of Formula (VII):

[0811]

[0812] pharmaceutically acceptable salt thereof wherein: X is selected from the group consisting of -CH2-S-S-CH2-, -C(CH3)2-S-S-CH2-,-CH2-S-S-C(CH3)2-, -C(CH3)2-S-S-C(CH3).--, -(CH2)2-S-S-CH2-, -CH2-S-S-(CH2)2, -(CH2)2-S-S-(CH2)2-, -C(CH3)2-S-S-(CH2)2-, -(CH2)2-S-S-C(CH3)2-, -(CH2)t-C(O)-NR8-(CH2)r- and -(CH2)r-NR8-C(O)-(CH2)t-; each of R1and R3is, independently, H, (Ci-Cio)alkyl or substituted (Ci-Cio)alkyl; each ofR2andR3is, independently, H, (Ci-Cio)alkyl, (Ci-Cio)heteroalkyl, aryl(Ci-Cs)alkyl, substituted (Ci-Cio)alkyl, substituted (Ci-Cio)heteroalkyl or substituted aryl(Ci-Cs)alkyl or R2and R3may be fused together to form a ring; R4is OH or NH2; each of R6and R7is, independently, H, (Ci-Cio)alkyl or substituted (Ci-Cio)alkyl; A1is an L- or D-amino acid or deleted; A2is H is, 2-Pal, 3-P X1, X2, X3, X4, X5)Phe, Taz, 2-Thi or 3-Thi; A3is D-Bal, D-1-Nal, D-2-Nal, D-Phe or X3, X4, X5)Phe; A4is Arg, hArg, Dab, Dap, Lys or Om; A5is Bal, 1-Nal, 2-Nal, (X1,

[0813]

[0814] X5)Phe or Trp; r is, independently for each occurrence thereof, 1, 2, 3, 4 or 5; and t is, independently for each occurrence thereof, 1 or 2; or pharmaceutically acceptable salts thereof.

[0815] In some embodiments of the compounds of Formula (VII), A1is Ala, D-Ala, Asn, Asp, Gin, Glu or Gly.

[0816] Example compounds according to Formula (VII) include:

[0817] (SEQ ID NO: 539) c[Hydantoin(C(O)-(Nle-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH2;

[0818] (SEQ ID NO: 540) c[Hydantoin(C(O)-(Ala-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH2;

[0819] (SEQ ID NO: 541) c[Hydantoin(C(O)-(D-Ala-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH2; (SEQ ID NO: 542) c[Hydantoin(C(O)-(Aib-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH2;

[0820] (SEQ ID NO: 543) c[Hydantoin(C(O)-(Val-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH2;

[0821] (SEQ ID NO: 544) c[Hydantoin(C(O)-(Abu-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH2;

[0822] (SEQ ID NO: 545) c[Hydantoin(C(O)-(Leu-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH2;

[0823] (SEQ ID NO: 546) c[Hydantoin(C(O)-(Ile-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH2;

[0824] (SEQ ID NO: 547) c[Hydantoin(C(O)-(Cha-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH2;

[0825] (SEQ ID NO: 548) c[Hydantoin(C(O)-(A6c-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH2;

[0826] (SEQ ID NO: 549) c[Hydantoin(C(O)-(Phe-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH2; (SEQ ID NO: 550) c[Hydantoin(C(O)-(Gly-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH2; and (SEQ ID NO: 551) c[Hydantoin(C(O)-(Gly-Cys))-Glu-His-D-Phe-Arg-Trp-Cys]-NH2, or pharmaceutically acceptable salts thereof.

[0827] In some embodiments, a compound of Formula (VII) is disclosed in International Application Publication Number WO2008 / 147556, which is incorporated herein by reference in its entirety.

[0828] In some embodiments, the MC4R agonist is a compound of Formula (VIII):

[0829] (R2R3)-A°-A1-C(A2-A3-A4-A5-A6-A7-A8-A9)-A10-R1(VIII)

[0830] or a pharmaceutically acceptable salt thereof wherein: A° is an aromatic amino acid; A1is Acc, HN-(CH2)m-C(O), an L- or D-amino acid; A2is Asp, Cys, D-Cys, hCys, D-h Pen; A3is Aib, Ala, -Ala, Gaba, Gly or a D-amino acid; A4is H is, 2-Pal, 3- X3, X4, X5)Phe, Taz, 2-Thi, or 3-Thi; A5is D-Bal, D-1-Nal, D-2-Nal, D-Phe,

[0831]

[0832] X3, X4, X5)Phe, L-Phe, D-Trp or D-(Et)Tyr; A6is Arg, hArg, Dab, Dap, Lys, Orn, or HN-CH((CH2)«-N(R4R5))-C(O); A7is Bal, D-Bal, Bip, D-Bip, 1-Nal, D-1-Nal, 2-Nal, D-2-Nal, or D-Trp; A8is Acc, Aha, Ahx, Ala, D-Ala, 0-Ala, Apn, Gaba, Cys, D-Cys, hCys, D-hCys, Dab, Dap, Lys, Orn, Pen, or

[0833]

[0834] or D-amino acid, or deleted; R1is OH, or NH2; each of R2and R3is, independently for each occurrence selected from the group consisting of H, (Ci-C3o)alkyl, (Ci-C3o)heteroalkyl, (Ci-C3o)acyl, (C2-C3o)alkenyl, (C2-C3o)alkynyl, aryl(Ci-C3o)alkyl, aryl(Ci-C3o)acyl, substituted (Ci-C3o)alkyl, substituted (Ci-C3o)heteroalkyl, substituted (Ci-C3o)acyl, substituted (C2-C3o)alkenyl, substituted (C2-C3o)alkynyl, substituted aryl(Ci-C3o)alkyl, and substituted aryl(Ci-C3o)acyl; each of R4and R5is, independently for each occurrence, H, (Ci-C4o)alkyl, (Ci-C4o)heteroalkyl, (Ci-C4o)acyl, (C2-C4o)alkenyl, (C2-C4o)alkynyl, aryl(Ci-C4o)alkyl, aryl(Ci-C4o)acyl, substituted (Ci-C4o)alkyl, substituted (Ci-C4o)heteroalkyl, substituted (Ci-C4o)acyl, substituted (C2-C4o)alkenyl, substituted (C2-C4o)alkynyl, substituted aryl(Ci-C4o)allyl, substituted aryl(Ci-C4o)acyl, (Ci-C4o)alkylsulfonyl, or -C(NH)-NH2; m is, independently for each occurrence, 1, 2, 3, 4, 5, 6 or 7; n is, independently for each occurrence, 1, 2, 3, 4 or 5; s is, independently for each occurrence, 1, 2, 3, 4, 5, 6, or 7; t is, independently for each occurrence, 1, 2, 3, 4, 5, 6, or 7; X1, X2, X3, X4, and X5each is, independently for each occurrence, H, F, Cl, Br, I, (Ci-Cio)alkyl, substituted (Ci-Cio)alkyl, (C2-Cio)alkenyl, substituted (C2-Cio)alkenyl, (C2-Cio)alkynyl, substituted (C2-Cio)alkynyl, aryl, substituted aryl, OH, NH2, NO2, or CN. In an embodiment of Formula (VIII), when R4is (Ci-C4o)acyl, aryl(Ci-C4o)acyl, substituted (Ci-C4o)acyl, substituted aryl(Ci-C4o)acyl, (Ci-C4o)alkyl sulfonyl, or -C(NH)-NH2, then R5is H or (Ci-C4o)alkyl, (Ci-C4o)heteroalkyl, (C2-C4o)alkenyl, (C2-C4o)alkynyl, aryl(Ci-C4o)alkyl, substituted (Ci-C4o)alkyl, substituted (Ci-C4o)heteroalkyl, substituted (C2-C4o)alkenyl, substituted (C2-C4o)alkynyl, or substituted aryl(Ci-C4o)alkyl.

[0835] In an embodiment of Formula (VIII), when R2is (Ci-C3o)acyl, aryl(Ci-C3o)acyl, substituted (Ci-C3o)acyl, or substituted aryl(Ci-C3o)acyl, then R3is H, (Ci-C3o)alkyl, (Ci-C3o)heteroalkyl, (C2-C3o)alkenyl, (C2-C3o)alkynyl, aryl(Ci-C3o)alkyl, substituted (Ci-C3o)alkyl, substituted (Ci-C3o)heteroalkyl, substituted (C2-C3o)alkenyl, substituted (C2-C3o)alkynyl, or substituted aryl(Ci-C3o)alkyl.

[0836] In an embodiment of Formula (VIII), when A2is Cys, D-Cys, hCys, D-hCys, Pen, or D-Pen, then A9is Cys, D-Cys, hCys, D-hCys, Pen, or D-Pen.

[0837] In an embodiment of Formula (VIII), when A2is Asp or Glu, then A9is Dab, Dap, Orn, or Lys.

[0838] In an embodiment of Formula (VIII), when A8is Ala or Gly, then A1is not Nle; or pharmaceutically acceptable salts thereof.

[0839] In some embodiments of Formula (VIII), A0is 1-Nal, 2-Nal, H is, Pff, Phe, Trp, or Tyr; A1is Arg; A2is Cys; A3is D-Ala; A4is H; A5is D-Phe; A6is Arg; A7is Trp; A8is deleted; A9is Cys; and A10is deleted; or pharmaceutically acceptable salts thereof.

[0840] Particular compounds of the immediately foregoing group of Formula (VIII) compounds include:

[0841] (SEQ ID NO: 552) Ac-Tyr-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2;

[0842] (SEQ ID NO: 553) Ac-2-Nal-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2;

[0843] (SEQ ID NO: 554) Ac-l-Nal-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2;

[0844] (SEQ ID NO: 555) Ac-Phe-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2;

[0845] (SEQ ID NO: 556) Ac-Trp-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2;

[0846] (SEQ ID NO: 557) Ac-Pff-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2;

[0847] (SEQ ID NO: 558) H-His-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; and

[0848] (SEQ ID NO: 559) Ac-His-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2,

[0849] or a pharmaceutically acceptable salt thereof. In some embodiments, the MC4R agonist is an agonist described in WO2014 / 144260 Al, incorporated herein by reference.

[0850] In one example embodiment, an MC4R agonist is a compound represented by Formula (IX):

[0851] R1- A1- A2- A3- A4- A5- A6- A7- A8- R2or a pharmaceutically acceptable salt thereof, wherein: R1is H, or a (Ci-Ce)acyl; R2is, -NR3R4, or -OR5wherein R3, R4, and R5are each independently is H or a (Ci-Cfi)alkyl; A1is an amino acid residue selected from Arg, Lys, Orn, His, Nle, Phe, Vai, Leu, Trp, Tyr, Ala, Ser, Thr, Gin, Asn, Asp, Glu, or TzAla; or A1is a moiety selected from an optionally substituted -(C1-C12)-alkyl, an optionally substituted -(Ce-Ci8)-aryl, an optionally substituted -(C5-Cis)-heteroaryl, an aralkyl wherein the aryl portion is an optionally substituted (C6-Cis)aryl, and the alkyl portion is an optionally substituted (Ci-Ci2)alkyl, or a heteroaralkyl, wherein the heteroaryl portion is an optionally substituted (Cs-Ci8)heteroaryl, and the alkyl portion is an optionally substituted (Ci-Ci2)alkyl; A2and A8is each independently an amino acid residue selected from Cys, hCys, Pen, Asp, Glu, Lys, Orn, Dbu, or Dpr, wherein A2and A8are pairwise selected so as to be able to form covalent bond between their respective side chains; A3is absent or is an amino acid residue selected from Ala, Tie, Vai, Leu, He, Cha, Pro, Ser, Thr, Lys, Arg, His, Phe, Gin, Sar, Gly, Asn, Aib, or residue Y, wherein Y is an amino acid selected from amino acids represented by the following structural formulas

[0852]

[0853] wherein: R11and R12, each independently, is H, -CH3, phenyl, or benzyl; R21, R22, R23, and R24, each independently is H, -CH3, -CF3, phenyl, benzyl, F, Cl, Br, I, -OCH3, or -OH; R31, R32, R33, R34, R41, R42, and R43, each independently is H, -CH3, -CF3, phenyl, benzyl, F, Cl, Br, I, -OCH3, or -OH; A4is absent or is an amino acid residue selected from Ate, Ala, QAla, Aib, Sar, Ser, Thr, Pro, Hyp, Asn, Gin, an optionally substituted His, Trp, Tyr, Lys, Arg, sChp, or residue X, where the X is an amino acid selected from amino acids represented by the following formulas:

[0854]

[0855] wherein: R51and R52, each independently, is H, -CH3, phenyl, or benzyl; R61, R62, R63, and R64, each independently is H, -CH3, -CF3, phenyl, benzyl, F, Cl, Br, I, -OCH3, or -OH; R71, R72, R73, R74, R81, R82, and R83, each independently is H, -CH3, -CF3, phenyl, benzyl, F, Cl, Br, I, -OCH3, or -OH; A5is an optionally substituted Phe, an optionally substituted 1-Nal, or an optionally substituted 2-Nal; A6is Arg; and A7is Trp, wherein any amino acid residue is either in L- or in D-configuration.

[0856] Exemplary compound of Formula (IX) include:

[0857] (SEQ ID NO: 560) Ac-Arg-c(Cys-D-Ala-His-D-Phe(p-F)-Arg-Trp-Cys)-NH2;

[0858] (SEQ ID NO: 561) Ac-Arg-c(Cys-D-Ala-Pro-D-Phe-Arg-Trp-Cys)-NH2;

[0859] (SEQ ID NO: 562) Ac-Arg-c(Cys-D-Ala-Pro-D-Phe(p-F)-Arg-Trp-Cys)-NH2;

[0860] (SEQ ID NO: 563) Ac-Arg-c(Cys-D-Ala-Pro-D-Phe(p-F)-Arg-Trp-Cys)-NH2;

[0861] (SEQ ID NO: 564) Ac-Arg-c(Cys-D-Ala-Ser-D-Phe(p-F)-Arg-Trp-Cys)-NH2;

[0862] (SEQ ID NO: 565) Ac-Arg-c(Cys-D-Ala-Thr-D-Phe(p-CN)-Arg-Trp-Cys)-NH2;

[0863] (SEQ ID NO: 566) Ac-Arg-c(Cys-D-Ala-Asn-D-Phe-Arg-Trp-Cys)-NH2;

[0864] (SEQ ID NO: 567) Ac-Arg-c(Cys-D-Ala-Gln-D-Phe-Arg-Trp-Cys)-NH2;

[0865] (SEQ ID NO: 568) Ac-Arg-c(Cys-D-Ala-Trp-D-Phe-Arg-Trp-Cys)-NH2;

[0866] (SEQ ID NO: 569) Ac-Arg-c(Cys-D-Val-His-D-Phe-Arg-Trp-Cys)-NH2;

[0867] (SEQ ID NO: 570) Ac-Arg-c(Cys-D-Val-Gln-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 571) Ac-Arg-c(Cys-D-Val-Pro-D-Phe-Arg-Trp-Cys)-NH2; and

[0868] (SEQ ID NO: 572) Ac-Arg-c(Cys-D-Ser-Pro-D-Phe-Arg-Trp-Cys)-NH2,

[0869] or a pharmaceutically acceptable salt thereof.

[0870] In yet another embodiment, the polypeptides of the present invention include any one of the following structural formulas:

[0871] (SEQ ID NO: 573) Ac-Arg-c(hCys-D-Ala-D-Phe-Arg-Trp-Cys)-NH2;

[0872] (SEQ ID NO: 574) Ac-Arg-c(hCys-Ala-D-Phe-Arg-Trp-Cys)-NH2;

[0873] (SEQ ID NO: 575) Ac-Arg-c(hCys-Ala-D-Phe-Arg-Trp-Cys)-OH;

[0874] (SEQ ID NO: 576) Ac-Arg-c(Cys-D-Ala-D-Phe-Arg-Trp-hCys)-NH2;

[0875] (SEQ ID NO: 577) Ac-Arg-c(Pen-D-Ala-D-Phe-Arg-Trp-hCys)-NH2;

[0876] (SEQ ID NO: 578) Ac-Arg-c(hCys-D-Ala-D-Phe(p-F)-Arg-Trp-Cys)-NH2;

[0877] (SEQ ID NO: 579) Ac-Arg-c(hCys-Pro-D-Phe-Arg-Trp-Cys)-NH2;

[0878] (SEQ ID NO: 580) Ac-Nle-c(hCys-Pro-D-Phe-Arg-Trp-Cys)-NH2;

[0879] (SEQ ID NO: 581) Arg-c(hCys-Pro-D-Phe-Arg-Trp-Cys)-NH2;

[0880] (SEQ ID NO: 582) CH3-(CH2)4-CO-c(hCys-Pro-D-Phe-Arg-Trp-Cys)-NH2; and

[0881] (SEQ ID NO: 583) Benzyl-CO-c(hCys-Pro-D-Phe-Arg-Trp-Cys)-NH2,

[0882] or a pharmaceutically acceptable salt thereof.

[0883] In a further embodiment, the polypeptides of the present invention include the polypeptide represented by any one of the following structural formulas:

[0884] (SEQ ID NO: 584) Ac-Arg-c(Asp-D-Ala-D-Phe-Arg-Trp-Dbu)-NH2;

[0885] (SEQ ID NO: 585) Ac-Arg-c(Glu-D-Ala-D-Phe-Arg-Trp-Dpr)-NH2;

[0886] (SEQ ID NO: 586) Ac-Arg-c(Glu-Ala-D-Phe-Arg-Trp-Dpr)-NH2;

[0887] (SEQ ID NO: 587) Ac-Arg-c(Dpr-D-Ala-D-Phe-Arg-Trp-Glu)-NH2;

[0888] (SEQ ID NO: 588) Ac-Arg-c(Dpr-D-Ala-D-Phe(4-F)-Arg-Trp-Glu)-NH2;

[0889] (SEQ ID NO: 589) Ac-Arg-c(Dpr-Ala-D-Phe-Arg-Trp-Glu)-NH2;

[0890] (SEQ ID NO: 590) Ac-Arg-c(Dpr-Ala-D-Phe-Arg-Trp-Glu)-OH;

[0891] (SEQ ID NO: 591) Ac-Nle-c(Dpr-Ala-D-Phe-Arg-Trp-Glu)-NH2;

[0892] (SEQ ID NO: 592) Arg-c(Dpr-Ala-D-Phe-Arg-Trp-Glu)-NH2;

[0893] (SEQ ID NO: 593) CH3-(CH2)4-CO-c(Dpr-Ala-D-Phe-Arg-Trp-Glu)-NH2; or

[0894] (SEQ ID NO: 594) Benzyl-CO-c(Dpr-Ala-D-Phe-Arg-Trp-Glu)-NH2, or a pharmaceutically acceptable salt thereof.

[0895] In yet another embodiment, the polypeptides of the present invention include a polypeptide represented by Formula (IX), wherein A4is an amino acid residue selected from Ate, Ala, QAla, Aib, Sar, Ser, Thr, Pro, Hyp, Asn, Gin, a substituted His, Trp, Tyr, Lys, Arg, sChp, or residue X. Examples of such peptides include peptides represented by any one of the following structural formulas:

[0896] (SEQ ID NO: 595) Ac-Arg-c(Cys-D-Ala-His(3-Me)-D-Phe-Arg-Trp-Cys)-NH2;

[0897] (SEQ ID NO: 596) Ac-Arg-c(Cys-D-Ala-His(l-Me)-D-Phe-Arg-Trp-Cys)-NH2;

[0898] (SEQ ID NO: 568) Ac-Arg-c(Cys-D-Ala-Trp-D-Phe-Arg-Trp-Cys)-NH2;

[0899] (SEQ ID NO: 567) Ac-Arg-c(Cys-D-Ala-Gln-D-Phe-Arg-Trp-Cys)-NH2;

[0900] (SEQ ID NO: 566) Ac-Arg-c(Cys-D-Ala-Asn-D-Phe-Arg-Trp-Cys)-NH2;

[0901] (SEQ ID NO: 597) Ac-Arg-c(Cys-D-Ala-Arg-D-Phe-Arg-Trp-Cys)-NH2;

[0902] (SEQ ID NO: 598) Ac-Arg-c(Cys-D-Ala-Tyr-D-Phe-Arg-Trp-Cys)-NH2;

[0903] (SEQ ID NO: 599) Ac- Arg- c(Cys-D-Ala-D-Pro-D-Phe-Arg-Trp-Cys)-NH2;

[0904] (SEQ ID NO: 561) Ac-Arg-c(Cys-D-Ala-Pro-D-Phe-Arg-Trp-Cys)-NH2;

[0905] (SEQ ID NO: 563) Ac-Arg-c(Cys-D-Ala-Pro-D-Phe(p-F)-Arg-Trp-Cys)-NH2;

[0906] (SEQ ID NO: 600) Ac- Arg- c(Cys-D-Ala-Atc-D-Phe-Arg-Trp-Cys)-NH2;

[0907] (SEQ ID NO: 601) Ac-Arg- c(Cys-D-Ala-QAla-D-Phe-Arg-Trp-Cys)-NH2;

[0908] (SEQ ID NO: 602) Ac-Arg- c(Cys-D-Ala-sChp-D-Phe-Arg-Trp-Cys)-NH2; or

[0909] (SEQ ID NO: 603) Ac-Arg- c(Cys-D-Ala-X-D-Phe-Arg-Trp-Cys)-NH2,

[0910] or a pharmaceutically acceptable salt thereof.

[0911] In example embodiments, the polypeptides of the present invention include a polypeptide represented by any one of the following structural formulas:

[0912] (SEQ ID NO: 574) Ac-Arg-c(hCys-Ala-D-Phe-Arg-Trp-Cys)-NH2;

[0913] (SEQ ID NO: 573) Ac-Arg-c(hCys-D-Ala-D-Phe-Arg-Trp-Cys)-NH2;

[0914] (SEQ ID NO: 604) Ac-Arg-c(hCys-D-Ala-D-Phe-Arg-Trp-Pen)-NH2;

[0915] (SEQ ID NO: 585) Ac-Arg-c(Glu-D-Ala-D-Phe-Arg-Trp-Dpr)-NH2;

[0916] (SEQ ID NO: 586) Ac-Arg-c(Glu-Ala-D-Phe-Arg-Trp-Dpr)-NH2;

[0917] (SEQ ID NO: 605) Ac-Arg-c(hCys-Aib-D-Phe-Arg-Trp-Cys)-NH2;

[0918] (SEQ ID NO: 606) Ac-Arg-c(hCys-Sar-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 607) Ac-Arg-c(hCys-Val-D-Phe-Arg-Trp-Cys)-NH2;

[0919] (SEQ ID NO: 608) Ac-Arg-c(hCys-D-Val-D-Phe-Arg-Trp-Cys)-NH2;

[0920] (SEQ ID NO: 609) Ac-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Cys)-NH2;

[0921] (SEQ ID NO: 610) Ac-Arg-c(hCys-D-Gln-D-Phe-Arg-Trp-Cys)-NH2;

[0922] (SEQ ID NO: 611) Ac-Arg-c(hCys-Ala-D-Phe-Arg-Trp-Pen)-NH2;

[0923] (SEQ ID NO: 612) Ac-Arg-c(D-Pen-D-Ala-D-Phe-Arg-Trp-hCys)-NH2;

[0924] (SEQ ID NO: 576) Ac-Arg-c(Cys-D-Ala-D-Phe-Arg-Trp-hCys)-NH2;

[0925] (SEQ ID NO: 613) Ac-Arg-c(Pen-D-Ala-D-Phe-Arg-Trp-hCys)-NH2;

[0926] (SEQ ID NO: 614) Ac-Arg-c(D-hCys-D-Ala-D-Phe-Arg-Trp-Cys)-NH2;

[0927] (SEQ ID NO: 579) Ac-Arg-c(hCys-Pro-D-Phe-Arg-Trp-Cys)-NH2; or

[0928] (SEQ ID NO: 615) Ac-Arg-c(hCys-D-Pro-D-Phe-Arg-Trp-Cys)-NH2,

[0929] or a pharmaceutically acceptable salt thereof.

[0930] In another embodiment, the polypeptides of the present invention include polypeptides represented by Formula (IX), wherein A3is an amino acid residue selected from Tie, Vai, Leu, He, Cha, Pro, Ser, Thr, Lys, Arg, His, Phe, Gin, Sar, Gly, Asn, or Aib; and A4is an amino acid residue selected from Ate, Ala, QAla, Aib, Sar, Ser, Thr, Pro, Hyp, Asn, Gin, a substituted His, Trp, Tyr, Lys, Arg, sChp, or residue X. Examples of such polypeptides are polypeptides represented by any one of the following structural formulas:

[0931] (SEQ ID NO: 616) Ac-Arg-c(Cys-Val-Gln-D-Phe-Arg-Trp-Cys)-NH2;

[0932] (SEQ ID NO: 570) Ac-Arg-c(Cys-D-Val-Gln-D-Phe-Arg-Trp-Cys)-NH2; or

[0933] (SEQ ID NO: 617) Ac-Arg-c(Cys-D-Val-His(l-Me)-D-Phe-Arg-Trp-Cys)-NH2,

[0934] or a pharmaceutically acceptable salt thereof.

[0935] In a further embodiment, the polypeptides of the present invention include a polypeptide represented by any one of the following structural formulas:

[0936] (SEQ ID NO: 618) Ac-TzAla-c(Cys-Ala-Gln-D-Phe-Arg-Trp-Cys)-NH2; or

[0937] (SEQ ID NO: 619) Ac-Glu-c(Cys-Ala-His-D-Phe-Arg-Trp-Cys)-NH2,

[0938] or a pharmaceutically acceptable salt thereof.

[0939] In yet another embodiment, the polypeptides of the present invention include a polypeptide represented by any one of the following structural formulas:

[0940] (SEQ ID NO: 596) Ac-Arg-c(Cys-D-Ala-His(l-Me)-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 567) Ac-Arg-c(Cys-D-Ala-Gln-D-Phe-Arg-Trp-Cys)-NH2; or

[0941] (SEQ ID NO: 566) Ac-Arg-c(Cys-D-Ala-Asn-D-Phe-Arg-Trp-Cys)-NH2,

[0942] or a pharmaceutically acceptable salt thereof.

[0943] In a further embodiment, the polypeptides of the present invention include a polypeptide represented by any one of the following structural formulas:

[0944] (SEQ ID NO: 620) Ac-Arg-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-NH2;

[0945] (SEQ ID NO: 621) Ac-Arg-c(Cys-D-Ile-His-D-Phe-Arg-Trp-Cys)-NH2;

[0946] (SEQ ID NO: 622) Ac-Arg-c(Cys-D-Tle-His-D-Phe-Arg-Trp-Cys)-NH2; or

[0947] (SEQ ID NO: 569) Ac-Arg-c(Cys-D-Val-His-D-Phe-Arg-Trp-Cys)-NH2,

[0948] or a pharmaceutically acceptable salt thereof.

[0949] In a further embodiment, the polypeptides of the present invention include a polypeptide represented by any one of the following structural formulas:

[0950] (SEQ ID NO: 623) Ac-Arg-c(Cys-D-Ala-His(l-Me)-D-2-Nal-Arg-Trp-Cys)-NH2;

[0951] (SEQ ID NO: 624) Ac-Arg-c(Cys-D-Ala-Gln-D-2-Nal-Arg-Trp-Cys)-NH2; or

[0952] (SEQ ID NO: 625) Ac-Arg-c(Cys-D-Ala-Asn-D-2-Nal-Arg-Trp-Cys)-NH2,

[0953] or a pharmaceutically acceptable salt thereof.

[0954] In a further embodiment, the polypeptides of the present invention include a polypeptide represented by any one of the following structural formulas:

[0955] (SEQ ID NO: 626) Ac-Arg-c(Cys-D-Ala-His(l-Me)-D-Phe-Arg-Trp-Cys)-OH;

[0956] (SEQ ID NO: 627) Ac-Arg-c(Cys-D-Ala-Gln-D-Phe-Arg-Trp-Cys)-OH; or

[0957] (SEQ ID NO: 628) Ac-Arg-c(Cys-D-Ala-Asn-D-Phe-Arg-Trp-Cys)-OH,

[0958] or a pharmaceutically acceptable salt thereof.

[0959] In one example embodiment, an MC4R agonist is a compound represented by Formula (X):

[0960]

[0961] pharmaceutically acceptable salt thereof, wherein: Ri is - NH-C(O)- or -C(O)-NH-; R2 is -H, -CH2-, or, R2, together with R3, forms a pyrrolidine ring optionally substituted with -OH; R3 is -(CH2)2- if R2 is -CH2-, and otherwise R3 is selected from

[0962]

[0963] and R4Care each independently selected from hydrogen, halo, (Ci-Cio)alkyl-halo, (Ci-Cio)alkyl-dihalo, (Ci-Cio)alkyl-trihalo, (Ci-Cio)alkyl, (Ci-Cio)alkoxy, (Ci-Cio)alkylthio, aryl, aryloxy, nitro, nitrile, sulfonamide, amino, hydroxyl, carboxy, and alkoxy-carbonyl; R5is -OH or -N(R6a)(R6b); R6aand R6bare each independently H or Ci to C4 linear, branched or cyclic alkyl chain; R7is -H or -C(O)-NH2; w is in each instance independently 0 to 5; x is 1 to 5; y is 1 to 5; z is in each instance independently 1 to 5.

[0964] In one example embodiment, R4a, R4b, and R4cis not hydrogen.

[0965] An example of a compound of Formula (X) is a cyclic peptide defined by Formula (XI):

[0966]

[0967] pharmaceutically acceptable salt thereof.

[0968] In one example embodiment, the MC4R agonist is Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2 (SEQ ID NO: 140) or a pharmaceutically acceptable salt thereof. In another example embodiment, the MC4R agonist is Hydantoin(C(O)-(Arg-Gly))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2 (SEQ ID NO: 148) or a pharmaceutically acceptable salt thereof.

[0969] In some embodiments, the MC4R agonist is an agonist described in WO2014 / 144260 Al, incorporated herein by reference.

[0970] In one example embodiment, the MC4 agonist is a compound represented by Formula (XII):

[0971] Ai-Yyy-c(Aaa-Xxx-D-Phe-Arg-Trp-Bbb)-A2(XII),

[0972] or a pharmaceutically acceptable salt thereof, wherein: Aaa and Bbb are selected from Cys, hCys, Pen capable of establishing a disulfide bridge; or Glu, Asp, Lys, Orn, Dpr, Dbu capable of establishing a lactam bridge; Xxx is Asn, Gin, Ser, Thr; Yyy is Lys, Arg, D-Lys, D-Arg; Al is H, Ac; A2 is OH, NH2.

[0973] In embodiments, the MC4R agonist is chosen from one or more of the following compounds, (or pharmaceutically acceptable salt thereof):

[0974] (SEQ ID NO: 629) Ac-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH2;

[0975] (SEQ ID NO: 630) Ac-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2;

[0976] (SEQ ID NO: 631) Ac-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2;

[0977] (SEQ ID NO: 632) Ac-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2;

[0978] (SEQ ID NO: 633) Ac-Arg-c(Glu-Gln-D-Phe-Arg-Trp-Dpr)-NH2;

[0979] (SEQ ID NO: 634) Ac-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH;

[0980] (SEQ ID NO: 635) H-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 636) H-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 637) Ac-D-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 638) H-D-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 639) Ac-D-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 640) H-D-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 641) Ac-Lys-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 642) Ac-Lys-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 643) H-Lys-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 644) H-Lys-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 645) Ac-D-Lys-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 646) H-D-Lys-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 647) Ac-D-Lys-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 648) H-D-Lys-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 649) Ac-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 650) H-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 651) H-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 652) Ac-D-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 653) H-D-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 654) Ac-D-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 655) H-D-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 656) Ac-Lys-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 657) Ac-Lys-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 658) H-Lys-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 659) H-Lys-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 660) Ac-D-Lys-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 661) H-D-Lys-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 662) Ac-D-Lys-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 663) H-D-Lys-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 664) Ac-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 665) H-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 666) H-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 667) Ac-D-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2;

[0981] (SEQ ID NO: 668) H-D-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2;

[0982] (SEQ ID NO: 669) Ac-D-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH;

[0983] (SEQ ID NO: 670) H-D-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH;

[0984] (SEQ ID NO: 671) Ac-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2;

[0985] (SEQ ID NO: 672) Ac-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH;

[0986] (SEQ ID NO: 673) H-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2;

[0987] (SEQ ID NO: 674) H-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH;

[0988] (SEQ ID NO: 675) Ac-D-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2;

[0989] (SEQ ID NO: 676) H-D-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2;

[0990] (SEQ ID NO: 677) Ac-D-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH;

[0991] (SEQ ID NO: 678) H-D-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH;

[0992] (SEQ ID NO: 679) Ac-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH;

[0993] (SEQ ID NO: 680) H-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2;

[0994] (SEQ ID NO: 681) H-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH;

[0995] (SEQ ID NO: 682) Ac-D-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2;

[0996] (SEQ ID NO: 683) H-D-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2;

[0997] (SEQ ID NO: 684) Ac-D-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH;

[0998] (SEQ ID NO: 685) H-D-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH;

[0999] (SEQ ID NO: 686) Ac-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2;

[1000] (SEQ ID NO: 687) Ac-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH;

[1001] (SEQ ID NO: 688) H-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2;

[1002] (SEQ ID NO: 689) H-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH;

[1003] (SEQ ID NO: 690) Ac-D-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2;

[1004] (SEQ ID NO: 691) H-D-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2;

[1005] (SEQ ID NO: 692) Ac-D-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2, or

[1006] (SEQ ID NO: 693) H-D-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2.

[1007] In some embodiments, the MC4R agonist is a compound of Formula (Xll-a): H-Yyy-c(Aaa-Xxx-D-Phe-Arg-Trp-Bbb)-NH2(Xll-a) or a pharmaceutically acceptable salt thereof, wherein: Aaa and Bbb are selected from Cys, hCys, Pen capable of establishing a disulfide bridge; or Glu, Asp, Lys, Orn, Dpr, Dbu capable of establishing a lactam bridge; Xxx is Asn, Gin, Ser, Thr; and Yyy is Lys, Arg, D-Lys, D-Arg.

[1008] In some embodiments, the compound of Formula (XILa) is selected from:

[1009] (SEQ ID NO: 635) H-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH2;

[1010] (SEQ ID NO: 643) H-Lys-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH2;

[1011] (SEQ ID NO: 646) H-D-Lys-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH2;

[1012] (SEQ ID NO: 650) H-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2;

[1013] (SEQ ID NO: 653) H-D-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2;

[1014] (SEQ ID NO: 658) H-Lys-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2;

[1015] (SEQ ID NO: 661) H-D-Lys-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2;

[1016] (SEQ ID NO: 665) H-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2;

[1017] (SEQ ID NO: 668) H-D-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2;

[1018] (SEQ ID NO: 673) H-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2;

[1019] (SEQ ID NO: 676) H-D-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2;

[1020] (SEQ ID NO: 680) H-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2;

[1021] (SEQ ID NO: 683) H-D-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2;

[1022] (SEQ ID NO: 688) H-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2;

[1023] (SEQ ID NO: 691) H-D-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2; and

[1024] (SEQ ID NO: 693) H-D-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2.

[1025] In some embodiments, the MC4R agonist is a compound of Formula (XILb):

[1026] Ac-Yyy-c(Aaa-Xxx-D-Phe-Arg-Trp-Bbb)-NH2(XILb)

[1027] or a pharmaceutically acceptable salt thereof, wherein: Aaa and Bbb are selected from Cys, hCys, Pen capable of establishing a disulfide bridge; or Glu, Asp, Lys, Orn, Dpr, Dbu capable of establishing a lactam bridge; Xxx is Asn, Gin, Ser, Thr; and Yyy is Lys, Arg, D-Lys, D-Arg.

[1028] In some embodiments, the compound of Formula (XILb) is selected from:

[1029] (SEQ ID NO: 629) Ac-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH2;

[1030] (SEQ ID NO: 630) Ac-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2;

[1031] (SEQ ID NO: 631) Ac-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2;

[1032] (SEQ ID NO: 632) Ac-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 633) Ac-Arg-c(Glu-Gln-D-Phe-Arg-Trp-Dpr)-NH2;

[1033] (SEQ ID NO: 637) Ac-D-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH2;

[1034] (SEQ ID NO: 641) Ac-Lys-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH2;

[1035] (SEQ ID NO: 645) Ac-D-Lys-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH2;

[1036] (SEQ ID NO: 652) Ac-D-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2;

[1037] (SEQ ID NO: 656) Ac-Lys-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2;

[1038] (SEQ ID NO: 660) Ac-D-Lys-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2;

[1039] (SEQ ID NO: 667) Ac-D-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2;

[1040] (SEQ ID NO: 671) Ac-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2;

[1041] (SEQ ID NO: 675) Ac-D-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2;

[1042] (SEQ ID NO: 682) Ac-D-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2;

[1043] (SEQ ID NO: 686) Ac-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2;

[1044] (SEQ ID NO: 690) Ac-D-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2; and

[1045] (SEQ ID NO: 692) Ac-D-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2.

[1046] In some embodiments, the MC4R agonist is a compound of Formula (XII-c):

[1047] Ai-Yyy-c(Aaa-Xxx-D-Phe-Arg-Trp-Bbb)-A2(XII-c)

[1048] or a pharmaceutically acceptable salt thereof, wherein: Ai is H or Ac; A2is OH or NH2; Yyy is L-Arg or D-Arg; Aaa and Bbb are selected from Cys, hCys, and Pen capable of establishing a disulfide bridge; or Glu, Asp, Lys, Orn, Dpr, and Dbu capable of establishing a lactam bridge; and Xxx is Asn, Gin, Ser, or Thr.

[1049] In some embodiments, the compound of Formula (XII-c) is selected from:

[1050] (SEQ ID NO: 629) Ac-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH2;

[1051] (SEQ ID NO: 630) Ac-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2;

[1052] (SEQ ID NO: 631) Ac-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2;

[1053] (SEQ ID NO: 632) Ac-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2;

[1054] (SEQ ID NO: 633) Ac-Arg-c(Glu-Gln-D-Phe-Arg-Trp-Dpr)-NH2;

[1055] (SEQ ID NO: 634) Ac-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH;

[1056] (SEQ ID NO: 635) H-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH2;

[1057] (SEQ ID NO: 636) H-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH;

[1058] (SEQ ID NO: 637) Ac-D-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH2;

[1059] (SEQ ID NO: 638) H-D-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 639) Ac-D-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH;

[1060] (SEQ ID NO: 640) H-D-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH;

[1061] (SEQ ID NO: 649) Ac-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH;

[1062] (SEQ ID NO: 650) H-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2;

[1063] (SEQ ID NO: 651) H-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH;

[1064] (SEQ ID NO: 652) Ac-D-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2;

[1065] (SEQ ID NO: 653) H-D-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2;

[1066] (SEQ ID NO: 654) Ac-D-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH;

[1067] (SEQ ID NO: 655) H-D-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH;

[1068] (SEQ ID NO: 664) Ac-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH;

[1069] (SEQ ID NO: 665) H-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2;

[1070] (SEQ ID NO: 666) H-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH;

[1071] (SEQ ID NO: 667) Ac-D-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2;

[1072] (SEQ ID NO: 668) H-D-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2;

[1073] (SEQ ID NO: 669) Ac-D-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH;

[1074] (SEQ ID NO: 670) H-D-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH;

[1075] (SEQ ID NO: 679) Ac-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH;

[1076] (SEQ ID NO: 680) H-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2;

[1077] (SEQ ID NO: 681) H-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH;

[1078] (SEQ ID NO: 682) Ac-D-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2;

[1079] (SEQ ID NO: 683) H-D-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2;

[1080] (SEQ ID NO: 684) Ac-D-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH; and

[1081] (SEQ ID NO: 685) H-D-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH.

[1082] In some embodiments, the MC4R agonist is a compound of Formula (Xll-d):

[1083] Ai-Yyy-c(Aaa-Xxx-D-Phe-Arg-Trp-Bbb)-A2(Xll-d)

[1084] or a pharmaceutically acceptable salt thereof, wherein: Ai is H or Ac; A2is OH or NH2; Yyy is L-Lys or D-Lys; Aaa and Bbb are selected from Cys, hCys, and Pen capable of establishing a disulfide bridge; or Glu, Asp, Lys, Orn, Dpr, and Dbu capable of establishing a lactam bridge; and Xxx is Asn, Gin, Ser, or Thr.

[1085] In some embodiments, the compound of Formula (XILd) is selected from:

[1086] (SEQ ID NO: 641) Ac-Lys-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 642) Ac-Lys-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH;

[1087] (SEQ ID NO: 643) H-Lys-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH2;

[1088] (SEQ ID NO: 644) H-Lys-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH;

[1089] (SEQ ID NO: 645) Ac-D-Lys-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 646) H-D-Lys-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 647) Ac-D-Lys-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 648) H-D-Lys-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 656) Ac-Lys-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 657) Ac-Lys-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH;

[1090] (SEQ ID NO: 658) H-Lys-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2;

[1091] (SEQ ID NO: 659) H-Lys-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH;

[1092] (SEQ ID NO: 660) Ac-D-Lys-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 661) H-D-Lys-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 662) Ac-D-Lys-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 663) H-D-Lys-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 671) Ac-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2;

[1093] (SEQ ID NO: 672) Ac-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH;

[1094] (SEQ ID NO: 673) H-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2;

[1095] (SEQ ID NO: 674) H-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH;

[1096] (SEQ ID NO: 675) Ac-D-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 676) H-D-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 677) Ac-D-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 678) H-D-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 686) Ac-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2;

[1097] (SEQ ID NO: 687) Ac-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH;

[1098] (SEQ ID NO: 688) H-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2;

[1099] (SEQ ID NO: 689) H-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH;

[1100] (SEQ ID NO: 690) Ac-D-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 691) H-D-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 692) Ac-D-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2, and (SEQ ID NO: 693) H-D-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2. Examples of administration of a compound or composition comprising a compound or pharmaceutical salt of a compound of the disclosure include peripheral administration. Examples of peripheral administration include oral, subcutaneous, intraperitoneal, intramuscular, intravenous, rectal, transdermal or intranasal forms of administration.

[1101] As used herein, peripheral administration can include all forms of administration of a compound or a composition comprising a compound of the instant disclosure which excludes intracranial administration. Examples of peripheral administration include, but are not limited to, oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous or subcutaneous injection, extended release, slow release implant, depot and the like), nasal, vaginal, rectal, sublingual or topical routes of administration, including transdermal patch applications and the like.

[1102] The nomenclature used to define the peptides is that typically used in the art wherein the amino group at the N-terminus appears to the left and the carboxyl group at the C-terminus appears to the right. Where the amino acid has D and L isomeric forms, it is the L form of the amino acid that is represented unless otherwise explicitly indicated.

[1103] The compounds of the disclosure useful for practicing the methods described herein may possess one or more chiral centers and so exist in a number of stereoisomeric forms. All stereoisomers and mixtures thereof are included in the scope of the present disclosure. Racemic compounds may either be separated using preparative HPLC and a column with a chiral stationary phase or resolved to yield individual enantiomers utilizing methods known to those skilled in the art. In addition, chiral intermediate compounds may be resolved and used to prepare chiral compounds of the disclosure.

[1104] The compounds described herein may exist in one or more tautomeric forms. All tautomers and mixtures thereof are included in the scope of the present disclosure. For example, a claim to 2-hydroxypyridinyl would also cover its tautomeric form, a-pyridonyl.

[1105] G-Protein Coupled Hormone Receptor (GCHR) Modulators

[1106] Hormone receptor modulators targeting, e.g., the glucagon receptor, the glucagon-like peptide- 1 receptor (GLP1R), the gastric inhibitory peptide receptor, the glucose-dependent insulinotropic polypeptide, and the amylin receptors, have been shown to be effective in treating obesity. However, administration of such modulators, when administered alone or in combination with other hormone receptor agonist peptides, often results in negative side effects including moderate to severe gastrointestinal distress, allergic reactions, hypoglycemia, kidney problems, and an increased risk of pancreatitis (Jastreboff AM, et al. Retatrutide Phase 2 Obesity Trial Investigators. Triple-Hormone-Receptor Agonist Retatrutide for Obesity - A Phase 2 Trial. N Engl J Med. 2023 Aug 10;389(6):514-526. doi: 10.1056 / NEJMoa2301972. Epub 2023 Jun 26. PMID: 37366315.).

[1107] The glucagon receptor is a 62 kDa protein that is activated by glucagon and is a member of the class B G-protein coupled family of receptors, coupled to G alpha i, Gs and to a lesser extent G alpha q. Stimulation of the receptor results in the activation of adenylate cyclase and phospholipase C and in increased levels of the secondary messengers intracellular cAMP and calcium. In humans, the glucagon receptor is encoded by the GCGR gene. A missense mutation at 17q25 in the GCGR gene is associated with diabetes mellitus type 2. Inactivating mutation of glucagon receptor in humans causes resistance to glucagon and is associated with pancreatic alpha cell hyperplasia, nesidioblastosis, hyperglucagonemia, and pancreatic neuroendocrine tumors, also known as Mahvash disease. Exemplary glucagon receptor agonists include survodutide, pemvidutide, and cotadutide. In some embodiments, the GCHR modulator comprises a glucagon receptor modulator. In some embodiments, the glucagon receptor modulator comprises survodutide, pemvidutide, retatrutide, cotadutide, mazdutide, efpegerglucagon, efocipegtrutide, MOD-6031, DR10624, DD01, XTL6001, NA-931, JNJ-64565111, NNC9204-0530, HM15275, SAR441255, MK-0893, PF-06291874, LY2409021, or LGD-6972. In some embodiments, the G-protein coupled hormone receptor (GCHR) agonist comprises survodutide, pemvidutide, or cotadutide. In some embodiments, the GCHR modulator comprises survodutide. In some embodiments, the GCHR modulator comprises pemvidutide. In some embodiments, the GCHR modulator comprises cotadutide. In some embodiments, the glucagon receptor modulator comprises survodutide. In some embodiments, the glucagon receptor modulator comprises pemvidutide. In some embodiments, the glucagon receptor modulator comprises retatrutide. In some embodiments, the glucagon receptor modulator comprises cotadutide. In some embodiments, the glucagon receptor modulator comprises mazdutide. In some embodiments, the glucagon receptor modulator comprises efpegerglucagon. In some embodiments, the glucagon receptor modulator comprises efocipegtrutide. In some embodiments, the glucagon receptor modulator comprises MOD-6031. In some embodiments, the glucagon receptor modulator comprises DR10624. In some embodiments, the glucagon receptor modulator comprises DD01. In some embodiments, the glucagon receptor modulator comprises XTL6001. In some embodiments, the glucagon receptor modulator comprises NA-931. In some embodiments, the glucagon receptor modulator comprises JNJ-64565111. In some embodiments, the glucagon receptor modulator comprises NNC9204-0530. In some embodiments, the glucagon receptor modulator comprises HM15275. In some embodiments, the glucagon receptor modulator comprises SAR441255. In some embodiments, the glucagon receptor modulator comprises MK-0893. In some embodiments, the glucagon receptor modulator comprises PF-06291874. In some embodiments, the glucagon receptor modulator comprises LY2409021. In some embodiments, the glucagon receptor modulator comprises. In some embodiments, the glucagon receptor modulator comprises LGD-6972.

[1108] The GLP1R is a G protein-coupled receptor found on beta cells of the pancreas and on neurons of the brain. It is involved in the control of blood sugar level by enhancing insulin secretion. In humans it is synthesized by the gene GLP1R. It is a member of the glucagon receptor family of GPCRs. GLP1R is composed of two domains, one extracellular (ECD) that binds the C-terminal helix of GLP-1, and one transmembrane (TMD) domain that binds the N-terminal region of GLP-1. In some embodiments, the GCHR modulator is a GLP1R agonist. Exemplary GLP1R agonists include semaglutide, albiglutide, dulaglutide, exendin-4, liraglutide, exenatide, lixisenatide, orforglipron, survodutide, pemvidutide, cotadutide, tirzepatide, and retatrutide. In some embodiments, the GLP1R agonist comprises semaglutide, albiglutide, dulaglutide, exendin-4, liraglutide, exenatide, lixisenatide, orforglipron, survodutide, pemvidutide, cotadutide, tirzepatide, retatrutide, beinaglutide, dapiglutide, ecnoglutide, bamadutide, mazdutide, bofanglutide, efocipegtrutide, exendin-3, exendin-4 (3-39), exendin-4 (9-39), danuglipron, lotiglipron, aleniglipron, ID 110521156, ECC5004, RGT-075, GS-4571, HD-7671, BLX-7006, TERN-601, CT-996, MOD-6031, VK2735, DR10624, TG103, AZD9550, DD01, DA-302168S, XTL6001, NA-931, HDM1002, NNC0519-0130, ROSE-010, BGM0504, JNJ-64565111, CT-868, amycretin, NNC9204-0530, HM15275, CT-388, SAR441255, or maridebart cafraglutide. In some embodiments, the GLP1R agonist is semaglutide, albiglutide, dulaglutide, exendin-4, liraglutide, exenatide, lixisenatide, orforglipron, survodutide, pemvidutide, cotadutide, tirzepatide, and retatrutide. In some embodiments, the GCHR modulator comprises semaglutide, albiglutide, dulaglutide, exendin-4, liraglutide, exenatide, lixisenatide, orforglipron, survodutide, pemvidutide, cotadutide, tirzepatide, or retatrutide. In some embodiments, the GCHR modulator comprises semaglutide. In some embodiments, the GCHR modulator comprises albiglutide. In some embodiments, the GCHR modulator comprises dulaglutide. In some embodiments, the GCHR modulator comprises exendin-4. In some embodiments, the GCHR modulator comprises liraglutide. In some embodiments, the GCHR modulator comprises exenatide. In some embodiments, the GCHR modulator comprises lixisenatide. In some embodiments, the GCHR modulator comprises orforglipron. In some embodiments, the GCHR modulator comprises survodutide. In some embodiments, the GCHR modulator comprises pemvidutide. In some embodiments, the GCHR modulator comprises cotadutide. In some embodiments, the GCHR modulator comprises tirzepatide. In some embodiments, the GCHR modulator comprises retatrutide. In some embodiments, the GLP1R agonist comprises semaglutide. In some embodiments, the GLP1R agonist comprises albiglutide. In some embodiments, the GLP1R agonist comprises dulaglutide. In some embodiments, the GLP1R agonist comprises exendin-4. In some embodiments, the GLP1R agonist comprises liraglutide. In some embodiments, the GLP1R agonist comprises exenatide. In some embodiments, the GLP1R agonist comprises lixisenatide. In some embodiments, the GLP1R agonist comprises orforglipron. In some embodiments, the GLP1R agonist comprises survodutide. In some embodiments, the GLP1R agonist comprises pemvidutide. In some embodiments, the GLP1R agonist comprises cotadutide. In some embodiments, the GLP1R agonist comprises tirzepatide. In some embodiments, the GLP1R agonist comprises retatrutide. In some embodiments, the GLP1R agonist comprises beinaglutide. In some embodiments, the GLP1R agonist comprises dapiglutide. In some embodiments, the GLP1R agonist comprises ecnoglutide. In some embodiments, the GLP1R agonist comprises bamadutide. In some embodiments, the GLP1R agonist comprises mazdutide. In some embodiments, the GLP1R agonist comprises bofanglutide. In some embodiments, the GLP1R agonist comprises efocipegtrutide. In some embodiments, the GLP1R agonist comprises exendin-3. In some embodiments, the GLP1R agonist comprises exendin-4 (3-39). In some embodiments, the GLP1R agonist comprises exendin-4 (9-39). In some embodiments, the GLP1R agonist comprises danuglipron. In some embodiments, the GLP1R agonist comprises lotiglipron. In some embodiments, the GLP1R agonist comprises aleniglipron. In some embodiments, the GLP1R agonist comprises ID110521156. In some embodiments, the GLP1R agonist comprises ECC5004. In some embodiments, the GLP1R agonist comprises RGT-075. In some embodiments, the GLP1R agonist comprises GS-4571. In some embodiments, the GLP1R agonist comprises HD-7671. In some embodiments, the GLP1R agonist comprises BLX-7006. In some embodiments, the GLP1R agonist comprises TERN-601. In some embodiments, the GLP1R agonist comprises CT-996. In some embodiments, the GLP1R agonist comprises MOD-6031. In some embodiments, the GLP1R agonist comprises VK2735. In some embodiments, the GLP1R agonist comprises DR10624. In some embodiments, the GLP1R agonist comprises TG103. In some embodiments, the GLP1R agonist comprises AZD9550. In some embodiments, the GLP1R agonist comprises DD01. In some embodiments, the GLP1R agonist comprises DA-302168S. In some embodiments, the GLP1R agonist comprises XTL6001. In some embodiments, the GLP1R agonist comprises NA-931. In some embodiments, the GLP1R agonist comprises HDM1002. In some embodiments, the GLP1R agonist comprises NNC0519-0130. In some embodiments, the GLP1R agonist comprises ROSE-010. In some embodiments, the GLP1R agonist comprises BGM0504. In some embodiments, the GLP1R agonist comprises JNJ-64565111. In some embodiments, the GLP1R agonist comprises CT-868. In some embodiments, the GLP1R agonist comprises amycretin. In some embodiments, the GLP1R agonist comprises NNC9204-0530. In some embodiments, the GLP1R agonist comprises HM15275. In some embodiments, the GLP1R agonist comprises CT-388. In some embodiments, the GLP1R agonist comprises SAR441255. In some embodiments, the GLP1R agonist comprises maridebart cafraglutide.

[1109] The gastric inhibitory peptide receptor, also known as the glucose-dependent insulinotropic polypeptide receptor (GIP-R), is a receptor that in humans is encoded by the GIPR gene. GIP-R is a member of the class B family of G protein coupled receptors. GIP-R is found on beta-cells in the pancreas where it serves as the receptor for the hormone gastric inhibitory polypeptide (GIP), a 42-amino acid polypeptide. Together with glucagon-like peptide- 1, GIP is largely responsible for the secretion of insulin after eating. It is involved in several other facets of the anabolic response. Exemplary gastric inhibitory peptide receptor agonists include tirzepatide and retatrutide. In some embodiments, the GCHR modulator comprises a GIP-R agonist. In some embodiments, the GIP-R agonist comprises tirzepatide, retatrutide, efocipegtrutide, VK2735, NA-931, NNC0519-0130, BGM0504, CT-868, HM15275, CT-388, SAR441255, or maridebart cafraglutide. In some embodiments, the GCHR modulator comprises tirzepatide and retatrutide. In some embodiments, the GCHR modulator comprises tirzepatide. In some embodiments, the GCHR modulator comprises retatrutide. In some embodiments, the GIP-R agonist comprises tirzepatide. In some embodiments, the GIP-R agonist comprises retatrutide. In some embodiments, the GIP-R agonist comprises efocipegtrutide. In some embodiments, the GIP-R agonist comprises VK2735. In some embodiments, the GIP-R agonist comprises NA-931. In some embodiments, the GIP-R agonist comprises NNC0519-0130. In some embodiments, the GIP-R agonist comprises BGM0504. In some embodiments, the GIP-R agonist comprises CT-868. In some embodiments, the GIP-R agonist comprises HM15275. In some embodiments, the GIP-R agonist comprises CT-388. In some embodiments, the GIP-R agonist comprises SAR441255. In some embodiments, the GIP-R agonist comprises maridebart cafraglutide.

[1110] The amylin receptors (AMYi, AMY2, and AMY3) are heterodimers of the calcitonin receptor (encoded by CALCR gene in humans) and one receptor activity modifying protein (in humans encoded by one of the genes RAMP1, RAMP2, and RAMP3). The amylin receptors bind to amylin, also known as islet amyloid polypeptide, a 37-amino acid peptide that is co-secreted with insulin from beta-cells in the pancreas and regulates gastric emptying and satiety. In some embodiments, the GCHR modulator is an amylin receptor agonist. Exemplary amylin receptor agonists include AZD6234, petrelintide, eloralintide, pramlintide, GUB014295, cagrilintide, and amycretin. In some embodiments, the amylin receptor agonist comprises AZD6234, petrelintide, eloralintide, pramlintide, GUB014295, cagrilintide, or amycretin. In some embodiments, the amylin receptor agonist comprises AZD6234. In some embodiments, the amylin receptor agonist comprises petrelintide. In some embodiments, the amylin receptor agonist comprises eloralintide. In some embodiments, the amylin receptor agonist comprises pramlintide. In some embodiments, the amylin receptor agonist comprises GUB014295. In some embodiments, the amylin receptor agonist comprises cagrilintide. In some embodiments, the amylin receptor agonist comprises amycretin.

[1111] G-protein coupled hormone receptor (GCHR) modulators that may be administered in combination with MC4R agonists according to the methods described herein include any GCHR modulator known in the art, such as, but not limited to, albiglutide (e.g., Tanzeum®), dulaglutide (e.g., Trulicity®), tirzepatide (e.g., Mounjaro® or Zepbound®), exendin-4 also known as exenatide (e.g., Byetta® or Bydureon®), exendin-4 (9-39), liraglutide (e.g., Victoza® or Saxenda®), lixisenatide (e.g., Adlynxin®), semaglutide (e.g., Ozempic® or Wegovy®), semaglutide with cagrilintide (CagriSema®), survodutide, pemvidutide, retatrutide, beinaglutide, dapiglutide, ecnoglutide, bamadutide, cotadutide, mazdutide, bofanglutide, efocipegtrutide, maridebart cafraglutide (e.g., MariTide), orforglipron, danuglipron, lotiglipron, aleniglipron, ID 110521156, ECC5004, RGT-075, GS-4571, HD-7671, BLX-7006, TERN-601, CT-996, MOD-6031, VK2735, DR10624, TG103, AZD9550, DD01, DA-302168S, XTL6001, NA-931 (e.g., Bioglutide), HDM1002, NNC0519-0130, ROSE-010, BGM0504, JNJ-6456511, CT-868, amycretin, GSK2890457, NNC9204-0530, efpegerglucagon, HM15275, CT-388, SAR441255, MK-0893, PF-06291874, LY2409021, LGD-6972, cagrilintide, AZD6234, petrelintide, eloralintide, pramlintide (Symlin®), and GUB014295. In some embodiments, the GCHR modulator comprises albiglutide. In some embodiments, the GCHR modulator comprises dulaglutide. In some embodiments, the GCHR modulator comprises tirzepatide. In some embodiments, the GCHR modulator comprises exendin-4. In some embodiments, the GCHR modulator comprises exendin-4 (9-39). In some embodiments, the GCHR modulator comprises liraglutide. In some embodiments, the GCHR modulator comprises lixisenatide. In some embodiments, the GCHR modulator comprises semaglutide. In some embodiments, the GCHR modulator comprises semaglutide with cagrilintide. In some embodiments, the GCHR modulator comprises survodutide. In some embodiments, the GCHR modulator comprises pemvidutide. In some embodiments, the GCHR modulator comprises retatrutide. In some embodiments, the GCHR modulator comprises beinaglutide. In some embodiments, the GCHR modulator comprises dapiglutide. In some embodiments, the GCHR modulator comprises ecnoglutide. In some embodiments, the GCHR modulator comprises bamadutide. In some embodiments, the GCHR modulator comprises cotadutide. In some embodiments, the GCHR modulator comprises mazdutide. In some embodiments, the GCHR modulator comprises bofanglutide. In some embodiments, the GCHR modulator comprises efocipegtrutide. In some embodiments, the GCHR modulator comprises maridebart cafraglutide. In some embodiments, the GCHR modulator comprises orforglipron. In some embodiments, the GCHR modulator comprises danuglipron. In some embodiments, the GCHR modulator comprises lotiglipron. In some embodiments, the GCHR modulator comprises aleniglipron. In some embodiments, the GCHR modulator comprises ID110521156. In some embodiments, the GCHR modulator comprises ECC5004. In some embodiments, the GCHR modulator comprises RGT-075. In some embodiments, the GCHR modulator comprises GS-4571. In some embodiments, the GCHR modulator comprises HD-7671. In some embodiments, the GCHR modulator comprises BLX-7006. In some embodiments, the GCHR modulator comprises TERN-601. In some embodiments, the GCHR modulator comprises CT-996. In some embodiments, the GCHR modulator comprises MOD-6031. In some embodiments, the GCHR modulator comprises VK2735. In some embodiments, the GCHR modulator comprises DR10624. In some embodiments, the GCHR modulator comprises TG103. In some embodiments, the GCHR modulator comprises AZD9550. In some embodiments, the GCHR modulator comprises DD01. In some embodiments, the GCHR modulator comprises DA-302168S. In some embodiments, the GCHR modulator comprises XTL6001. In some embodiments, the GCHR modulator comprises NA-931. In some embodiments, the GCHR modulator comprises HDM1002. In some embodiments, the GCHR modulator comprises NNC0519-0130. In some embodiments, the GCHR modulator comprises ROSE-010. In some embodiments, the GCHR modulator comprises BGM0504. In some embodiments, the GCHR modulator comprises JNJ-6456511. In some embodiments, the GCHR modulator comprises CT-868. In some embodiments, the GCHR modulator comprises amycretin. In some embodiments, the GCHR modulator comprises GSK2890457. In some embodiments, the GCHR modulator comprises NNC9204-0530. In some embodiments, the GCHR modulator comprises efpegerglucagon. In some embodiments, the GCHR modulator comprises HM15275. In some embodiments, the GCHR modulator comprises CT-388. In some embodiments, the GCHR modulator comprises SAR441255. In some embodiments, the GCHR modulator comprises MK-0893. In some embodiments, the GCHR modulator comprises PF-06291874. In some embodiments, the GCHR modulator comprises LY2409021. In some embodiments, the GCHR modulator comprises LGD-6972. In some embodiments, the GCHR modulator comprises cagrilintide. In some embodiments, the GCHR modulator comprises AZD6234. In some embodiments, the GCHR modulator comprises petrelintide. In some embodiments, the GCHR modulator comprises eloralintide. In some embodiments, the GCHR modulator comprises pramlintide. In some embodiments, the GCHR modulator comprises GUB014295.

[1112] G-protein coupled hormone receptor (GCHR) agonists that may be administered in combination with MC4R agonists according to the methods described herein include any GCHR modulator known in the art, such as, but not limited to, albiglutide, dulaglutide (e.g., Trulicity®), tirzepatide, exendin-4, exenatide, liraglutide, lixisenatide, semaglutide (e.g., Ozempic® or Wegovy®), semaglutide with cagrilintide (CagriSema®), survodutide, pemvidutide, retatrutide, orforglipron. In some embodiments, exemplary GCHR modulators comprise any peptide as described in, for example, any of the following patent publications: US11858918B2, US11851419B2, EP4048664A1, US20190010162A1, EP3157949A1, EP3129396B1, EP3129395B1, US9694053B2, US9750788B2, EP3080154B1, EP3080150B1, EP3400957A1, US20090286723A1, US8765796B2, US9982029B2, EP2127676A2, US20080280815A1, and US10519211B2.

[1113] In some embodiments, the GCHR modulator is an agonist of the GLP1R (e.g., semaglutide, albiglutide, dulaglutide, exendin-3, exendin-4, exendin-4 (3-39), exendin-4 (9-39), liraglutide, exenatide, lixisenatide, beinaglutide, ecnoglutide, bamadutide, bofanglutide, orforglipron, danuglipron, lotiglipron, aleniglipron, ID110521156, ECC5004, RGT-075, GS-4571, HD-7671, BLX-7006, TERN-601, CT-996, TG103, DA-302168S, HDM1002, or ROSE-010). In some embodiments, the GCHR modulator is a dual agonist of the GLP1R and the glucagon receptor (e.g., survodutide, pemvidutide, cotadutide, mazdutide, MOD-6031, DR10624, DD01, XTL6001, JNJ-64565111, or NNC9204-0530). In some embodiments, the GCHR modulator is a dual agonist of the GLP1R and the gastric inhibitory peptide receptor (e.g., tirzepatide, VK2735, NNC0519-0130, BGM0504, CT-868, or CT-388). In some embodiments, the GCHR modulator is an agonist of the GLP1R and an antagonist of the gastric inhibitory peptide receptor (e.g., maridebart cafraglutide). In some embodiments, the GCHR modulator is a dual agonist of the GLP1R and the amylin receptors (e.g., amycretin). In some embodiments, the GCHR modulator is a triple agonist of the GLP1R, the glucagon receptor, and the glucosedependent insulinotropic polypeptide (e.g., retatrutide, NA-931, HM15275, efocipegtrutide, or SAR441255). In some embodiments, the GCHR modulator is an agonist of the glucagon receptor (e.g., efpegerglucagon). In some embodiments, the GCHR modulator is an antagonist of the glucagon receptor (e.g., MK-0893, PF-06291874, LY2409021, or LGD-6972). In some embodiments, the GCHR modulator is an agonist of the amylin receptors (e.g., cagrilintide, AZD6234, petrelintide, eloralintide, pramlintide, or GUB014295).

[1114] In some embodiments, the GCHR modulator is an agonist of the GLP1R (e.g., semaglutide, orforglipron, albiglutide, dulaglutide, exendin-4, liraglutide, exenatide, or lixisenatide). In some embodiments, the GCHR modulator is a dual agonist of the GLP1R and the glucagon receptor (e.g., survodutide, pemvidutide, or cotadutide). In some embodiments, the GCHR modulator is a dual agonist of the GLP1R and the gastric inhibitory peptide receptor (e.g., tirzepatide). In some embodiments, the GCHR modulator is a triple agonist of the GLP1R, the glucagon receptor, and the glucose-dependent insulinotropic polypeptide (e.g., retatrutide).

[1115] In some embodiments, the GCHR modulator is short-acting (e.g., exenatide or lixisenatide). In some embodiments, a short-acting GCHR modulator, as described herein, may have a half-life of less than 24 hours (e.g., less than 18 hours, 12 hours, 8 hours, 6 hours, 4 hours, or 2 hours). For example, in some embodiments, a short-acting GCHR modulator may have a half-life of less than 18 hours. In some embodiments, a short-acting GCHR modulator may have a half-life of less than 12 hours. In some embodiments, a short-acting GCHR modulator may have a half-life of less than 8 hours. In some embodiments, a short-acting GCHR modulator may have a half-life of less than 6 hours. In some embodiments, a short-acting GCHR modulator may have a half-life of less than 4 hours. In some embodiments, a short-acting GCHR modulator may have a half-life of less than 2 hours.

[1116] In some embodiments, the GCHR modulator is long-acting (e.g., liraglutide, exenatide, or dulaglutide). In some embodiments, a long-acting GCHR modulator, as described herein, may have a half-life of greater than 24 hours (e.g., greater than 36 hours, 48 hours, 72 hours, or 96 hours). For example, in some embodiments, a long-acting GCHR modulator may have a half-life of greater than 36 hours. In some embodiments, a long-acting GCHR modulator may have a halflife of greater than 48 hours. In some embodiments, a long-acting GCHR modulator may have a half-life of greater than 72 hours. In some embodiments, a long-acting GCHR modulator may have a half-life of greater than 96 hours.

[1117] In some embodiments, the GCHR modulator may be any compound, peptide, or bioconjugate that binds to GLP1R and augments, amplifies, enhances, or increases the endogenous GLP1R activity, e.g., by 0.1% or more (e.g., by about 0.5%, 1%, 5%, 10%, 25%, 50%, 75%, 90%, 95%, or more). For example, in some embodiments, the GCHR modulator may be any compound, peptide, or bioconjugate that binds to GLP1R and augments, amplifies, enhances, or increases the endogenous GLP1R activity, e.g., by 0.5% or more. In some embodiments, the GCHR modulator may be any compound, peptide, or bioconjugate that binds to GLP1R and augments, amplifies, enhances, or increases the endogenous GLP1R activity, e.g., by 1% or more. In some embodiments, the GCHR modulator may be any compound, peptide, or bioconjugate that binds to GLP1R and augments, amplifies, enhances, or increases the endogenous GLP1R activity, e.g., by 5% or more. In some embodiments, the GCHR modulator may be any compound, peptide, or bioconjugate that binds to GLP1R and augments, amplifies, enhances, or increases the endogenous GLP1R activity, e.g., by 10% or more. In some embodiments, the GCHR modulator may be any compound, peptide, or bioconjugate that binds to GLP1R and augments, amplifies, enhances, or increases the endogenous GLP1R activity, e.g., by 25% or more. In some embodiments, the GCHR modulator may be any compound, peptide, or bioconjugate that binds to GLP1R and augments, amplifies, enhances, or increases the endogenous GLP1R activity, e.g., by 50% or more. In some embodiments, the GCHR modulator may be any compound, peptide, or bioconjugate that binds to GLP1R and augments, amplifies, enhances, or increases the endogenous GLP1R activity, e.g., by 75% or more. In some embodiments, the GCHR modulator may be any compound, peptide, or bioconjugate that binds to GLP1R and augments, amplifies, enhances, or increases the endogenous GLP1R activity, e.g., by 90% or more. In some embodiments, the GCHR modulator may be any compound, peptide, or bioconjugate that binds to GLP1R and augments, amplifies, enhances, or increases the endogenous GLP1R activity, e.g., by 95% or more. In some embodiments, the GCHR modulator may be any compound, peptide, or bioconjugate that binds to GLP1R and augments, amplifies, enhances, or increases the endogenous GLP1R activity, e.g., by more than 95%.

[1118] In some embodiments, the GCHR modulator may be any peptide that binds to GLP1R and augments, amplifies, enhances, or increases the endogenous GLP1R activity, e.g., by 0.1% or more (e.g., by about 0.5%, 1%, 5%, 10%, 25%, 50%, 75%, 90%, 95%, or more). For example, in some embodiments, the GCHR modulator may be any peptide that binds to GLP1R and augments, amplifies, enhances, or increases the endogenous GLP1R activity, e g., by 0.5% or more. In some embodiments, the GCHR modulator may be any peptide that binds to GLP1R and augments, amplifies, enhances, or increases the endogenous GLP1R activity, e.g., by 1% or more. In some embodiments, the GCHR modulator may be any peptide that binds to GLP1R and augments, amplifies, enhances, or increases the endogenous GLP1R activity, e.g., by 5% or more. In some embodiments, the GCHR modulator may be any peptide that binds to GLP1R and augments, amplifies, enhances, or increases the endogenous GLP1R activity, e.g., by 10% or more. In some embodiments, the GCHR modulator may be any peptide that binds to GLP1R and augments, amplifies, enhances, or increases the endogenous GLP1R activity, e.g., by 25% or more. In some embodiments, the GCHR modulator may be any peptide that binds to GLP1R and augments, amplifies, enhances, or increases the endogenous GLP1R activity, e.g., by 50% or more. In some embodiments, the GCHR modulator may be any peptide that binds to GLP1R and augments, amplifies, enhances, or increases the endogenous GLP1R activity, e g., by 75% or more. In some embodiments, the GCHR modulator may be any peptide that binds to GLP1R and augments, amplifies, enhances, or increases the endogenous GLP1R activity, e.g., by 90% or more. In some embodiments, the GCHR modulator may be any peptide that binds to GLP1R and augments, amplifies, enhances, or increases the endogenous GLP1R activity, e.g., by 95% or more. In some embodiments, the GCHR modulator may be any peptide that binds to GLP1R and augments, amplifies, enhances, or increases the endogenous GLP1R activity, e.g., by more than 95%.

[1119] In some embodiments, the GCHR modulator may be any GCHR modulator that reduces appetite. In some embodiments, the GCHR modulator may be any GCHR modulator that improves satiety. In some embodiments, the GCHR modulator may be any GCHR modulator that reduces gastric motility.

[1120] In some embodiments, the GCHR modulator may be any compound, peptide, or bioconjugate that binds to the glucagon receptor and augments, amplifies, enhances, or increases the endogenous glucagon receptor activity, e.g., by 0.1% or more (e g., by about 0.5%, 1%, 5%, 10%, 25%, 50%, 75%, 90%, 95%, or more). For example, in some embodiments, the glucagon receptor agonist may be any compound, peptide, or bioconjugate that binds to the glucagon receptor and augments, amplifies, enhances, or increases the endogenous glucagon receptor activity, e.g., by 0.5% or more. In some embodiments, the glucagon receptor agonist may be any compound, peptide, or bioconjugate that binds to the glucagon receptor and augments, amplifies, enhances, or increases the endogenous glucagon receptor activity, e.g., by 1% or more. In some embodiments, the glucagon receptor agonist may be any compound, peptide, or bioconjugate that binds to the glucagon receptor and augments, amplifies, enhances, or increases the endogenous glucagon receptor activity, e.g., by 5% or more. In some embodiments, the glucagon receptor agonist may be any compound, peptide, or bioconjugate that binds to the glucagon receptor and augments, amplifies, enhances, or increases the endogenous glucagon receptor activity, e.g., by 10% or more. In some embodiments, the glucagon receptor agonist may be any compound, peptide, or bioconjugate that binds to the glucagon receptor and augments, amplifies, enhances, or increases the endogenous glucagon receptor activity, e.g., by 25% or more. In some embodiments, the glucagon receptor agonist may be any compound, peptide, or bioconjugate that binds to the glucagon receptor and augments, amplifies, enhances, or increases the endogenous glucagon receptor activity, e.g., by 50% or more. In some embodiments, the glucagon receptor agonist may be any compound, peptide, or bioconjugate that binds to the glucagon receptor and augments, amplifies, enhances, or increases the endogenous glucagon receptor activity, e.g., by 75% or more. In some embodiments, the glucagon receptor agonist may be any compound, peptide, or bioconjugate that binds to the glucagon receptor and augments, amplifies, enhances, or increases the endogenous glucagon receptor activity, e.g., by 90% or more. In some embodiments, the glucagon receptor agonist may be any compound, peptide, or bioconjugate that binds to the glucagon receptor and augments, amplifies, enhances, or increases the endogenous glucagon receptor activity, e.g., by 95% or more. In some embodiments, the glucagon receptor agonist may be any compound, peptide, or bioconjugate that binds to the glucagon receptor and augments, amplifies, enhances, or increases the endogenous glucagon receptor activity, e.g., by more than 95%.

[1121] In some embodiments, the GCHR modulator may be any compound, peptide, or bioconjugate that binds to the glucagon receptor and reduces, blocks, dampens, or decreases the endogenous glucagon receptor activity, e.g., by 0.1% or more (e g., by about 0.5%, 1%, 5%, 10%, 25%, 50%, 75%, 90%, 95%, or more). For example, in some embodiments, the glucagon receptor agonist may be any compound, peptide, or bioconjugate that binds to the glucagon receptor and reduces, blocks, dampens, or decreases the endogenous glucagon receptor activity, e.g., by 0.5% or more. In some embodiments, the glucagon receptor agonist may be any compound, peptide, or bioconjugate that binds to the glucagon receptor and reduces, blocks, dampens, or decreases the endogenous glucagon receptor activity, e.g., by 1% or more. In some embodiments, the glucagon receptor agonist may be any compound, peptide, or bioconjugate that binds to the glucagon receptor and reduces, blocks, dampens, or decreases the endogenous glucagon receptor activity, e.g., by 5% or more. In some embodiments, the glucagon receptor agonist may be any compound, peptide, or bioconjugate that binds to the glucagon receptor and reduces, blocks, dampens, or decreases the endogenous glucagon receptor activity, e.g., by 10% or more. In some embodiments, the glucagon receptor agonist may be any compound, peptide, or bioconjugate that binds to the glucagon receptor and reduces, blocks, dampens, or decreases the endogenous glucagon receptor activity, e.g., by 25% or more. In some embodiments, the glucagon receptor agonist may be any compound, peptide, or bioconjugate that binds to the glucagon receptor and reduces, blocks, dampens, or decreases the endogenous glucagon receptor activity, e.g., by 50% or more. In some embodiments, the glucagon receptor agonist may be any compound, peptide, or bioconjugate that binds to the glucagon receptor and reduces, blocks, dampens, or decreases the endogenous glucagon receptor activity, e.g., by 75% or more. In some embodiments, the glucagon receptor agonist may be any compound, peptide, or bioconjugate that binds to the glucagon receptor and reduces, blocks, dampens, or decreases the endogenous glucagon receptor activity, e.g., by 90% or more. In some embodiments, the glucagon receptor agonist may be any compound, peptide, or bioconjugate that binds to the glucagon receptor and reduces, blocks, dampens, or decreases the endogenous glucagon receptor activity, e.g., by 95% or more. In some embodiments, the glucagon receptor agonist may be any compound, peptide, or bioconjugate that binds to the glucagon receptor and reduces, blocks, dampens, or decreases the endogenous glucagon receptor activity, e.g., by more than 95%.

[1122] In some embodiments, the GCHR modulator may be any peptide that binds to the glucagon receptor and augments, amplifies, enhances, or increases the endogenous glucagon receptor activity, e.g., by 0.1% or more (e.g., by about 0.5%, 1%, 5%, 10%, 25%, 50%, 75%, 90%, 95%, or more). For example, in some embodiments, the glucagon receptor agonist peptide may be any peptide that binds to the glucagon receptor and augments, amplifies, enhances, or increases the endogenous glucagon receptor activity, e.g., by 0.5% or more. In some embodiments, the glucagon receptor agonist peptide may be any peptide that binds to the glucagon receptor and augments, amplifies, enhances, or increases the endogenous glucagon receptor activity, e g., by 1% or more. In some embodiments, the glucagon receptor agonist peptide may be any peptide that binds to the glucagon receptor and augments, amplifies, enhances, or increases the endogenous glucagon receptor activity, e.g., by 5% or more. In some embodiments, the glucagon receptor agonist peptide may be any peptide that binds to the glucagon receptor and augments, amplifies, enhances, or increases the endogenous glucagon receptor activity, e.g., by 10% or more. In some embodiments, the glucagon receptor agonist peptide may be any peptide that binds to the glucagon receptor and augments, amplifies, enhances, or increases the endogenous glucagon receptor activity, e.g., by 25% or more. In some embodiments, the glucagon receptor agonist peptide may be any peptide that binds to the glucagon receptor and augments, amplifies, enhances, or increases the endogenous glucagon receptor activity, e.g., by 50% or more. In some embodiments, the glucagon receptor agonist peptide may be any peptide that binds to the glucagon receptor and augments, amplifies, enhances, or increases the endogenous glucagon receptor activity, e.g., by 75% or more. In some embodiments, the glucagon receptor agonist peptide may be any peptide that binds to the glucagon receptor and augments, amplifies, enhances, or increases the endogenous glucagon receptor activity, e g., by 90% or more. In some embodiments, the glucagon receptor agonist peptide may be any peptide that binds to the glucagon receptor and augments, amplifies, enhances, or increases the endogenous glucagon receptor activity, e.g., by 95% or more. In some embodiments, the glucagon receptor agonist peptide may be any peptide that binds to the glucagon receptor and augments, amplifies, enhances, or increases the endogenous glucagon receptor activity, e.g., by more than 95%.

[1123] In some embodiments, the glucagon receptor agonist peptide may be any glucagon receptor agonist peptide that reduces appetite. In some embodiments, the glucagon receptor agonist peptide may be any glucagon receptor agonist peptide that improves satiety. In some embodiments, the glucagon receptor agonist peptide may be any glucagon receptor agonist peptide that reduces gastric motility.

[1124] In some embodiments, the GCHR modulator may be any compound, peptide, or bioconjugate that binds to the gastric inhibitory peptide receptor and augments, amplifies, enhances, or increases the endogenous gastric inhibitory peptide receptor activity, e.g., by 0.1% or more (e.g., by about 0.5%, 1%, 5%, 10%, 25%, 50%, 75%, 90%, 95%, or more). For example, in some embodiments, the gastric inhibitory peptide receptor agonist peptide may be any compound, peptide, or bioconjugate that binds to the gastric inhibitory peptide receptor and augments, amplifies, enhances, or increases the endogenous gastric inhibitory peptide receptor activity, e.g., by 0.5% or more. In some embodiments, the gastric inhibitory peptide receptor agonist peptide may be any compound, peptide, or bioconjugate that binds to the gastric inhibitory peptide receptor and augments, amplifies, enhances, or increases the endogenous gastric inhibitory peptide receptor activity, e.g., by 1% or more. In some embodiments, the gastric inhibitory peptide receptor agonist peptide may be any compound, peptide, or bioconjugate that binds to the gastric inhibitory peptide receptor and augments, amplifies, enhances, or increases the endogenous gastric inhibitory peptide receptor activity, e.g., by 5% or more. In some embodiments, the gastric inhibitory peptide receptor agonist peptide may be any compound, peptide, or bioconjugate that binds to the gastric inhibitory peptide receptor and augments, amplifies, enhances, or increases the endogenous gastric inhibitory peptide receptor activity, e.g., by 10% or more. In some embodiments, the gastric inhibitory peptide receptor agonist peptide may be any compound, peptide, or bioconjugate that binds to the gastric inhibitory peptide receptor and augments, amplifies, enhances, or increases the endogenous gastric inhibitory peptide receptor activity, e.g., by 25% or more. In some embodiments, the gastric inhibitory peptide receptor agonist peptide may be any compound, peptide, or bioconjugate that binds to the gastric inhibitory peptide receptor and augments, amplifies, enhances, or increases endogenous the gastric inhibitory peptide receptor activity, e.g., by 50% or more. In some embodiments, the gastric inhibitory peptide receptor agonist peptide may be any compound, peptide, or bioconjugate that binds to the gastric inhibitory peptide receptor and augments, amplifies, enhances, or increases the endogenous gastric inhibitory peptide receptor activity, e.g., by 75% or more. In some embodiments, the gastric inhibitory peptide receptor agonist peptide may be any compound, peptide, or bioconjugate that binds to the gastric inhibitory peptide receptor and augments, amplifies, enhances, or increases the endogenous gastric inhibitory peptide receptor activity, e.g., by 90% or more. In some embodiments, the gastric inhibitory peptide receptor agonist peptide may be any compound, peptide, or bioconjugate that binds to the gastric inhibitory peptide receptor and augments, amplifies, enhances, or increases the endogenous gastric inhibitory peptide receptor activity, e.g., by 95% or more. In some embodiments, the gastric inhibitory peptide receptor agonist peptide may be any compound, peptide, or bioconjugate that binds to the gastric inhibitory peptide receptor and augments, amplifies, enhances, or increases the endogenous gastric inhibitory peptide receptor activity, e.g., by more than 95%.

[1125] In some embodiments, the GCHR modulator may be any compound, peptide, or bioconjugate that binds to the gastric inhibitory peptide receptor and reduces, blocks, dampens, or decreases the endogenous gastric inhibitory peptide receptor activity, e.g., by 0.1% or more (e.g., by about 0.5%, 1%, 5%, 10%, 25%, 50%, 75%, 90%, 95%, or more). For example, in some embodiments, the gastric inhibitory peptide receptor agonist may be any compound, peptide, or bioconjugate that binds to the gastric inhibitory peptide receptor and reduces, blocks, dampens, or decreases the endogenous gastric inhibitory peptide receptor activity, e.g., by 0.5% or more. In some embodiments, the gastric inhibitory peptide receptor agonist may be any compound, peptide, or bioconjugate that binds to the gastric inhibitory peptide receptor and reduces, blocks, dampens, or decreases the endogenous gastric inhibitory peptide receptor activity, e.g., by 1% or more. In some embodiments, the gastric inhibitory peptide receptor agonist may be any compound, peptide, or bioconjugate that binds to the gastric inhibitory peptide receptor and reduces, blocks, dampens, or decreases the endogenous gastric inhibitory peptide receptor activity, e.g., by 5% or more. In some embodiments, the gastric inhibitory peptide receptor agonist may be any compound, peptide, or bioconjugate that binds to the gastric inhibitory peptide receptor and reduces, blocks, dampens, or decreases the endogenous gastric inhibitory peptide receptor activity, e.g., by 10% or more. In some embodiments, the gastric inhibitory peptide receptor agonist may be any compound, peptide, or bioconjugate that binds to the gastric inhibitory peptide receptor and reduces, blocks, dampens, or decreases the endogenous gastric inhibitory peptide receptor activity, e.g., by 25% or more. In some embodiments, the gastric inhibitory peptide receptor agonist may be any compound, peptide, or bioconjugate that binds to the gastric inhibitory peptide receptor and reduces, blocks, dampens, or decreases the endogenous gastric inhibitory peptide receptor activity, e.g., by 50% or more. In some embodiments, the gastric inhibitory peptide receptor agonist may be any compound, peptide, or bioconjugate that binds to the gastric inhibitory peptide receptor and reduces, blocks, dampens, or decreases the endogenous gastric inhibitory peptide receptor activity, e.g., by 75% or more. In some embodiments, the gastric inhibitory peptide receptor agonist may be any compound, peptide, or bioconjugate that binds to the gastric inhibitory peptide receptor and reduces, blocks, dampens, or decreases the endogenous gastric inhibitory peptide receptor activity, e.g., by 90% or more. In some embodiments, the gastric inhibitory peptide receptor agonist may be any compound, peptide, or bioconjugate that binds to the gastric inhibitory peptide receptor and reduces, blocks, dampens, or decreases the endogenous gastric inhibitory peptide receptor activity, e.g., by 95% or more. In some embodiments, the gastric inhibitory peptide receptor agonist may be any compound, peptide, or bioconjugate that binds to the gastric inhibitory peptide receptor and reduces, blocks, dampens, or decreases the endogenous gastric inhibitory peptide receptor activity, e.g., by more than 95%. In some embodiments, the GCHR modulator may be any peptide that binds to the gastric inhibitory peptide receptor and augments, amplifies, enhances, or increases the endogenous gastric inhibitory peptide receptor activity, e.g., by 0.1% or more (e.g., by about 0.5%, 1%, 5%, 10%, 25%, 50%, 75%, 90%, 95%, or more). For example, in some embodiments, the gastric inhibitory peptide receptor agonist peptide may be any peptide that binds to the gastric inhibitory peptide receptor and augments, amplifies, enhances, or increases the endogenous gastric inhibitory peptide receptor activity, e.g., by 0.5% or more. In some embodiments, the gastric inhibitory peptide receptor agonist peptide may be any peptide that binds to the gastric inhibitory peptide receptor and augments, amplifies, enhances, or increases the endogenous gastric inhibitory peptide receptor activity, e.g., by 1% or more. In some embodiments, the gastric inhibitory peptide receptor agonist peptide may be any peptide that binds to the gastric inhibitory peptide receptor and augments, amplifies, enhances, or increases the endogenous gastric inhibitory peptide receptor activity, e.g., by 5% or more. In some embodiments, the gastric inhibitory peptide receptor agonist peptide may be any peptide that binds to the gastric inhibitory peptide receptor and augments, amplifies, enhances, or increases the endogenous gastric inhibitory peptide receptor activity, e.g., by 10% or more. In some embodiments, the gastric inhibitory peptide receptor agonist peptide may be any peptide that binds to the gastric inhibitory peptide receptor and augments, amplifies, enhances, or increases the endogenous gastric inhibitory peptide receptor activity, e.g., by 25% or more. In some embodiments, the gastric inhibitory peptide receptor agonist peptide may be any peptide that binds to the gastric inhibitory peptide receptor and augments, amplifies, enhances, or increases endogenous the gastric inhibitory peptide receptor activity, e.g., by 50% or more. In some embodiments, the gastric inhibitory peptide receptor agonist peptide may be any peptide that binds to the gastric inhibitory peptide receptor and augments, amplifies, enhances, or increases the endogenous gastric inhibitory peptide receptor activity, e.g., by 75% or more. In some embodiments, the gastric inhibitory peptide receptor agonist peptide may be any peptide that binds to the gastric inhibitory peptide receptor and augments, amplifies, enhances, or increases the endogenous gastric inhibitory peptide receptor activity, e.g., by 90% or more. In some embodiments, the gastric inhibitory peptide receptor agonist peptide may be any peptide that binds to the gastric inhibitory peptide receptor and augments, amplifies, enhances, or increases the endogenous gastric inhibitory peptide receptor activity, e.g., by 95% or more. In some embodiments, the gastric inhibitory peptide receptor agonist peptide may be any peptide that binds to the gastric inhibitory peptide receptor and augments, amplifies, enhances, or increases the endogenous gastric inhibitory peptide receptor activity, e.g., by more than 95%.

[1126] In some embodiments, the gastric inhibitory peptide receptor agonist peptide may be any gastric inhibitory peptide receptor agonist peptide that reduces appetite. In some embodiments, the gastric inhibitory peptide receptor agonist peptide may be any gastric inhibitory peptide receptor agonist peptide that improves satiety. In some embodiments, the gastric inhibitory peptide receptor agonist peptide may be any gastric inhibitory peptide receptor agonist peptide that reduces gastric motility.

[1127] GLP1 sequences and exemplary GCHR modulators are provided in Table 2 below.

[1128] Table 2. Exemplary sequences

[1129]

[1130]

[1131] In some embodiments, the GCHR modulator may comprise an amino acid sequence, or a fragment thereof, sharing at least 70% or more (e.g., at least 75%, 80%, 85%, 90%, 95%, 99%, or more) sequence identity with the amino acid sequence of any one of SEQ ID NOs: 694-706, or a fragment thereof. For example, in some embodiments, the GCHR modulator may comprise an amino acid sequence, or a fragment thereof, sharing at least 75% or more sequence identity with the amino acid sequence of any one of SEQ ID NOs: 694-721, or a fragment thereof. In some embodiments, the GCHR modulator may comprise an amino acid sequence, or a fragment thereof, sharing at least 80% or more sequence identity with the amino acid sequence of any one of SEQ ID NOs: 694-721, or a fragment thereof. In some embodiments, the GCHR modulator may comprise an amino acid sequence, or a fragment thereof, sharing at least 85% or more sequence identity with the amino acid sequence of any one of SEQ ID NOs: 694-721, or a fragment thereof. In some embodiments, the GCHR modulator may comprise an amino acid sequence, or a fragment thereof, sharing at least 90% or more sequence identity with the amino acid sequence of any one of SEQ ID NOs: 694-721, or a fragment thereof. In some embodiments, the GCHR modulator may comprise an amino acid sequence, or a fragment thereof, sharing at least 95% or more sequence identity with the amino acid sequence of any one of SEQ ID NOs: 694-721, or a fragment thereof. In some embodiments, the GCHR modulator may comprise an amino acid sequence, or a fragment thereof, sharing at least 99% or more sequence identity with the amino acid sequence of any one of SEQ ID NOs: 694-721, or a fragment thereof. In some embodiments, the GCHR modulator may comprise an amino acid sequence, or a fragment thereof, sharing more than 99% sequence identity with the amino acid sequence of any one of SEQ ID NOs: 694-721, or a fragment thereof.

[1132] In some embodiments, the GCHR modulator may comprise an amino acid sequence, or a fragment thereof, sharing at least 70% or more (e.g., at least 75%, 80%, 85%, 90%, 95%, 99%, or more) sequence homology with the amino acid sequence of any one of SEQ ID NOs: 694-721, or a fragment thereof. For example, in some embodiments, the GCHR modulator may comprise an amino acid sequence, or a fragment thereof, sharing at least 75% or more sequence homology with the amino acid sequence of any one of SEQ ID NOs: 694-721, or a fragment thereof. In some embodiments, the GCHR modulator may comprise an amino acid sequence, or a fragment thereof, sharing at least 80% or more sequence homology with the amino acid sequence of any one of SEQ ID NOs: 694-721, or a fragment thereof. In some embodiments, the GCHR modulator may comprise an amino acid sequence, or a fragment thereof, sharing at least 85% or more sequence homology with the amino acid sequence of any one of SEQ ID NOs: 694-721, or a fragment thereof. In some embodiments, the GCHR modulator may comprise an amino acid sequence, or a fragment thereof, sharing at least 90% or more sequence homology with the amino acid sequence of any one of SEQ ID NOs: 694-721, or a fragment thereof. In some embodiments, the GCHR modulator may comprise an amino acid sequence, or a fragment thereof, sharing at least 95% or more sequence homology with the amino acid sequence of any one of SEQ ID NOs: 694-721, or a fragment thereof. In some embodiments, the GCHR modulator may comprise an amino acid sequence, or a fragment thereof, sharing at least 99% or more sequence homology with the amino acid sequence of any one of SEQ ID NOs: 694-721, or a fragment thereof. In some embodiments, the GCHR modulator may comprise an amino acid sequence, or a fragment thereof, sharing more than 99% sequence homology with the amino acid sequence of any one of SEQ ID NOs: 694-721, or a fragment thereof. In some embodiments, the GCHR modulator may be administered daily. In some embodiments, the GCHR modulator may be administered every other day. In some embodiments, the GCHR modulator may be administered twice per week. In some embodiments, the GCHR modulator may be administered once per week. In some embodiments, the GCHR modulator may be administered once every other week. In some embodiments, the GCHR modulator may be administered once every 4 weeks. In some embodiments, the GCHR modulator may be administered once per month. In some embodiments, the GCHR modulator may be administered once every 8 weeks. In some embodiments, the GCHR modulator may be administered once every 16 weeks.

[1133] In some embodiments, the GCHR modulator may be administered orally, intravenously, intraperitoneally, or subcutaneously. In some embodiments, the GCHR modulator may be administered orally. In some embodiments, the GCHR modulator may be administered intravenously. In some embodiments, the GCHR modulator may be administered intraperitoneally. In some embodiments, the GCHR modulator may be administered subcutaneously.

[1134] In another aspect, the GCHR modulators for use in the methods described herein include small molecule GCHR modulators. GCHR modulators that may be administered in combination with MC4R agonists according to the methods describe herein include any GLP-1 small molecule agonists known in the art, e.g., any of the small molecule agonists described in US20220298148A1, US20220306614A1, US11858918B2, US11851419B2, US20230021705A1, and US20210171499A1, which are hereby incorporated by reference in their entirety.

[1135] In some embodiments, the GCHR modulator is a compound of Formula (XIII):

[1136]

[1137] or a pharmaceutically acceptable salt thereof wherein R1is a phenyl or a 6 membered heteroaryl optionally substituted with 1, 2, or 3 R4; X1is -C(H)= or -C(R8)=; X4is -C(H)=, -C(R8)=, or N; each R4is independently halogen or -CN; each R5is independently C1-9 alkyl, Ci-s haloalkyl, or halogen; each R8is independently halogen; and n is 0, 1, 2, or 3.

[1138] In some embodiments, the GCHR modulator is a compound selected from the following:

[1139]

[1140]

[1141] In another aspect, the GCHR modulators for use in the methods described herein include small molecule GCHR modulators. GCHR modulators that may be administered in combination with MC4R agonists according to the methods describe herein include any GLP-1 small molecule agonists known in the art, e.g., any of the small molecule agonists described in US10208019B2, US10669259B2, US10851081B2, US11512070B2, US11802121B2, US12319669B2, or US20250257052A1, which are hereby incorporated by reference in their entirety.

[1142] In some embodiments, the GCHR modulator is a compound of Formula (Xlll-a):

[1143]

[1144] or a pharmaceutically acceptable salt thereof, wherein each R1is independently halogen, -CN, -Ci-3alkyl, or -OCnsalkyl, wherein the alkyl of Ci-3alkyl and OCi-3alkyl is substituted with 0 to 3 F atoms; m is 0, 1, 2, or 3; each R2is independently F, Cl, or -CN; p is 0, 1 or 2; each R3is independently F, -OH, -CN, -Ci-3alkyl, -OCi-3alkyl, or -C3-4cycloalkyl, or 2 R3s may together cyclize to form -C3-4spirocycloalkyl, wherein the alkyl of Ci-3alkyl and OCi-salkyl, cycloalkyl, or spirocycloalkyl may be substituted as valency allows with 0 to 3 F atoms and with 0 to 1 -OH; q is 0, 1, or 2; Y is CH or N; R4is -Ci-3alkyl, -Co-3alkylene-C3-6cycloalkyl, -Co-3alkylene-R5, or -Ci-salkylene-R6, wherein said alkyl may be substituted as valency allows with 0 to 3 substituents independently selected from 0 to 3 F atoms and 0 to 1 substituent selected from -Co-ialkylene-CN, -Co-ialkylene-OR°, and -N(RN)2, and wherein said alkylene and cycloalkyl may be independently substituted as valency allows with 0 to 2 substituents independently selected from 0 to 2 F atoms and 0 to 1 substituent selected from -Co-ialkylene-CN, -Co-ialkylene-OR°, and -N(RN); R3is a 4- to 6-membered heterocycloalkyl, wherein said heterocycloalkyl may be substituted with 0 to 2 substituents as valency allows independently selected from 0 to 1 oxo (=0), 0 to 1 -CN, 0 to 2 F atoms, and 0 to 2 substituents independently selected from -Ci-3alkyl and -OCi salkyl, wherein the alkyl of Ci-3alkyl and OCi-3alkyl may be substituted with 0 to 3 substituents as valency allows independently selected from 0 to 3 F atoms, 0 to 1 -CN, and 0 to 1 -OR°; R6is a 5- to 6-membered heteroaryl, wherein said heteroaryl may be substituted with 0 to 2 substituents as valency allows independently selected from 0 to 2 halogens, 0 to 1 substituent selected from -OR° and -N(RN)2, and 0 to 2 -Ci-3alkyl, wherein the alkyl may be substituted with 0 to 3 substituents as valency allows independently selected from 0 to 3 F atoms, and 0 to 1 -OR°; each R° is independently H, or -Ci-3alkyl, wherein Ci-3alkyl may be substituted with 0 to 3 F atoms; each RNis independently H, or -Ci-3alkyl; Z1is CH or N; Z2and Z3are each independently -CRZor N, provided that when Z1or Z3is N, Z2is -CRZ; and each Rzis independently H, F, Cl, or -CH3.

[1145] In some embodiments, the GCHR modulator is a compound selected from:

[1146]

[1147] pharmaceutically acceptable salt thereof.

[1148] GCHR modulators that may be administered in combination with MC4R agonists according to the methods describe herein include any GLP-1 small molecule agonists known in the art, e.g., any of the small molecule agonists described in USRE50455E1, US10858356B2, US11814381B2, US12187724B2, US12331049B2, US12410168B2, US12331050B2, or US20250092041 Al, which are hereby incorporated by reference in their entirety.

[1149] In some embodiments, the GCHR modulator is a compound of Formula (Xlll-b):

[1150]

[1151] wherein, X is — N= or — CRa=; Rais selected from a hydrogen atom, a halogen atom, and Ci-6 alkyl; Y is selected from — C(=O) —, — CHR —, and — S(=O)2 —; R is a hydrogen atom or Ci-6 alkyl; Q1is Ce-io aryl or 5 to 10 membered heteroaryl, wherein Ce-io aryl and 5 to 10 membered heteroaryl are optionally substituted with one to five substituents independently elected from a halogen atom, Ci-6 alkyl (wherein Ci-6 alkyl is optionally substituted with one or more halogen atoms), and Ci-6 alkoxy; Q2is 3 to 12 membered heterocyclyl or 5 to 10 membered heteroaryl, wherein 3 to 12 membered heterocyclyl and 5 to 10 membered heteroaryl are optionally substituted with one to three substituents independently selected from a halogen atom, Ci-6 alkyl (wherein Ci-6 alkyl is optionally substituted with one or more halogen atoms), Ci-6 alkoxy, and — NRQaRQb, and two Ci-6 alkyl groups together with a carbon atom to which they are attached may form C3-8 carbocyclic ring; and RQaand RQbare independently selected from a hydrogen atom, C1-6 alkyl, and (C1-6 alkyl)carbonyl; R1, R2and R3are each independently selected from a hydrogen atom and C1-6 alkyl (wherein, C1-6 alkyl is optionally substituted with one or more substituents independently selected from a halogen atom, C1-6 alkoxy, and hydroxy); R4, R5and R6are independently selected from a hydrogen atom, a halogen atom, and C1-6 alkyl; R7and R8are independently a hydrogen atom or C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more substituents independently selected from a halogen atom and C3-15 cycloalkyl, or R7and R8together with a carbon atom to which they are attached may form C3-15 cycloalkane ring, wherein C3-15 cycloalkane ring formed by R7and R8together is optionally substituted with one to three C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more substituents independently selected from a halogen atom, hydroxy, — NR7:lR7b, C1-6 alkoxy, and 3 to 12 membered heterocyclyl, and R7aand R7bare independently selected from a hydrogen atom, C1-6 alkyl, and (Ci-6alkyl)carbonyl; nl is an integer of 0 to 3; n2 is an integer of 0 to 5; R9is selected from the group consisting of

[1152]

[1153] R9a, R9b, R9C, R9d, and R9gare each independently selected from a hydrogen atom, Ci- 6 alkyl (wherein C1-6 alkyl is optionally substituted with one or more substituents independently selected from a halogen atom and C1-6 alkoxy), and (C1-6 alkyl)carbonyl; R9eis a hydrogen atom, or C1-6 alkyl that is optionally substituted with one or more halogen atoms; R9fis a hydrogen atom or C1-6 alkyl; R91’ is a hydrogen atom, C1-6 alkyl, (C1-6 alkyl)carbonyl, cyano, or —

[1154] S(= O)n3 — R91; n3 is an integer of 0 to 2; and R91is C1-6 alkyl; Z1is selected from the group consisting of

[1155]

[1156] wherein Rzais selected from a hydrogen atom, Ci-6 alkyl, and (Ci-6 alkyl)carbonyl; Rzband Rzcare independently a hydrogen atom or Ci-6 alkyl; n4 is an integer of 1 to 3; n5 and n6 are independently an integer of 0 to 10 (* represents a binding position with a pyrazolopyridine structure, and ** represents a binding position with Z2); Z2is selected from the group consisting of Ci-6 alkyl, C3-15 cycloalkyl, 3 to 12 membered heterocyclyl, Ce-io aryl and 5 to 10 membered heteroaryl, wherein C3-15 cycloalkyl, 3 to 12 membered heterocyclyl, Ce-io aryl, and 5 to 10 membered heteroaryl are optionally substituted with one to five substituents independently selected from Group A: Group A: a) oxo, b) a halogen atom, c) cyano, d) — NRzdRze; wherein Rzdand Rzeare independently selected from a hydrogen atom, C1-6 alkyl and (Ci-ealkyl)carbonyl, wherein C1-6 alkyl is optionally substituted with one or more substituents independently selected from hydroxy, a halogen atom and C1-6 alkoxy, e) — C(=O) — NRztRzg; wherein Rzfand Rzgare independently selected from a hydrogen atom, C1-6 alkyl and (Ci-6alkyl)carbonyl, wherein Ci-6 alkyl is optionally substituted with one or more substituents independently selected from hydroxy, a halogen atom and C1-6 alkoxy, f) — S(=O)n7 — Rzh; wherein n7 is an integer of 0 to 2; and Rzhis a hydrogen atom or C1-6 alkyl, g) C1-6 alkyl; wherein C1-6 alkyl is optionally substituted with one or more substituent independently selected from a halogen atom, hydroxy, — NRzlRzj, C1-6 alkoxy, and 3 to 12 membered heterocyclyl, wherein RZ1and Rziare independently a hydrogen atom or C1-6 alkyl, and wherein 3 to 12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from hydroxy, C1-6 alkyl and 3 to 12 membered heterocyclyl, h) C1-6 alkoxy; wherein C1-6 alkoxy is optionally substituted with one or more substituent independently selected from hydroxy, a halogen atom, and C1-6 alkoxy, i) 3 to 12 membered heterocyclyl; wherein 3 to 12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from C1-6 alkyl and (Ci-ealkyl)carbonyl, j) Ce-10 aryl; wherein Ce-io aryl is optionally substituted with one or more (C1-6 alkyl)carbonyl, and k) 5 to 10 membered heteroaryl; wherein 5 to 10 membered heteroaryl is optionally substituted with one or more substituents independently selected from C1-6 alkyl, C1-6 alkoxy, — NRzkRzl, and 3 to 12 membered heterocyclyl, wherein Rzkand Rzlare independently selected from a hydrogen atom, C1-6 alkyl and (C1-6 alkyl)carbonyl, and wherein 3 to 12 membered heterocyclyl is optionally substituted with one or more substituents independently selected from Ci-6 alkyl and (Ci-6 alkyl)carbonyl; or a salt thereof.

[1157] In some embodiments, the GCHR modulator is a compound selected from:

[1158]

[1159]

[1160] pharmaceutically acceptable salt thereof. GCHR modulators that may be administered in combination with MC4R agonists according to the methods describe herein include any GLP-1 small molecule agonists known in the art, e.g., any of the small molecule agonists described in US10934279B2, US10683281B2, US10676465B2, US20210163455A1, or US12378230B2, which are hereby incorporated by reference in their entirety.

[1161] In some embodiments, the GCHR modulator is a compound of Formula (XIII-c):

[1162]

[1163] (Xlll-c),

[1164] or a pharmaceutically acceptable salt thereof, wherein R is F, Cl, or -CN; p is 0 or 1; Ring A is phenyl or a 6-membered heteroaryl; m is 0, 1, 2, or 3; each R1is independently selected from halogen, -CN,-Ci-3alkyl, or -OCi-3alkyl, wherein the alkyl of Cnsalkyl and OCi-3alkyl is ubstituted with 0 to 3 F atoms; R2is H or -Cnsalkyl, wherein alkyl is substituted with 0 to 1 OH; each R3is independently F, -OH, -CN, -Ci-3alkyl, -OCi-3alkyl, or -C3-4cycloalkyl, or 2 R3s may together cyclize to form -C3-4spirocycloalkyl, wherein the alkyl of Cnsalkyl and OCnsalkyl, cycloalkyl, or spirocycloalkyl may be substituted as valency allows with 0 to 3 F atoms and with 0 to 1 -OH; q is 0, 1, or 2; X-L is N-CH2, CHCH2, or cyclopropyl; Y is CH or N; R4is -Cisalkyl, -Co-3alkylene-C3-6cycloalkyl, -Co-3alkylene-R5, or -Ci-salkylene-R6, wherein said alkyl may be substituted as valency allows with 0 to 3 substituents independently selected from 0 to 3 F atoms and 0 to 1 substituent selected from -Co-ialkylene-CN, -Co-ialkylene-OR°, -SO2-N(RN)2, -C(O)-N(Rn)2, -N(C=O)(Rn), and -N(Rn)2, and wherein said alkylene and cycloalkyl may be independently substituted as valency allows with 0 to 2 substituents independently selected from 0 to 2 F atoms and 0 to 1 substituent selected from -Co-ialkylene-CN, -Co-ialkylene-OR0, and -N(RN)2; R5is a 4- to 6-membered heterocycloalkyl, wherein said heterocycloalkyl may be substituted with 0 to 2 substituents as valency allows independently selected from: 0 to 1 oxo (=0), 0 to 1 -CN, 0 to 2 F atoms, and 0 to 2 substituents independently selected from -Ci salkyl and -OCi-3alkyl, wherein the alkyl of Ci-salkyl and OCi-3alkyl may be substituted with 0 to 3 substituents as valency allows independently selected from: 0 to 3 F atoms, 0 to 1 -CN, and 0 to 1 -OR0; R6is a 5- to 6-membered heteroaryl, wherein said heteroaryl may be substituted with 0 to 2 substituents as valency allows independently selected from: 0 to 2 halogens, 0 to 1 substituent selected from -OR° and -N(RN)2, and 0 to 2 -Ci-3alkyl, wherein the alkyl may be substituted with 0 to 3 substituents as valency allows independently selected from 0 to 3 F atoms, and 0 to 1 -OR0; each R° is independently H, or -Ci-3alkyl, wherein Ci-3alkyl may be substituted with 0 to 3 F atoms; each RNis independently H, or -Ci-3alkyl; Z1, Z2, and Z3are each -CRZ, or one of Z1, Z2, and Z3is N and the other two are -CRZ; and each Rzis independently H, F, Cl, or -CH3.

[1165] In some embodiments, the GCHR modulator is a compound selected from:

[1166]

[1167] GCHR modulators that may be administered in combination with MC4R agonists according to the methods describe herein include any GLP-1 small molecule agonists known in the art, e.g., any of the small molecule agonists described in US11492365B2 or US11926643B2, which are hereby incorporated by reference in their entirety.

[1168] In some embodiments, the GCHR modulator is a compound of Formula (XHI-d):

[1169]

[1170] (Xlll-d),

[1171] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[1172] Q1, Q2, Q3, Q4, and Q5are defined according to (AA) or (BB) below:

[1173] (AA)

[1174] Q1and Q5are independently selected from the group consisting of N, CH, and CRQA;

[1175] Q2, Q3, and Q4are independently selected from the group consisting of N, CH, CRQA, and CRQB, provided that at least one of Q2, Q3, and Q4is CRQB; each —

[1176] is a single bond or double bond, provided that the ring including Q3-Q5is aromatic;

[1177] IBB) Q1is a bond;

[1178] Q2, Q3, Q4, and Q5are independently selected from the group consisting of O, S, N, NH, NRC, CH, CRQA, and CRQB, provided that at least one of Q2, Q3, Q4, and Q5is CRQB;

[1179] each = is a single bond or double bond, provided that the ring including Q1- Q5is aromatic;

[1180] RQBis P (=O)RaRb, wherein Raand Rbare independently selected from the group consisti ng of Ci-6 alkyl which is optionally substituted with from 1- 6 substituents each independently selected from the group consisting of Ci-6 alkoxy, C3- 6 cycloalkyl, and halo; C3-6 cycloalkyl optionally substituted with from 1- 3 substituents each independently selected from the group consisting of Ci- 3 alkyl and halo; and Ce-io aryl optionally substituted with from 1-3 independently selected Ci- 3 alkyl; or

[1181] Raand Rbtaken together with the phosphorous atom to which each is attached form a rin g including from 5-8 ring atoms, wherein from 0- 2 ring atoms (in addition to the phosphorous attached to Raand Rb) are heteroatoms each indepen dently selected from the group consisting of: O, S, and N, wherein the ring is optionally substitut ed with from 1-3 independently selected Ci-6 alkyl;

[1182] each RQAis independently selected from the group consisting of: (a) halo; (b) cyano; (c) OH; (d) -NRcRd; (e) C(=O)NRcRd; (f) S(=0)o-2Re; (g) Ci- 6 alkyl optionally substituted with from 1-6 independently selected Rf; (h) Ci- 6 alkoxy optionally substituted with from 1- 6 substituents each independently selected from the group consisting of: hydroxy, halo, and Ci- 6 alkoxy; (i) 3- 12 membered heterocyclyl optionally substituted with one or more substituents each independent ly selected from the group consisting of Ci-6 alkyl and C(=O)(Ci-6 alkyl); (j) Ce- 10 aryl optionally substituted with from 1-3 independently selected C(=O)(C i-6 alkyl); and (k) 5- 10 membered heteroaryl optionally substituted with from 1-6 independently selected Rg;

[1183] or a pair of RQAon adjacent carbon atoms, taken together with the atom to which each is attached, forms a ring including from 5-8 ring atoms, wherein from 0- 2 ring atoms are heteroatoms each independently selected from the group consisting of O, N, and S, wherein said ring is optionally substituted with from 1-2 independently selected Rhgroups;

[1184] L2is selected from the group consisting of:

[1185]

[1186] wherein act represents the point of attachment to the ring containing Q’-Q5;

[1187] nl is an integer from 1-3;

[1188] L2Ais a bond or Ci-io alkylene;

[1189] RLais selected from the group consisting of H, Ci-6 alkyl, and C(=O)(C i-6 alkyl); each of RLband RLcis independently selected from the group consisting of H and Ci-6 alkyl;

[1190] Ring A is Ce-io aryl, C5-7 cycloalkyl, 5-7 membered heterocyclyl, or 5- 10 membered heteroaryl, each of which is optionally substituted with from 1- 5 substituents each independently selected from the group consisting of halo, C1-6 alkyl, Ci- 6 haloalkyl, and C1-6 alkoxy; R1, R2, and R3are each independently selected from the group consisting of H and Ci-6 alkyl which is optionally substituted with from 1- 6 substituents each independently selected from the group consisting of halo, -OH, and Ci- 6 alkoxy;

[1191] L1is selected from the group consisting of: -C(=O)-, -CH2-, -CH(C 1-6 alkyl)-, and -S(=O)2;

[1192] Ring B is selected from the group consisting of:

[1193]

[1194] wherein bb represents point of attachment to L1;

[1195] R4, R5, R6, and R7are independently selected from the group consisting of: H, halo, and C1-6 alkyl;

[1196] L3is a bond or C1-3 alkylene;

[1197] L4is a bond or C1-5 alkylene;

[1198] R8aand R8bare independently selected from the group consisting of: H and Ci- 6 alkyl optionally substituted with one or more substituents independently selected from the grou p consisting of: halo and C3-15 cycloalkyl; or

[1199] R8aand R8btaken together with the carbon atom to which each is attached forms a C3- 15 cycloalkyl ring which is optionally substituted with from 1-3 independently selected Ci- 6 alkyl, wherein the C1-6 alkyl is optionally substituted with from 1-6 independently selected Rf;

[1200] R9is selected from the group consisting of: C(=O)OH, C(=O)(OC 1- 6 alkyl), C(=O)NR9aR9b, (IX-1), (IX-2), (IX-3), and (IX-4):

[1201]

[1202] R9bis H, C1-6 alkyl, C(=O)(C 1-6 alkyl), S(0)o-2(C 1-6 alkyl), or cyano; R9C, R9d, R9e, R9t, and R9gare each independently selected from the group consisting of: H; Ci-6 alkyl optionally substituted with from 1-6 independently selected halo and Ci-6 alkoxy; and C(=O)(Ci-6 alkyl);

[1203] Ring C is selected from the group consisting of 3-12 membered heterocyclyl; C3- 15 cycloalkyl; and 5- 10 membered heteroaryl, each of which is optionally substituted with from 1-3 RCa;

[1204] each RCais independently selected from the group consisting of: halo, C 1-6 alkyl, C 1- 6 haloalkyl, C1-6 alkoxy, and NRcRd;

[1205] or a pair of RCaon the same or different ring atoms, taken together with the ring atom(s) t o which each is attached, forms a carbocyclic ring including from 3-8 ring atoms;

[1206] each Rcand Rdare independently selected from the group consisting of: H, Ci- 6 alkyl, C(=O)(Ci-6 alkyl), C(=O)(C3-6 cycloalkyl), C(=O)O(Ci-6 alkyl), S(O)i-2(Ci- 6 alkyl), and S(O)i-2(C3-6 cycloalkyl), wherein the C1-6 alkyl, C(=O)(Ci-6 alkyl), C(=O)(C3- 6 cycloalkyl), C(=O)O(Ci-6 alkyl), S(O)i-2(Ci-6 alkyl), and S(O)i-2(C 3- 6 cycloalkyl) are each optionally substituted with from 1- 6 substituents independently selected from the group consisting of: -OH, halo, and C1-6 alkoxy;

[1207] Reis H, C1-6 alkyl, or C1-6 haloalkyl;

[1208] each Rfis independently selected from the group consisting of halo, -OH, NRcRd, Ci- 6 alkoxy, C1-6 haloalkoxy, and 3- 12 membered heterocyclyl which is optionally substituted with from 1- 4 substituents each independently selected from the group consisting of -OH, C1-6 alkyl, and 3-12 membered heterocyclyl;

[1209] each Rgis independently selected from the group consisting of: C1-6 alkyl, Ci- 6 alkoxy, NRcRd, and 3 to 12 membered heterocyclyl optionally substituted with one or more sub stituents each independently selected from the group consisting of C1-6 alkyl and C(=O)Ci- 6 alkyl; and

[1210] each Rhis independently selected from the group consisting of halo, cyano, C1-6 alkyl, Ci-6 haloalkyl, -OH, NH2, NH(Ci-3alkyl), N(CI-3 alkyl)2, C1-3 alkoxy, and C1-3 haloalkoxy. In some embodiments, the GCHR modulator is a compound selected from:

[1211]

[1212]

[1213] pharmaceutically acceptable salt thereof.

[1214] GCHR modulators that may be administered in combination with MC4R agonists according to the methods describe herein include any GLP-1 small molecule agonists known in the art, e.g., any of the small molecule agonists described in US12037339B2, US11584751B1, or US20250059192A1, which are hereby incorporated by reference in their entirety.

[1215] In some embodiments, the GCHR modulator is a compound of Formula (Xlll-e):

[1216]

[1217] or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherei n:

[1218]

[1219] Ri is (CRCRC)O-2-C3-C6cycloalkyl, (CRcRc)o-2-phenyl, or (CRcRc)o-2-heteroaryl comprising one 5-or 6-membered ring and 1- 3 heteroatoms selected from N, O, and S, wherein the cycloalkyl, phenyl, or heteroaryl is optiona lly substituted with one or more substituents independently selected from Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, OH, halogen, NH2, NH-(Ci-Ce alkyl), N(Ci- Ce alkyl)2, CN, NO2, and C3-C6 cycloalkyl, wherein the cycloalkyl is a spiro-, bridged-, or monocycloalkyl;

[1220] each Rc is independently H, C1-C3 alkyl, or C1-C3 haloalkyl;

[1221] R2 is C3-C10 cycloalkyl, phenyl, heterocyclyl comprising one or two 5-or 6-membered rings and 1- 3 heteroatoms selected from N, O, and S, or heteroaryl comprising one or two 5-or 6-membered rings and 1- 3 heteroatoms selected from N, O, and S, wherein the cycloalkyl, phenyl, heterocyclyl, or hetero aryl is optionally substituted with one or more substituents independently selected from Ci-Ce alkyl optionally substituted with Ci-Ce alkoxy, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, OH, halogen, NH2, NH-(Ci-Ce alkyl), N(Ci- Ce alkyl)2, CN, and NO2, wherein the cycloalkyl is a spiro-, bridged-, or mono-cycloalkyl;

[1222]

[1223] is a bicyclic heteroaryl ring selected from

[1224]

[1225]

[1226] each R3 is independently halogen, C3- C10 cycloalkyl, phenyl, heterocyclyl comprising one or two 3-to 6-membered rings and 1- 3 heteroatoms selected from N, O, and S, or heteroaryl comprising one or two 5-or 6-membered rings and 1- 3 heteroatoms selected from N, O, and S, wherein the cycloalkyl, phenyl, heterocyclyl, or hetero aryl is optionally substituted with one or more substituents independently selected from Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, OH, halogen, NH2, NH-(Ci-Cealkyl), N(Ci-Ce alkyl)2, CN, and NO2, wherein the cycloalkyl is a spiro-, bridged-, or monocycloalkyl, provided that at least one R3 is cycloalkyl, phenyl, heterocyclyl, or heteroaryl;

[1227] R4 is Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, NH-(Ci-Ce alkyl), N(Ci-Ce alkyl), or CN;

[1228]

[1229] or phenylenyl, wherein the phenylenyl is optionally substituted with one or more substituents ind ependently selected from Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci- Ce haloalkoxy, and halogen, or wherein when the phenylenyl is substituted with two substituents attached to adjacent carbon atoms in the phenylenyl ring, the two substituents, together with the carbon atoms to which they are attached, may form a 5-or 6-membered ring optionally comprising 1-3 heteroatoms selected from N, O, and S;

[1230] R5 and Re are each independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci- Ce haloalkoxy, OH, or halogen, or R5 and Re, together with the carbon atom to which they are att ached, form C3- Ce cycloalkyl optionally substituted with one or more substituents independently selected from C i-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, OH, and halogen; and

[1231] T is C(O)OH, (CH2)NHS(O)2-(Ci-Ce alkyl), or heteroaryl comprising one 5-or 6-membered ring and 1- 3 heteroatoms selected from N, O, and S, wherein the heteroaryl is optionally substituted with Ci -Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, OH, halogen, or oxo, and when L is

[1232]

[1233] T is not C(O)OH, or when L is phenylenyl substituted with two substituents attached to a djacent carbon atoms in the phenylenyl ring, and the two substituents, together with the carbon at oms to which they are attached, form a 5-or 6-membered ring, T is H,

[1234]

[1235] T is oxadi azol onyl, each R3 is independently F, heterocyclyl comprising one or two 3-to 6-membered rings and 1- 3 heteroatoms selected from N, O, and S, or heteroaryl comprising one or two 5-or 6-membered rings and 1- 3 heteroatoms selected from N, O, and S, wherein the heterocyclyl or heteroaryl is optionally sub

[1236] stituted,

[1237]

[1238] and Rs and Re, together with the carbon atom to which they are attached, form C3- Ce cycloalkyl, then the C3-C6 cycloalkyl is unsubstituted;

[1239]

[1240] Rs and Re, together with the carbon atom to which they are attached, form unsubstituted C3- Ce cycloalkyl, and R3 is heterocyclyl comprising one 6-membered ring and 1-3 heteroatoms selected from N, O, and S, then R3 is substituted;

[1241] provided that when

[1242]

[1243] T is oxadi azol onyl,

[1244]

[1245] and R5 and Re are each methyl, then R3 is not heteroaryl comprising one 6-membered ring and 1- 3 heteroatoms selected from N, O, and S; and

[1246] provided that when

[1247]

[1248] Rs and Re are each H, and R3 is heterocyclyl comprising one 6-membered ring and 1-3 heteroatoms selected from N, O, and S, then R3 is substituted.

[1249] In some embodiments, the GCHR modulator is a compound selected from:

[1250]

[1251]

[1252] pharmaceutically acceptable salt or tautomer thereof.

[1253] GCHR modulators that may be administered in combination with MC4R agonists according to the methods describe herein include any GLP-1 small molecule agonists known in the art, e.g., any of the small molecule agonists described in US7598285B2 or US7799818B2, which are hereby incorporated by reference in their entirety. In some embodiments, the GCHR modulator is a compound of Formula (XIII-f):

[1254]

[1255] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[1256] each R1is H or is selected from the group consisting of:

[1257] (a) halo, OH, CO2R4, CN, SOpR5or NO2,

[1258] (b) Ci-ealkyl or OCi-ealkyl optionally substituted with: (1) 1-5 halo groups up to a perhaloalkyl group; (2) CO2R4; (3) phenyl optionally substituted as follows: (i) 1-5 halo groups, (ii) 1 CO2R4, CN, S(O)pR5, NO2or C(O)NR6R7group, (iii) 1-2 Ci-ioalkyl or alkoxy groups, each optionally substituted with: 1-5 halo, up to perhaloalkyl, and 1-2 OH or CO2R4groups;

[1259] each R2is selected from R1as defined above, or 2 R2groups can be taken together to represent a fused 5-6 membered cyclic structure containing 1-2 oxygen atoms, and 1-2 carbon atoms each of which is optionally substituted with 1-2 F atoms;

[1260] R3is H or C1-3alkyl;

[1261] R4is H or Ci-ealkyl;

[1262] R’ represents a member selected from the group consisting of: Ci-ioalkyl, Aryl or Ar-Ci-loalkyl;

[1263] R6and R7each independently represent H or Ci-3alkyl; and

[1264] p is 0, 1 or 2.

[1265] In some embodiments, the GCHR modulator is a compound selected from:

[1266]

[1267]

[1268] GCHR modulators that may be administered in combination with MC4R agonists according to the methods describe herein include any GLP-1 small molecule agonists known in the art, e.g., any of the small molecule agonists described in US8507533B2, US9073871B2, US9452999B2, or US20160362392A1, which are hereby incorporated by reference in their entirety.

[1269] In some embodiments, the GCHR modulator is a compound of Formula (Xlll-g):

[1270]

[1271] or a pharmaceutically acceptable salt thereof, wherein

[1272] R1is a 5 membered heteroaryl group attached through either a carbon or nitrogen atom and which is optionally fused to a (C4-C?)cycloalkyl, phenyl or 6 membered heteroaryl; wherein the optionally fused 5 membered heteroaryl is optionally substituted with one to four substituents each independently selected from halo, -S(O)2-(Ci-C3)alkyl, -S-(Ci-C3)alkyl, hydroxy, -C(0)NRaRb, (C3-C5)cycloalkyl, cyano, phenyl which is optionally substituted with one to three halo, cyano, (Ci-C3)alkyl or (Ci-C3)alkoxy, 6 membered heteroaryl which is optionally substituted with one to three halo, cyano, (Ci-C3)alkyl or (Ci-C3)alkoxy, (Ci-Ce)alkyl optionally substituted with one to three fluoro, or (Ci-Ce)alkoxy optionally substituted with one to three fluoro;

[1273] Raand Rbare each independently H or (Ci-C3)alkyl;

[1274] R2is H or methyl; R3is tetrazolyl, -CH2-tetrazolyl, -(CH2)2SO3H or -(CH2)2CO2H, -CH2CHFCO2H or -CH2CHOHCO2H;

[1275] A1, A2, A3and A4are each independently CR4or N, with the proviso that no more than two of A1, A2, A3and A4are N;

[1276] R4at each occurrence is independently H, halo, cyano, (Ci-C3)alkyl optionally substituted with one to three fluoro, or (Ci-C3)alkoxy optionally substituted with one to three fluoro;

[1277] L is -X-CH(R5)- or -CH(R5)-X-;

[1278] X is CH2, O or NH;

[1279] R is (Ci-C6)alkyl which is optionally substituted with one to three fluoro, hydroxy or methoxy; (C3-C?)cycloalkyl which is optionally substituted with one to two (Ci-C3)alkyl which are optionally substituted with one to three fluoro and wherein one to two carbons of the (C3-C?)cycloalkyl can be replaced with a NH, N(Ci-C3)alkyl, O or S; or (C3-C?)cycloalkyl-(Ci-Ce)alkyl wherein the (C3-C?)cycloalkyl group of said (C3-C7)cycloalkyl-(Ci-Ce)alkyl is optionally substituted with one to two (Ci-C3)alkyl which are optionally substituted with one to three fluoro;

[1280] B1, B2, B3and B4are each independently CR6or N, with the proviso that no more than two of B1, B2, B3and B4are N; and

[1281] R6at each occurrence is independently H, halo, (Ci-C3)alkyl optionally substituted with one to three fluoro, or (Ci-C3)alkoxy optionally substituted with one to three fluoro.

[1282] In some embodiments, the GCHR modulator is a compound selected from:

[1283]

[1284]

[1285] pharmaceutically acceptable salt thereof.

[1286] GCHR modulators that may be administered in combination with MC4R agonists according to the methods describe herein include any GLP-1 small molecule agonists known in the art, e.g., any of the small molecule agonists described in US7816557B2, US20100324140A1, or US8609892B2, which are hereby incorporated by reference in their entirety.

[1287] In some embodiments, the GCHR modulator is a compound of Formula (Xlll-h):

[1288]

[1289] or a pharmaceutically acceptable salt thereof wherein:

[1290] Y is -O- or -S-;

[1291] Q, D, X, and T independently represent carbon (substituted with hydrogen or the optional substituents as indicated herein), or nitrogen (optionally substituted with oxygen), provided that no more than two of Q, D, X, and T are nitrogen;

[1292] Ri is -H, -OH, or -halogen;

[1293] R2 is -H or -(C1-C3) alkyl (optionally substituted with 1 to 3 halogens);

[1294] R3 and R4 are independently - H, -halogen, -CN, -OH, -(C1-C7) alkoxy, -(C1-C7) alkyl(optionally substituted with 1 to 3 halogens), or -(C2-C7) alkenyl;

[1295] R5 is selected from the group consisting of -H, -(C1-C12) alkyl(optionally substituted with 1 to 3 halogens), -(C3-Ci2)cycloalkyl, -phenyl, -phenyl-phenyl-(Ci-Ci2)alkyl, -aryl, -aryl-(Ci-Ci2)alkyl, -heteroaryl, -heteroaryl-(Ci-Ci2)alkyl, -(C2-Ci2)alkenyl, -(C3-Ci2)cycloalkenyl, -heterocycloalkyl, -aryl-(C2-Cio)alkenyl, -heteroaryl-(C2-Cio)alkenyl, -(C2-Ci2)alkynyl, -(C3-Ci2)cycloalkynyl, -aryl-(C2-Ci2)alkynyl, and -heteroaryl-(C2-Ci2)alkynyl, and wherein -(Ci-Ci2)alkyl, -(C3-Ci2)cycloalkyl, -phenyl, -phenyl-phenyl-(Ci-Ci2)alkyl, -aryl, -aryl-(Ci-Ci2)alkyl, -heteroaryl, -heteroaryl-(Ci-Ci2)alkyl, -heterocycloalkyl, -(C2-Ci2)alkenyl, -(C3- Ci2)cycloalkenyl, -aryl-(C2-Cio)alkenyl, -heteroaryl-(C2-Cio)alkenyl, -(C2-Ci2)alkynyl, -(C3-Ci2)cycloalkynyl, -aryl-(C2-Ci2)alkynyl, -heteroaryl-(C2-Ci2)alkynyl, are each optionally substituted with from one to three substituents each independently selected from the group consisting of -hydrogen, -hydroxy, -cyano, -nitro, -halo, -oxo, -(Ci-C7)alkyl (optionally substituted with 1 to 3 halogens), -(Ci-C7)alkyl-C(O)OR12, -(Ci-C7)alkoxy, -(C3-C7)cycloalkyl, -C(0)R12, -C(0)0R12, -0C(0)R12, -OS(O)2R12, -N(R12)2, -NR12C(O)R12, -NR12SO2R12, -SR12, -S(O)R12, -S(O)2R12, and -S(O)2N(R12)2;

[1296] R6 and R7 are independently at each occurrence selected from the group consisting of -H, -halogen, -hydroxy, -CN, -(C1-C7) alkoxy, -(C2-C?)alkenyl, -(Ci-Cio)alkyl (optionally substituted with 1 to 3 halogens), -(C3-Ci2)cycloalkyl, tert-butoxyiminomethyl, l,3-dioxan-2-yl, hydroxymethyl, formyl, hydroxyiminomethyl, morphylino-4-yl-methyl, 4-methylpentyloxy, and pentyloxy; provided however that wherein D is nitrogen, then R6 or R7 are not attached to D, and provided that wherein T is nitrogen, then R6 or R7 are not attached to T, and provided that wherein Q is nitrogen, then R6 or R7 are not attached to Q, and provided that wherein X is nitrogen, then R6 or R7 are not attached to X; wherein R6 and R7 may optionally form a six membered ring with the atoms to which they are attached, and the ring so formed may optionally contain up to two oxygens, and further the ring so formed may optionally be substituted with up to four halogens;

[1297] R8 and R9 are independently at each occurrence selected from the group consisting of -hydrogen, -hydroxy, -CN, -nitro, -halo, -(Ci-C7)alkyl(optionally substituted with 1 to 3 halogens), -(Ci-C7)alkoxy, -(C3-C7)cycloalkyl, -aryl, -aryl-(Ci-C?)alkyl, -heteroaryl, -heteroaryl-(Ci-C7)alkyl, -aryloxy, -C(0)R12, -C00R12, -0C(0)R12, -OS(O)2R12, -N(R12)2, -NR12C(O)R12, -NR12SO2 R12, -SR12, -S(O)R12, -S(O)2R12, -O(C2-C7)alkenyl, and -S(O)2N(R12)2; and wherein -(Ci-C7)alkyl, -(Ci-C7)alkoxy, -(C3-C7)cycloalkyl, -aryl, -aryl-(Ci-C7)alkyl, -heteroaryl, -heteroaryl-(Ci-C7)alkyl, -aryloxy, and -O(C2-C7)alkenyl are each optionally substituted with from one to three substituents independently selected from the group consisting of -hydrogen, -hydroxy, -cyano, -nitro, -halo, -oxo, -(Ci-C7)alkyl, -(Ci-C7)alkyl-C(0)0R12, -(Ci-C7)alkoxyl, -(C3-C7)cycloalkyl, -heterocycloalkyl, -C(0)R12, -C00R12, -0C(0)R12, -OS(O)2R12, -N(R12)2, -NR12C(O)R12, -NR12SO2R12, -SR12, -S(O)R12, -S(O)2R12, and -S(O)2N(R12)2; RIO is selected from the group consisting of -H, halogen, -(Ci-Ci2)alkyl(optionally substituted with 1 to 3 halogens), -cycloalkyl, -aryl, -aryl-(Ci-C?)alkyl, -heteroaryl, -heteroaryl -(Ci-C?)alkyl, -(C2-Ci2)alkenyl, -(C3-Ci2)cycloalkenyl, -aryl-(C2-Cio)alkenyl, -heteroaryl-(C2-Cio)alkenyl, -(C2-Ci2)alkynyl, -(C3-Ci2)cycloalkynyl, -aryl-(C2-Ci2)alkynyl, and -heteroaryl-(C2-Ci2)alkynyl;

[1298] R11 is independently at each occurrence selected from the group consisting of -H, -halogen,

[1299]

[1300] , wherein A, G, and E independently represent carbon (substituted with hydrogen or the optional substituents as indicated herein) or nitrogen, provided that no more than two of A, G, and E are nitrogen; provided however that wherein A is nitrogen, then R8, R9, and R14 are not attached to A, and provided that wherein G is nitrogen, then R8, R9, and R14 are not attached to G, and provided that wherein E is nitrogen, then R8, R9, and R14 are not attached to E,

[1301]

[1302] , wherein m is an integer of 0, 1, 2, or 3, and when m is 0 then (CH2)m is a bond, and

[1303]

[1304] , provided however that wherein D is nitrogen, then Rll is not attached to D, and provided that wherein T is nitrogen, then Rll is not attached to T, and provided that wherein Q is nitrogen, then R11 is not attached to Q, and provided that wherein X is nitrogen, then Rll is not attached to X;

[1305] R12 is independently at each occurrence selected from the group consisting of -hydrogen, -(C1-C7) alkyl(optionally substituted with 1 to 3 halogens), and -aryl; R13 is independently at each occurrence selected from the group consisting of -hydrogen, -halogen, -(C1-C7) alkyl(optionally substituted with 1 to 3 halogens), phenyl, and -(C2-C?)alkenyl; and

[1306] R14 is independently at each occurrence -H, halogen, or -(C1-C7) alkyl (optionally substituted with 1 to 3 halogens).

[1307] In some embodiments, the GCHR modulator is a compound selected from:

[1308]

[1309] GCHR modulators that may be administered in combination with MC4R agonists according to the methods describe herein include any GLP-1 small molecule agonists known in the art, e.g., any of the small molecule agonists described in US8907103B2, US9783494B2, US10221130B2, or US11352321B2, which are hereby incorporated by reference in their entirety.

[1310] In some embodiments, the GCHR modulator is a compound of Formula (Xlll-i):

[1311]

[1312] (Xlll-i),

[1313] wherein:

[1314] R44is H, CH3or CH3CH2: R45is C1-6-alkyl, alkenyl, alkoxy, C3-6-cycloalkyl, C4-8-cycloalkenyl, C4-s-bi cycloalkenyl, aryl or heteroaryl, any of which can be optionally substituted with one or more substituents selected from Ci-ealkyl, CF3, F, CN or OCF3;

[1315] L is phenyl, indenyl, benzoxazol-2-yl, C3-6-cycloalkyl, C4-s-cycloalkenyl or C4-8-bicycloalkenyl, any of which can be optionally substituted with one or more substituents selected from F, Cl, CH3, CF3. OCF3 or CN; and

[1316] R46represents one or more substituents selected from H, F, Cl, CH3, CF3, OCF3 or CN; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[1317] In some embodiments, the GCHR modulator is a compound selected from:

[1318]

[1319]

[1320] Methods of Use

[1321] Disclosed herein are methods for treating and / or preventing obesity or a related condition with a combination of an MC4R agonist, e.g., an MC4R agonist as described herein of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) or (XII), and a GCHR modulator, e.g., a GLP1R agonist as described herein. Exemplary diseases include obesity or an obesity-related disorder (e.g., obesity). In some embodiments, the obesity is associated with a mutation in an MC4R pathway agonizable gene. In some embodiments, the obesity is monogenic obesity. In some embodiments, the obesity is acquired hypothalamic obesity (HO).

[1322] In some embodiments, the disease, disorder or condition is a disease, disorder, or condition associated with obesity, e.g., the disease, disorder or condition is a metabolic disorder. In some embodiments, the metabolic disorder is hyperinsulinism (HI), congenital hyperinsulinism (CHI), persistent hyperinsulinism, or transient hyperinsulinism. In some embodiments, the metabolic disorder is a hyperinsulinism-related syndrome, e.g., Beckwith- Wiedemann syndrome, hyperinsulinism-hyperammonaemia (HTHA) syndrome, Sotos syndrome, Turner syndrome, Costello syndrome, Kabuki syndrome, and the like.

[1323] In some embodiments, the disease, disorder, or condition is obesity. In some embodiments, the disease, disorder, or condition is diabetes, e.g., Type 1 or Type 2 diabetes, or first-phase diabetes or a pre-diabetes syndrome. In some embodiments, the disease, disorder, or condition is a genetic or epigenetic disorder associated with obesity, e.g., Prader-Willi syndrome, Alstrbm syndrome, Bardet-Biedl syndrome, or Smith-Magenis syndrome. In some embodiments, the disease, disorder, or condition is Prader-Willi syndrome. In some embodiments, the disease, disorder, or condition is Alstrbm syndrome. In some embodiments, the disease, disorder, or condition is Bardet-Biedl syndrome. In some embodiments, the metabolic disorder is Smith-Magenis syndrome.

[1324] In some embodiments, the methods described herein may treat, prevent, or alleviate at least one of a symptom of a disease, disorder, or condition, e.g., an increase in waist circumference of at least 2 cm relative to a reference (e.g., the waist circumference of a subject before onset of the metabolic disorder); an increase in blood pressure relative to a reference (e.g., the blood pressure of a subject before onset of the metabolic disorder); hyperglycemia or an increase in fasting blood sugar relative to a reference (e.g., the fasting blood sugar of a subject before the onset of the metabolic disorder); an increase in thirst (e.g., an increase in thirst relative to a reference, e.g., the level of thirst of a subject before the onset the metabolic disorder); an increase in fatigue (e g., an increase in fatigue relative to a reference, e.g., the level of fatigue of a subject before the onset of a metabolic disorder); or an increase in urination (e.g., an increase in urination relative to a reference, e.g., the frequency or amount of urination of a subject before the onset of a metabolic disorder).

[1325] In some embodiments, the methods described herein prevent or slow the onset of a disease, disorder, or condition, e.g., obesity or a metabolic disorder.

[1326] In some embodiments, the subject has a comorbidity, e.g., obesity, hyperphagia, or hyperphagia-related syndromes, unwanted appetite, hypoglycemia, hyperglycemia, hyperlipidemia, hypercholesterolemia, or hypertriglyceridemia. In some embodiments, the metabolic disorder is pre-diabetes, type I diabetes,...

Claims

1. CLAIMS1. A method of treating a disease or disorder, e.g., obesity, in a subject comprising administering to the subject:3.(i) a G-protein coupled hormone receptor (GCHR) modulator; and4.(ii) a melanocortin receptor 4 (MC4R) agonist;5.thereby treating obesity in the subject.

2. The method of claim 1, wherein the MC4R agonist is a peptide.

3. The method of claim 1, wherein the GCHR modulator is a peptide or a small molecule.

4. The method of claim 1, wherein the GCHR modulator comprises a glucagon-like peptide- 1 receptor (GLP1R) agonist, a dual GLP1R, or a triple GLP1R.

5. The method of claim 4, wherein the GCHR modulator is a GLP1R agonist.

6. The method of claim 5, wherein the GLP1R agonist comprises semaglutide, orforglipron, albiglutide, dulaglutide, exendin-4, tirzepatide, liraglutide, exenatide, or lixisenatide.

7. The method of claim 1, wherein the GCHR modulator comprises a dual GLP1R and gastric inhibitory peptide agonist.

8. The method of claim 7, wherein the dual GLP1R and gastric inhibitory peptide agonist comprises survodutide, pemvidutide, or cotadutide.

9. The method of claim 1, wherein the GCHR modulator comprises a triple GLP1R, gastric inhibitory peptide, and glucose-dependent insulinotropic polypeptide agonist.

10. The method of claim 9, wherein the triple GLP1R, gastric inhibitory peptide, and glucose-dependent insulinotropic polypeptide agonist comprises retatrutide.

11. The method of claim 1, wherein the MC4R agonist is a compound of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), or a pharmaceutically acceptable salt thereof.

12. The method of claim 11, wherein the MC4R agonist is a compound of Formula (I):16.(R2R3)-A1-C(A2-A3-A4-A5-A6-A7-A8-A9)-A10-R1(I), or a pharmaceutically acceptable salt thereof, wherein A1is Acc, HN — (CH )™ — C(O), L- or D-amino acid, or deleted; A2is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Asp, or Glu; A3is Gly, Ala, P-Ala, Gaba, Aib, D-amino acid, or deleted; A4is His, 2-Pal, 3-Pal, 4-Pal, Taz, 2-Thi, 3-Thi, or (X1, X2, X3, X4, X5)Phe; A5is D-Phe, D-1-Nal, D-2-Nal, D-Trp, D-Bal, D-(X\ X2, X3, X4, X5)Phe, L-Phe or D-(Et)Tyr; A6is Arg, hArg, Dab, Dap, Lys, Orn, or HN-CH((CH2)«-N(R4R5))-C(O); A7is Trp, 1-Nal, 2-Nal, Bal, Bip, D-Trp, D-2-Nal, D-Bal or D-Bip; A8is Gly, D-Ala, Acc, Ala, 13-Ala, Gaba, Apn, Ahx, Aha, HN-(CH2 ) -C(O), or deleted; A9is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Dab, Dap, Orn, or Lys; A10is Acc, HN-(CH2)t-C(O), L- or D-amino acid, or deleted; R1is OH or NH2; each of R2and R3is, independently for each occurrence, selected from the group consisting of H, (Ci-C3o)alkyl, (Ci-C3o)heteroalkyl, (Ci-C3o)acyl, (C2-C3o)alkenyl, (C2-C3o)alkynyl, aryl(Ci-C3o)alkyl, aryl(Ci-C3o)acyl, substituted (Ci-C3o)alkyl, substituted (Ci-C3o)heteroalkyl, substituted (Ci-C3o)acyl, substituted (C2-C3o)alkenyl, substituted (C2-C3o)alkynyl, substituted aryl(Ci-C3o)alkyl, and substituted aryl(Ci-C3o)acyl; each of R4and R5is, independently for each occurrence, H, (Ci-C4o)alkyl, (Ci-C4o)heteroalkyl, (Ci-C4o)acyl, (C2-C4o)alkenyl, (C2-C4o)alkynyl, aryl(Ci-C4o)alkyl, aryl(Ci-C4o)acyl, substituted (Ci-C4o)alkyl, substituted (Ci-C4o)heteroalkyl, substituted (Ci-C4o)acyl, substituted (C2-C4o)alkenyl, substituted (C2-C4o)alkynyl, substituted aryl(Ci-C4o)alkyl, substituted aryl(Ci-C4o)acyl, (Ci-C4o)alkylsulfonyl, or -C(NH)-NH2; m is, independently for each occurrence, 1, 2, 3, 4, 5, 6 or 7; n is, independently for each occurrence, 1, 2, 3, 4 or 5; s is, independently for each occurrence, 1, 2, 3, 4, 5, 6, or 7; t is, independently for each occurrence, 1, 2, 3, 4, 5, 6, or 7; X', X2, X3, X4, and X5each is, independently for each occurrence, H, F, Cl, Br, I, -(C1-C10) alkyl, substituted (C1-C10) alkyl, (C2-C10) alkenyl, substituted (C2-C10) alkenyl, (C2-C10) alkynyl, substituted (C2-C10) alkynyl, aryl, substituted aryl, OH, NH2, NO2, or CN.

13. The method of claim 12, wherein the compound of Formula (I) is selected from any one of SEQ ID NOs.: 1-147, or a pharmaceutically acceptable salt thereof.

14. The method of claim 13, wherein the compound of Formula (I) is (SEQ ID NO: 140) Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2. or a pharmaceutically acceptable salt thereof.

15. The method of claim 11, wherein the MC4R agonist is a compound of Formula (II):

22.

23. Cys, D-Cys, Dab, Dap, Glu, Lys, Orn, Pen or D-Pen; R1is H, (Ci-Cio)alkyl or substituted (Ci-Cio)alkyl; R2and R3each is, independently, H, (Ci-Cio)alkyl, (Ci-Cio)heteroalkyl, aryl(Ci-Cs)alkyl, substituted (Ci-Cio)alkyl, substituted (Ci-Cio)heteroalkyl or substituted aryl(Ci-Cs)alkyl or R2and R3may be fused together form a cyclic moiety; R4is OH, NH2, CO2 H or C(0)NH2; R5and R6each is, independently, H, (Ci-Cio)alkyl, (Ci-Cio)heteroalkyl, aryl(Ci-Cs)alkyl, substituted (Ci-Cio)alkyl, substituted (Ci-Cio)heteroalkyl or substituted aryl(Ci-Cs)alkyl or R5and R6may be fused together form a cyclic moiety; R7and R8each is, independently, H, (Ci-Cio)alkyl, (Ci-Cio)heteroalkyl, aryl(Ci-Cs)alkyl, substituted (Ci-Cio)alkyl, substituted (Ci-Cio)heteroalkyl or substituted aryl(Ci-Cs)alkyl; or R7and R8may be fused together form a cyclic moiety; R9is H, (Ci-Cio)alkyl or substituted (Ci-Cio)alkyl; and n is, independently for each occurrence thereof, 0, 1, 2, 3, 4, 5, 6 or 7; or a pharmaceutically acceptable salt thereof.

16. The method of claim 15, wherein the compound of Formula (II) is selected from any one of SEQ ID NOs.: 148-186, or a pharmaceutically acceptable salt thereof.

17. The method of claim 11, wherein the MC4R agonist is a compound of Formula (III):

26.

27. pharmaceutically acceptable salt thereof, wherein X is selected from the group consisting of -CH2-S-S-CH2-, -C(CH3)2-S-S-CH2-, -CH2-S-S-C(CH3)2-, -C(CH3)2-S-S-C(CH3)2-, -(CH2)2-S-S-CH2-, -CH2-S-S-(CH2)2-, -(CH2)2-S-S-(CH2)2-, -C(CH3)2-S-S-(CH2)2-, -(CH2)2-S-S-C(CH3)2-, -(CH2)r-C(O)-NR8-(CH2>-and -(CH2)r-NR8-C(O)-(CH2)r-; R2each is, independently, H, (Ci-Cio)alkyl or substituted (Ci-Cio)alkyl; R3is -OH or -NH2; R4and R3each is, independently, H, (Ci-Cio)alkyl or substituted (Ci-Cio)alkyl; X1is29.

30. is, 2-Pal, 3-Pal, 4-Pal, (X he, Taz, 2-Thi, 3-Thi or is deleted; A2is D-Bal, D-1-Nal, D-2-Nal, D-Phe X4, X5)Phe; A3is Arg, hArg, Dab, Dap, Lys or Orn; A4is Bal, 1-Nal, 2-Nal,31. 32.5)Phe or Trp; R6and R7each is, independently for each occurrence thereof, H, (Ci-Cio)heteroalkyl, aryl(Ci-Cs)alkyl, substituted (Ci-Cio)alkyl, substituted (Ci-Cio)heteroalkyl or substituted aryl(Ci-Cs)alkyl provided thatR6and R7may be joined together to form a ring; R8is H, (Ci-Cio)alkyl or substituted (Ci-Cio)alkyl; r is, independently for each occurrence thereof, 1, 2, 3, 4 or 5; and t is, independently for each occurrence thereof, 1 or 2.

18. The method of claim 17, wherein the compound of Formula (III) is selected from any one of SEQ ID NOs.: 187-212, or a pharmaceutically acceptable salt thereof.

19. The method of claim 11, wherein the MC4R agonist is a compound of Formula (IV):35.(R2R3)-A1-c(A2-A3-A4-A5-A6-A7-A8-A9)-NH2(IV) or a pharmaceutically acceptable salt thereof, wherein A1is Nle or deleted; A2is Cys or Asp; A3is Glu or D-Ala; A4is His; A5is D-Phe; A6is Arg; A7is Trp, 2-Nal or Bal; A8is Gly, Ala, D-Ala, 3-Ala, Gaba or Apn; A9is Cys or Lys; each of R2and R3is independently selected from the group consisting of H or (Ci-C6)acyl.

20. The method of claim 19, wherein the compound of Formula (IV) is selected from any one of SEQ ID NOs.: 213-223, or a pharmaceutically acceptable salt thereof.

21. The method of claim 11, wherein the MC4R agonist is a compound of Formula (V):38.(R2R3)-B1-A1-c(A2-A3-A4-A5-A6-A7-A8-A9)-A10-A11-A12-A13-B2-B3-R1(V) or a pharmaceutically acceptable salt thereof: B1is a peptide moiety which contains 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids, wherein at least 5 amino acids are independently selected from the group consisting of L- Arg, D-Arg, L-hArg and D-hArg, or B1is optionally deleted; A1is Acc, HN-(CH2)m-C(O), L- or D-amino acid or deleted; A2is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Asp or Glu; A3is Gly, Glu, Ala, P-Ala, Gaba, Aib, D-amino acid or deleted; A4is H is, 2-Pal, 3-Pal, 4-Pal, Taz, 2-Thi, 3-Thi or (X', X2, X3, X4, X5)Phe; A5is D-Phe, D-1-Nal, D-2-Nal, D-Trp, D-Bal, D-(X’, X2, X3, X4, X5)Phe, D-(Et)Tyr, D-Dip, D-Bip or D-Bpa; A6is Arg, hArg, Dab, Dap, Lys, Om or HN-CH((CH2)»-N(R4R5))-C(O); A7is Trp, 1-Nal, 2-Nal, Bal, Bip, Dip, Bpa, D-Trp, D-1-Nal, D-2-Nal, D-Bal, D-Bip, D-Dip or D-Bpa; A8is Gly, D-Ala, Acc, Ala, 0-Ala, Gaba, Apn, Ahx, Aha, HN-(CH2)5-C(O) or deleted; A9is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Dab, Dap, Orn or Lys; A10is Acc, HN-(CH2)t-C(O), Pro, hPro, 3-Hyp, 4-Hyp, Thr, an L- or D-amino acid or deleted; A11is Pro, hPro, 3-Hyp, 4-Hyp or deleted; A12is Lys, Dab, Dap, Arg, hArg or deleted; A13is Asp, Glu or deleted; B2is a peptide moiety containing 1, 2, 3, 4, or 5 amino acids or deleted, B3is a peptide moiety which contains 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acids wherein at least 5 amino acids are independently selected from the group consisting of L-Arg, D-Arg, L-hArg and D-hArg, or is deleted; R1is OH or NH2; R2and R3each is, independently for each occurrence, selected from the group consisting of H, (Ci-C3o)alkyl, (Ci-C3o)heteroalkyl, (Ci-C3o)acyl, (C2-C3o)alkenyl, (C2-C3o)alkynyl, aryl(Ci-C3o)alkyl, aryl(Ci-C3o)acyl, substituted (Ci-C3o)alkyl, substituted (Ci-C3o)heteroalkyl, substituted (Ci-C3o)acyl, substituted (C2-C3o)alkenyl, substituted (C2-C3o)alkynyl, substituted aryl(Ci-C3o)alkyl and substituted aryl(Ci-C3o)acyl; R4and R5each is, independently for each occurrence, H, (Ci-C4o)alkyl, (Ci-C4o)heteroalkyl, (Ci-C4o)acyl, (C2-C4o)alkenyl, (C2-C4o)alkynyl, aryl(Ci-C4o)alkyl, aryl(Ci-C4o)acyl, substituted (Ci-C4o)alkyl, substituted (Ci-C4o)heteroalkyl, substituted (Ci- C4o)acyl, substituted (C2-C4o)alkenyl, substituted (C2-C4o)alkynyl, substituted aryl(Ci-C4o)alkyl, substituted aryl(Ci-C4o)acyl, (Ci-C4o)alkylsulfonyl or C(NH)-NH2; n is, independently for each occurrence, 1, 2, 3, 4 or 5; m is, independently for each occurrence, 1, 2, 3, 4, 5, 6 or 7; s is, independently for each occurrence, 1, 2, 3, 4, 5, 6 or 7; t is, independently for each occurrence, 1, 2, 3, 4, 5, 6 or 7; X1, X2, X3, X4and X5each is, independently for each occurrence, H, F, Cl, Br, I, -(Ci-Cio) alkyl, substituted (Ci-Cio) alkyl, (C2-C10) alkenyl, substituted (C2-C10) alkenyl, (C2-C10) alkynyl, substituted (C2-C10) alkynyl, aryl, substituted aryl, OH, NH2, NO2 or CN.

22. The method of claim 21, wherein the compound of Formula (V) is selected from any one of SEQ ID NOs.: 224-531, or a pharmaceutically acceptable salt thereof23. The method of claim 11, wherein the MC4R agonist is a compound of Formula (VI):41.Ac-c(Cys-Glu-His-A1-Arg-A2-A3-Cys)-(Pro)2-Lys-Asp-NH2 (VI) or pharmaceutically acceptable salts thereof, wherein: A1is the D-isomer of X-Phe or 2-Nal where X is halogen; A2is Bal, 1-Nal, 2-Nal, or Trp; and A3is Aib, Ala, 0-Ala or Gly.

24. The method of claim 23, wherein the compound of Formula (VI) is selected from any one of SEQ ID NOs.: 532-538, or a pharmaceutically acceptable salt thereof25. The method of claim 11, wherein the MC4R agonist is a compound of Formula (VII):

45.

46. pharmaceutically acceptable salt thereof wherein: X is selected from the group consisting of -CH2-S-S-CH2-, -C(CH3)2-S-S-CH2-,-CH2-S-S-C(CH3)2-, -C(CH3)2-S-S-C(CH3, -(CH2)2-S-S-CH2-, -CH2-S-S-(CH2)2, -(CH2)2-S-S-(CH2)2-, -C(CH3)2-S-S-(CH2)2-, -(CH2)2-S-S-C(CH3)2-, -(CH2-C(O)-NR8-(CH2)r- and -(CH2),-NR8-C(O)-(CH2)t-; each of R1and R3is, independently, H, (Ci-Cio)alkyl or substituted (Ci-Cio)alkyl; each ofR2andR3is, independently, H, (Ci-Cio)alkyl, (Ci-Cio)heteroalkyl, aryl(Ci-Cs)alkyl, substituted (Ci-Cio)alkyl, substituted (Ci-Cio)heteroalkyl or substituted aryl(Ci-Cs)alkyl or R2and R3may be fused together to form a ring; R4is OH or NH2; each of R6and R7is, independently, H, (Ci-Cio)alkyl or substituted (Ci-Cio)alkyl; A1is an L- or D-amino acid or deleted; A2is H is, 2-Pal, 3-Pal, 4-Pal, (X1, X2, X3, X4, X5)Phe, Taz, 2-Thi or 3-Thi; A3is D-Bal, D-1-Nal, D-2-Nal, D-Phe or D-(X’, X2, X3, X4, X5)Phe; A4is Arg, hArg, Dab, Dap, Lys or Om; A5is Bal, 1-Nal, 2-Nal, (X1, X2, X3, X4, X3)Phe or Trp; r is, independently for each occurrence thereof, 1, 2, 3, 4 or 5; and t is, independently for each occurrence thereof, 1 or 2; or pharmaceutically acceptable salts thereof.

26. The method of claim 25, wherein the compound of Formula (VII) is selected from any one of SEQ ID NOs.: 539-551, or a pharmaceutically acceptable salt thereof27. The method of claim 11, wherein the MC4R agonist is a compound of Formula (VIII):49.(R2R3)-A°-A1-c(A2-A3-A4-A5-A6-A7-A8-A9)-A10-R1(VIII)50.or a pharmaceutically acceptable salt thereof wherein: A0is an aromatic amino acid; A1is Acc, HN-(CH2)m-C(0), an L- or D-amino acid; A2is Asp, Cys, D-Cys, hCys, D-hCys, Glu, Pen, or D-Pen; A3is Aib, Ala, 0-Ala, Gaba, Gly or a D-amino acid; A4is H is, 2-Pal, 3-Pal, 4-Pal, (X1, X2, X3, X4, X5)Phe, Taz, 2-Thi, or 3-Thi; A5is D-Bal, D-1-Nal, D-2-Nal, D-Phe, L-Phe, D-(X’, X2, X3, X4, X5)Phe, L-Phe, D-Trp or D-(Et)Tyr; A6is Arg, hArg, Dab, Dap, Lys, Orn, or HN-CH((CH2)n-N(R4R5))-C(O); A7is Bal, D-Bal, Bip, D-Bip, 1-Nal, D-1-Nal, 2-Nal, D-2-Nal, or D-Trp; A8is Acc, Aha, Ahx, Ala, D-Ala, P-Ala, Apn, Gaba, Gly, HN-(CH2)«-C(0), or deleted; A9is Cys, D-Cys, hCys, D-hCys, Dab, Dap, Lys, Om, Pen, or D-Pen; A10is Acc, HN-(CH2)f-C(O), L-or D-amino acid, or deleted; R1is OH, or NH2; each of R2and R3is, independently for each occurrence selected from the group consisting of H, (Ci-C3o)alkyl, (Ci-C3o)heteroalkyl, (Ci-C3o)acyl, (C2-C3o)alkenyl, (C2-C3o)alkynyl, aryl(Ci-C3o)alkyl, aryl(Ci-C3o)acyl, substituted (Ci-C3o)alkyl, substituted (Ci-C3o)heteroalkyl, substituted (Ci-C3o)acyl, substituted (C2-C3o)alkenyl, substituted (C2-C3o)alkynyl, substituted aryl(Ci-C3o)alkyl, and substituted aryl(Ci-C3o)acyl; each of R4and R?is, independently for each occurrence, H, (Ci-C4o)alkyl, (Ci-C4o)heteroalkyl, (Ci-C4o)acyl, (C2-C4o)alkenyl, (C2-C4o)alkynyl, aryl(Ci-C4o)alkyl, aryl(Ci-C4o)acyl, substituted (Ci-C4o)alkyl, substituted (Ci-C4o)heteroalkyl, substituted (Ci-C4o)acyl, substituted (C2-C4o)alkenyl, substituted (C2-C4o)alkynyl, substituted aryl(Ci-C4o)allyl, substituted aryl(Ci-C4o)acyl, (Ci-C4o)alkylsulfonyl, or -C(NH)-NH2; m is, independently for each occurrence, 1, 2, 3, 4, 5, 6 or 7; n is, independently for each occurrence, 1, 2, 3, 4 or 5; s is, independently for each occurrence, 1, , 3, 4, 5, 6, or 7; t is, independently for each occurrence, 1, 2, 3, 4, 5, 6, or 7; X1, X2, X3, X4, and X5each is, independently for each occurrence, H, F, Cl, Br, I, (Ci-Cio)alkyl, substituted (Ci-Cio)alkyl, (C2-Cio)alkenyl, substituted (C2-Cio)alkenyl, (C2-Cio)alkynyl, substituted (C2-Cio)alkynyl, aryl, substituted aryl, OH, NH2, NO2, or CN.

28. The method of claim 27, wherein the compound of Formula (VIII) is selected from any one of SEQ ID NOs.: 552-559, or a pharmaceutically acceptable salt thereof29. The method of claim 11, wherein the MC4R agonist is a compound of Formula (IX):

54. 56.(IX), or a pharmaceutically acceptable salt thereof, wherein: R1is H, or a (Ci-C6)acyl; R2is, -NR3R4, or -OR5wherein R3, R4, and R5are each independently is H or a (Ci-Ce)alkyl; A1is an amino acid residue selected from Arg, Lys, Orn, His, Nle, Phe, Vai, Leu, Trp, Tyr, Ala, Ser, Thr, Gin, Asn, Asp, Glu, or TzAla; or A1is a moiety selected from an optionally substituted -(Ci-Ci2)-alkyl, an optionally substituted -(Ce-Cis)-aryl, an optionally substituted -(C5-Cis)-heteroaryl, an aralkyl wherein the aryl portion is an optionally substituted (C6-Cis)aryl, and the alkyl portion is an optionally substituted (Ci-Cn)alkyl, or a heteroaralkyl, wherein the heteroaryl portion is an optionally substituted (C5-Cis)heteroaryl, and the alkyl portion is an optionally substituted (Ci-Ci2)alkyl; A2and A8is each independently an amino acid residue selected from Cys, hCys, Pen, Asp, Glu, Lys, Orn, Dbu, or Dpr, wherein A2and A8are pairwise selected so as to be able to form covalent bond between their respective side chains; A3is absent or is an amino acid residue selected from Ala, Tie, Vai, Leu, He, Cha, Pro, Ser, Thr, Lys, Arg, His, Phe, Gin, Sar, Gly, Asn, Aib, or residue Y, wherein Y is an amino acid selected from amino acids represented by the following structural formulas57.

58. wherein: R11and R12, each independently, is H, -CH3, phenyl, or benzyl; R21, R22, R23, and R24, each independently is H, -CH3, -CF3, phenyl, benzyl, F, Cl, Br, I, -OCH3, or -OH; R31, R32, R33, R34, R41, R42, and R43, each independently is H, -CH3, -CF3, phenyl, benzyl, F, Cl, Br, I, -OCH3, or -OH; A4is absent or is an amino acid residue selected from Ate, Ala, QAla, Aib, Sar, Ser, Thr, Pro, Hyp, Asn, Gin, an optionally substituted His, Trp, Tyr, Lys, Arg, sChp, or residue X, where the X is an amino acid selected from amino acids represented by the following formulas:

60.

61. wherein: R51and R52, each independently, is H, -CH3, phenyl, or benzyl; R61, R62, R63, and R64, each independently is H, -CH3, -CF3, phenyl, benzyl, F, Cl, Br, I, -OCH3, or -OH; R71, R72, R73, R74, R81, R82, and R83, each independently is H, -CH3, -CF3, phenyl, benzyl, F, Cl, Br, I, -OCH3, or -OH; A5is an optionally substituted Phe, an optionally substituted 1-Nal, or an optionally substituted 2-Nal; A6is Arg; and A7is Trp, wherein any amino acid residue is either in L- or in D-configuration.

30. The method of claim 29, wherein the compound of Formula (IX) is selected from any one of SEQ ID NOs.: 560-622, or a pharmaceutically acceptable salt thereof31. The method of claim 11, wherein the MC4R agonist is a compound of Formula (X):

64.

65. pharmaceutically acceptable salt thereof, wherein: Ri is - NH-C(O)- or -C(O)-NH-; R2 is -H, -CH2-, or, R2, together with R3, forms a pyrrolidine ring optionally substituted with -OH; R3 is -(CH2)2- if R2 is -CH2-, and otherwise R3 is selected from67.

68. and R4eare each independently selected from hydrogen, halo, (Ci-Cio)alkyl-halo, (Ci-Cio)alkyl- dihalo, (Ci-Cio)alkyl-trihalo, (Ci-Cio)alkyl, (Ci-Cio)alkoxy, (Ci-Cio)alkylthio, aryl, aryloxy, nitro, nitrile, sulfonamide, amino, hydroxyl, carboxy, and alkoxy-carbonyl; R5is -OH or - N(R6a)(R6b); R6aand R6bare each independently H or Ci to C4 linear, branched or cyclic alkyl chain; R7is -H or -C(0)-NH2; w is in each instance independently 0 to 5; x is 1 to 5; y is 1 to 5; z is in each instance independently 1 to 5.

32. The method of claim 11, wherein the MC4R agonist is a compound of Formula (XI):

70.

71. pharmaceutically acceptable salt thereof.

33. The method of claim 11, wherein the MC4R agonist is a compound of Formula (XII):73.Ai-Yyy-c(Aaa-Xxx-D-Phe-Arg-Trp-Bbb)-A2 (XII), or a pharmaceutically acceptable salt thereof, wherein: Aaa and Bbb are selected from Cys, hCys, Pen capable of establishing a disulfide bridge; or Glu, Asp, Lys, Orn, Dpr, Dbu capable of establishing a lactam bridge; Xxx is Asn, Gin, Ser, Thr; Yyy is Lys, Arg, D-Lys, D-Arg; Al is H, Ac; A 2 is OH, NH2.

34. The method of claim 11 or 33, wherein the compound of Formula (XII) is selected from (SEQ ID NO: 629) Ac-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH2;75.(SEQ ID NO: 630) Ac-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2;76.(SEQ ID NO: 631) Ac-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2; and77.(SEQ ID NO: 632) Ac-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2; or a pharmaceutically acceptable salt thereof.

35. The method of claim 34, wherein the compound of Formula (XII) is (SEQ ID NO: 629) Ac-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH2, or a pharmaceutically acceptable salt thereof.

36. The method of claim 34, wherein the compound of Formula (XII) is (SEQ ID NO: 630) Ac-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2, or a pharmaceutically acceptable salt thereof.

37. The method of claim 34, wherein the compound of Formula (XII) is (SEQ ID NO: 631) Ac-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2, or a pharmaceutically acceptable salt thereof.

38. The method of claim 34, wherein the compound of Formula (XII) is (SEQ ID NO: 632) Ac-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2, or a pharmaceutically acceptable salt thereof.

39. The method of claim 11, wherein the MC4R agonist is a compound of Formula (I) and the GCHR is selected from semaglutide, orforglipron, albiglutide, dulaglutide, exendin-4, tirzepatide, liraglutide, exenatide, lixisenatide, survodutide, pemvidutide, cotadutide, and retatrutide.

40. The method of claim 11, wherein the MC4R agonist is a compound of Formula (II) and the GCHR is selected from semaglutide, orforglipron, albiglutide, dulaglutide, exendin-4, tirzepatide, liraglutide, exenatide, lixisenatide, survodutide, pemvidutide, cotadutide, and retatrutide.

41. The method of claim 11, wherein the MC4R agonist is a compound of Formula (III) and the GCHR is selected from semaglutide, orforglipron, albiglutide, dulaglutide, exendin-4, tirzepatide, liraglutide, exenatide, lixisenatide, survodutide, pemvidutide, cotadutide, and retatrutide.

42. The method of claim 11, wherein the MC4R agonist is a compound of Formula (IV) and the GCHR is selected from semaglutide, orforglipron, albiglutide, dulaglutide, exendin-4, tirzepatide, liraglutide, exenatide, lixisenatide, survodutide, pemvidutide, cotadutide, and retatrutide.

43. The method of claim 11, wherein the MC4R agonist is a compound of Formula (V) and the GCHR is selected from semaglutide, orforglipron, albiglutide, dulaglutide, exendin-4, tirzepatide, liraglutide, exenatide, lixisenatide, survodutide, pemvidutide, cotadutide, and retatrutide.

44. The method of claim 11, wherein the MC4R agonist is a compound of Formula (VI) and the GCHR is selected from semaglutide, orforglipron, albiglutide, dulaglutide, exendin-4, tirzepatide, liraglutide, exenatide, lixisenatide, survodutide, pemvidutide, cotadutide, and retatrutide.

45. The method of claim 11, wherein the MC4R agonist is a compound of Formula (VII) and the GCHR is selected from semaglutide, orforglipron, albiglutide, dulaglutide, exendin-4, tirzepatide, liraglutide, exenatide, lixisenatide, survodutide, pemvidutide, cotadutide, and retatrutide.

46. The method of claim 11, wherein the MC4R agonist is a compound of Formula (VIII) and the GCHR is selected from semaglutide, orforglipron, albiglutide, dulaglutide, exendin-4, tirzepatide, liraglutide, exenatide, lixisenatide, survodutide, pemvidutide, cotadutide, and retatrutide.

47. The method of claim 11, wherein the MC4R agonist is a compound of Formula (IX) and the GCHR is selected from semaglutide, orforglipron, albiglutide, dulaglutide, exendin-4, tirzepatide, liraglutide, exenatide, lixisenatide, survodutide, pemvidutide, cotadutide, and retatrutide.

48. The method of claim 11, wherein the MC4R agonist is a compound of Formula (X) and the GCHR is selected from semaglutide, orforglipron, albiglutide, dulaglutide, exendin-4, tirzepatide, liraglutide, exenatide, lixisenatide, survodutide, pemvidutide, cotadutide, and retatrutide.

49. The method of claim 11, wherein the MC4R agonist is a compound of Formula (XI) and the GCHR is selected from semaglutide, orforglipron, albiglutide, dulaglutide, exendin-4, tirzepatide, liraglutide, exenatide, lixisenatide, survodutide, pemvidutide, cotadutide, and retatrutide.

50. The method of claim 11, wherein the MC4R agonist is a compound of Formula (XII) and the GCHR is selected from semaglutide, orforglipron, albiglutide, dulaglutide, exendin-4, tirzepatide, liraglutide, exenatide, lixisenatide, survodutide, pemvidutide, cotadutide, and retatrutide.

51. The method of claim 1, wherein the GCHR comprises semaglutide, tirzepatide, liraglutide, exenatide, or retatrutide.

52. The method of claim 1, wherein each of the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof is independently formulated as a pharmaceutical composition.

53. The method of claim 1, wherein each of the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof is formulated together as a single pharmaceutical composition.

54. The method of claim 1, wherein each of the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof is administered concomitantly to the human subject.

55. The method of claim 1, wherein the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof are administered within 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, or more of each other.

56. The method of claim 1, wherein the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof are administered within 30 minutes of each other.

57. The method of claim 1, wherein the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof are administered within 1 hour of each other.

58. The method of claim 1, wherein the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof are administered within 2 hours of each other.

59. The method of claim 1, wherein the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof are administered within 6 hours of each other.

60. The method of claim 1, wherein the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof are administered within 12 hours of each other.

61. The method of claim 1, wherein the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof are administered within 24 hours of each other.

62. The method of claim 1, wherein the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof is administered sequentially to the human subject.

63. The method of claim 1, wherein administered sequentially comprises administration of the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof within 24 hours.

64. The method of claim 1, wherein the GCHR modulator or a pharmaceutically acceptable salt thereof is administered first to the human subject, followed by the MC4R agonist or a pharmaceutically acceptable salt thereof.

65. The method of claim 1, wherein the MC4R agonist or a pharmaceutically acceptable salt thereof is administered first to the human subject, followed by the GCHR modulator or a pharmaceutically acceptable salt thereof.

66. The method of claim 1, wherein the GCHR modulator or a pharmaceutically acceptable salt thereof is administered for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, or more prior to administration of the MC4R agonist or a pharmaceutically acceptable salt thereof.

67. The method of claim 1, wherein the MC4R agonist or a pharmaceutically acceptable salt thereof is administered for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, or more prior to administration of the GCHR modulator or a pharmaceutically acceptable salt thereof.

68. The method of claim 1, wherein the GCHR modulator or a pharmaceutically acceptable salt thereof is administered at a dosage of between 0.1 to 500 mg.

69. The method of claim 68, wherein the GCHR modulator or a pharmaceutically acceptable salt thereof is administered at a dosage of 0.1 mg.

70. The method of claim 68, wherein the GCHR modulator or a pharmaceutically acceptable salt thereof is administered at a dosage of 1 mg.

71. The method of claim 68, wherein the GCHR modulator or a pharmaceutically acceptable salt thereof is administered at a dosage of 10 mg.

72. The method of claim 68, wherein the GCHR modulator or a pharmaceutically acceptable salt thereof is administered at a dosage of 50 mg.

73. The method of claim 68, wherein the GCHR modulator or a pharmaceutically acceptable salt thereof is administered at a dosage of 100 mg.

74. The method of claim 68, wherein the GCHR modulator or a pharmaceutically acceptable salt thereof is administered at a dosage of 200 mg.

75. The method of claim 68, wherein the GCHR modulator or a pharmaceutically acceptable salt thereof is administered at a dosage of 250 mg.

76. The method of claim 68, wherein the GCHR modulator or a pharmaceutically acceptable salt thereof is administered at a dosage of 500 mg.

77. The method of claim 1, wherein the MC4R agonist or a pharmaceutically acceptable salt thereof is administered at a dosage of between 0.1 to 10 mg.

78. The method of claim 77, wherein the MC4R agonist or a pharmaceutically acceptable salt thereof is administered at a dosage of 0.1 mg.

79. The method of claim 77, wherein the MC4R agonist or a pharmaceutically acceptable salt thereof is administered at a dosage of 0.5 mg.

80. The method of claim 77, wherein the MC4R agonist or a pharmaceutically acceptable salt thereof is administered at a dosage of 1 mg.

81. The method of claim 77, wherein the MC4R agonist or a pharmaceutically acceptable salt thereof is administered at a dosage of 2.5 mg.

82. The method of claim 77, wherein the MC4R agonist or a pharmaceutically acceptable salt thereof is administered at a dosage of 5 mg.

83. The method of claim 77, wherein the MC4R agonist or a pharmaceutically acceptable salt thereof is administered at a dosage of 10 mg.

84. The method of claim 1, wherein the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof are administered orally.

85. The method of claim 1, wherein the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof are administered subcutaneously.

86. The method of claim 1, wherein the GCHR modulator or a pharmaceutically acceptable salt thereof is administered orally and the MC4R agonist or a pharmaceutically acceptable salt thereof are administered subcutaneously.

87. The method of claim 1, wherein the GCHR modulator or a pharmaceutically acceptable salt thereof is administered subcutaneously and the MC4R agonist or a pharmaceutically acceptable salt thereof are administered orally.

88. The method of claim 1, wherein the GCHR modulator or a pharmaceutically acceptable salt thereof is administered orally.

89. The method of claim 1, wherein the GCHR modulator or a pharmaceutically acceptable salt thereof is administered subcutaneously.

90. The method of claim 1, wherein the MC4R agonist or a pharmaceutically acceptable salt thereof is administered orally.

91. The method of claim 1, wherein the MC4R agonist or a pharmaceutically acceptable salt thereof is administered subcutaneously.

92. The method of claim 1, wherein the obesity is a genetic obesity or a non-genetic obesity.

93. The method of claim 1, wherein the subject has been diagnosed with obesity.

94. The method of claim 1, wherein the subject has been diagnosed with hypothalamic obesity.

95. The method of claim 1, wherein the subject has a body mass index (BMI) greater than 30.

96. The method of claim 1, wherein the subject has a waist circumference of greater than 40 cm.

97. The method of claim 1, wherein the subject has a waist-to-hip circumference ratio of greater than 2.

98. The method of claim 1, wherein the subject has a mutation in an MC4R pathway agonizable gene.

99. The method of claim 98, wherein the MC4R pathway agonizable gene comprises ARL6, RAI1, SRC1, BBS19, BBS21, CEP290, IFT74, LZTFL1, MKS1, TRIM32, WDPCP, RPS6KA3, HTR2C, KSR2, PROK2, RAB23, MRAP2, AFF4, ADCY3, TUB, OTP, GPR101, or TBX3.

100. The method of claim 98, wherein the subject has a mutation in POMC, LEPR, PCSK1, SRC1, or SH2B1.

101. The method of claim 1, wherein the efficacy of the combination of the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof is at least Xi-fold greater than the efficacy of either of the GCHR modulator or the MC4R agonist alone at the molar amount used in the combination, wherein Xi is 1, 1.25, 1.5, 1.75, 2, 2.5, or greater.

102. The method of claim 101, wherein the GCHR modulator and the MC4R agonist are administered in an alternating manner or in phases, wherein during each phase, only one of the GCHR modulator and the MC4R agonist are administered.

103. The method of claim 102, wherein the phases comprise periods of time.

104. The method of claim 102, wherein the phases comprise administration of different doses of the GCHR modulator and the MC4R agonist.

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