Methods for treating obesity with MC4R agonists

Abstract

The present disclosure relates to methods of treating a disease, disorder, or condition (e.g., obesity, such as hypothalamic obesity) in a subject using a melanocortin-4 receptor (MC4R) agonist. There is a need for treatment of obesity and obesity-related disorders, including non-genetic obesity and related disorders. The present disclosure features, inter alia, the treatment of a disease or disorder, such as obesity, e.g., non-genetic obesity, e.g., hypothalamic obesity, with a compound (e.g., an MC4R agonist) or composition thereof.

Description

[Technical Field]

[0001] Priority claims This application claims priority to U.S. Application No. 63 / 426,612, filed November 18, 2022, U.S. Application No. 63 / 426,642, filed November 18, 2022, and U.S. Application No. 63 / 426,647, filed November 18, 2022. The contents of the foregoing applications are incorporated herein by reference in their entireties. [Background technology]

[0002] There is a need for treatments for obesity and obesity-related disorders, including non-genetic obesity and related disorders. Summary of the Invention

[0003] The present disclosure features, inter alia, the treatment of diseases or disorders such as obesity, eg, non-genetic obesity, eg, hypothalamic obesity, with compounds (eg, MC4R agonists) or compositions thereof. In some embodiments, the MC4R agonist is a compound of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXXII), (XXXIII), (XXXIV), (XXXV), or (XXXVI) (e.g., as described herein), or a pharmaceutically acceptable salt thereof. MC4R agonists can be used to treat subjects diagnosed or identified as having a disease or disorder, e.g., a disease or disorder described herein, such as obesity (e.g., hypothalamic obesity), cancer, or a metabolic disorder.

[0004] An MC4R agonist, for example, a compound of any one of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXXII), (XXXIII), (XXXIV), (XXXV), or (XXXVI), or a pharmaceutically acceptable salt thereof, may be provided as a composition (e.g., a pharmaceutical composition) comprising a pharmaceutically acceptable excipient. In one embodiment, the pharmaceutically acceptable excipient comprises a polyethylene glycol (e.g., a modified polyethylene glycol), a lipid (e.g., a neutral lipid or a phospholipid). In one embodiment, the pharmaceutically acceptable excipient comprises a modified polyethylene glycol. In one embodiment, the pharmaceutically acceptable excipient comprises a lipid, such as a neutral diacyl lipid or a phospholipid. In another embodiment, the pharmaceutically acceptable excipient is an oil. In yet another embodiment, the pharmaceutically acceptable excipient is an excipient capable of forming a depot or other long-acting composition, for example, to prolong the release of the MC4R agonist from the composition.

[0005] The MC4R agonist or composition thereof may be provided in a unit dosage form. For example, the unit dosage form may contain about 0.01 mg to 100 mg of the MC4R agonist. In one embodiment, the unit dosage form contains 0.1 mg to 100 mg, e.g., 0.1 mg to 50 mg, 0.1 mg to 25 mg, 0.1 mg to 10 mg, 1 mg to 100 mg, 1 mg to 50 mg, 1 mg to 25 mg, 1 mg to 10 mg, 5 mg to 100 mg, 5 mg to 50 mg, 5 mg to 25 mg, 5 mg to 15 mg, or 5 mg to 10 mg.

[0006] The MC4R agonist or composition thereof may be administered to a subject daily, weekly, or monthly. In one embodiment, the MC4R agonist or composition thereof is administered daily, for example, once a day, twice a day, or three times a day. In one embodiment, the MC4R agonist or composition thereof is administered weekly, for example, once a week, once every two weeks, or once every three weeks. In embodiments, the MC4R agonist or composition thereof is administered daily for a period of at least 3 weeks, e.g., at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 weeks or more, or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months or more, or at least 1, 2, 3, 4 years or more.

[0007] In embodiments, the method includes administering an MC4R agonist or a composition thereof in a unit dosage form suitable for injection, e.g., subcutaneous injection, to a subject. In embodiments, the unit dosage form is disposed in a delivery device, e.g., a syringe (e.g., a prefilled syringe), an implantable device, a needleless hypodermic injection device, an infusion pump (e.g., an implantable infusion pump), or an osmotic delivery system. In embodiments, the MC4R agonist is administered subcutaneously, e.g., by subcutaneous injection. In another embodiment, the MC4R agonist is administered orally, e.g., as a tablet, capsule, pill, liquid, or other oral dosage form.

[0008] In embodiments, the subject is obese, e.g., severely obese. In embodiments, the subject has early-onset severe obesity. In embodiments, the subject is bulimic. In embodiments, the subject experiences severe hunger. In embodiments, the subject has a weight of 25 kg / m or less prior to administration of the MC4R agonist, e.g., when the MC4R agonist is prescribed or at the time of the first administration. 2 More than (e.g., ≥ 25, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 kg / m 2In embodiments, the subject has a body mass index (BMI) of 35 kg / m or greater prior to administration of the MC4R agonist, e.g., when the MC4R agonist is prescribed or at the time of the first administration. 2 More than (e.g., ≥ 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 kg / m 2 In embodiments, the subject has a body mass index (BMI) of 40 kg / m or greater prior to administration of the MC4R agonist, e.g., when the MC4R agonist is prescribed or at the time of the first administration. 2 More than (e.g., ≥ 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55 kg / m 2 In embodiments, the subject has a body mass index (BMI) of 45 kg / m or greater prior to administration of the MC4R agonist, e.g., when the MC4R agonist is prescribed or at the time of the first administration. 2 More than (e.g., ≥ 46, 47, 48, 49, 50, 51, 52, 53, 54, 55 kg / m 2 have a body mass index (BMI) of 18.2 or higher.

[0009] In embodiments, the subject has a BMI above the 85th to 95th percentile prior to administration of the MC4R agonist or composition thereof, eg, when the MC4R agonist is prescribed or at the time of first administration.

[0010] In embodiments, the subject has failed one or more previous therapies, e.g., exercise, diet, or behavioral therapies, prior to administration of the MC4R agonist or composition thereof, e.g., when the agonist is prescribed or at the time of first administration.

[0011] In embodiments, the subject has a lower body weight after administration of the MC4R agonist or composition thereof than before administration of the agonist.

[0012] In embodiments, administration of an MC4R agonist or composition thereof results in a reduction in the subject's body weight by about 1 kg to 3 kg after 1 week of treatment, about 1 kg to 6 kg after 2 weeks of treatment, about 2 kg to 12 kg after 4 weeks of treatment, about 4 kg to 24 kg after 8 weeks of treatment, or about 8 kg to 48 kg after 16 weeks of treatment, compared to the subject's body weight before treatment. In embodiments, administration of an MC4R agonist or composition thereof results in a reduction in BMI of about 1%, 2%, 3%, 5%, 6%, 7%, 8%, 9%, 10%, or more, for at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more weeks.

[0013] In embodiments, administration of an MC4R agonist or composition thereof does not result in a detectable / significant decrease in resting metabolic rate (REE) in a subject, e.g., over a period of 24 hours, 1 week, or 30 days or more, compared to a control REE (e.g., when expressed as REE per kg of lean body mass, e.g., the REE in a subject before treatment or a predetermined REE, e.g., in a subject with a similar pre-treatment BMI).

[0014] In embodiments, administration of an MC4R agonist or composition thereof results in a reduction in food intake of at least 5 kcal / kg / day, e.g., 5, 10, 20, 30, 40, 50, 60, 70, 80, or 90 kcal / kg / day or more. In embodiments, the reduction in food intake is relative to baseline food intake. In embodiments, the baseline food intake is at least 100 kcal / kg / day, e.g., for a pediatric subject at about 1 year of age. In embodiments, the baseline food intake is at least 40 kcal / kg / day, e.g., for a pediatric subject, e.g., in late adolescence.

[0015] In embodiments, administration of an MC4R agonist or composition thereof results in a decrease in the subject's waist circumference compared to a control (e.g., the subject's waist circumference before treatment) when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more weeks after initiation of treatment.

[0016] In embodiments, administration of an MC4R agonist or composition thereof does not result in a detectable increase in the subject's blood pressure (e.g., diastolic and / or systolic blood pressure) compared to the subject's blood pressure before treatment when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more weeks after initiation of treatment. In embodiments, administration of an MC4R agonist or composition thereof results in a detectable decrease in the subject's blood pressure (e.g., diastolic and / or systolic blood pressure) compared to the subject's blood pressure before treatment when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more weeks after initiation of treatment. In embodiments, administration of an MC4R agonist or composition thereof results in a decrease in the subject's systolic blood pressure of at least 3 mmHg (e.g., at least 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7 mmHg, or more) compared to the subject's blood pressure before treatment when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more weeks after initiation of treatment. In embodiments, administration of an MC4R agonist or composition thereof results in a reduction in the subject's diastolic blood pressure of at least 4 mmHg (e.g., at least 4, 7, 7.5, 8, 8.5, 9, 9.5, 10 mmHg or more) compared to the subject's blood pressure before treatment, when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 weeks or more after initiation of treatment.

[0017] In embodiments, administration of an MC4R agonist or composition thereof results in reduced hunger in a subject, which may result in reduced food intake, a reduced resting metabolic rate (REE), weight loss, reduced waist circumference, and / or reduced blood pressure in the subject.

[0018] In an embodiment, the subject is a mammal, e.g., a human. In one embodiment, the subject is an adult (e.g., 18 years of age or older). In one embodiment, the subject is a pediatric subject, e.g., a child.

[0019] In embodiments, the method further includes obtaining knowledge about the subject's genotype, e.g., obtaining knowledge about the genotype of genes that can activate the MC4R pathway, e.g., genes listed in Table 1. In embodiments, the knowledge is obtained, e.g., directly from the subject's sample (e.g., serum, urine, or tissue (e.g., biopsy) sample).

[0020] In embodiments, the MC4R agonist or composition thereof is administered in response to detection of a predetermined sequence, e.g., a mutation, in a gene capable of activating the MC4R pathway, e.g., a gene listed in Table 1. In embodiments, the predetermined sequence, e.g., a mutation, is detected in a nucleic acid by a method selected from one or more of a nucleic acid hybridization assay, an amplification-based assay, a PCR-RFLP assay, real-time PCR, sequencing (e.g., DNA sequencing, e.g., next-generation sequencing or Sanger sequencing, bisulfite sequencing, or pyrosequencing), a screening assay, FISH, spectral karyotyping or MFISH, comparative genomic hybridization, in situ hybridization, SSP, HPLC, or mass spectrometry genotyping. In embodiments, the predetermined sequence, e.g., a mutation, is detected in a subject. In embodiments, the predetermined sequence, e.g., a mutation, is detected in a nucleic acid molecule or polypeptide in a sample from the subject. In embodiments, the sample comprises blood, serum, urine, or cells derived from a tissue (e.g., a biopsy) from the subject. In embodiments, the method includes obtaining knowledge of the genotype of the subject, for example, obtaining knowledge of the genotype of mutations in the genes listed in.

[0021] In some embodiments, the compound is a peptide-based MC4R agonist. In some embodiments, the compound is a small molecule-based MC4R agonist. In some embodiments, the compound is a peptidomimetic MC4R agonist. In some embodiments, the compound is a compound of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXXII), (XXXIII), (XXXIV), (XXXV), or (XXXVI), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of any one of Formulas (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXXII), (XXXIII), (XXXIV), (XXXV), or (XXXVI), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is not Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH (SEQ ID NO: 140; Compound No. 1014) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is not hydantoin (C(O)-(Arg-Gly))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH (SEQ ID NO: 13) or a pharmaceutically acceptable salt thereof.In some embodiments, a compound of any one of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXXII), (XXXIII), (XXXIV), (XXXV), or (XXXVI) is formulated as a pharmaceutical composition.

[0022] 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. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. Additionally, the materials, methods, and examples are illustrative only and not intended to be limiting. Other features, objects, and advantages of the present disclosure will be apparent from the description and drawings, and from the claims. DETAILED DESCRIPTION OF THE INVENTION

[0023] Described herein are methods for treating a disease or disorder, such as obesity (e.g., hypothalamic obesity), in a subject by administering a therapeutic agent that targets the melanocortin 4 receptor (MC4R) pathway, e.g., an MC4R agonist. In one embodiment, the subject has hypothalamic obesity. In one embodiment, the subject has been identified as having or diagnosed with hypothalamic obesity. In one embodiment, administering the MC4R agonist to the subject results in significant weight loss, decreased hunger, and / or increased metabolic rate in the subject. Exemplary MC4R agonists, as well as related formulations and methods of use, are described in further detail herein.

[0024] definition As used herein, "about" and "approximately" generally refer to an acceptable degree of error for the quantity measured, given the nature or precision of the measurement. Exemplary degrees of error are within 20 percent (%), typically within 10%, and more typically within 5% of a given value or range of values.

[0025] The terms "obtain" or "obtaining," as used herein, refer to obtaining a physical entity or value, e.g., a numerical value, or knowledge of a genotype or nucleic acid or polypeptide (e.g., knowledge of their sequence or mutational status), e.g., by "directly obtaining" or "indirectly obtaining" the physical entity, value, or knowledge. "Directly obtaining" means performing a physical process (e.g., performing a synthetic or analytical method) to obtain the physical entity, value, or knowledge. "Indirectly obtaining" refers to receiving the physical entity, value, or knowledge from another party or source (e.g., a third-party laboratory that directly obtained the physical entity, value, or knowledge). Directly obtaining a physical entity includes performing a process that involves a physical change of a physical substance, e.g., a starting material. Exemplary changes include creating a physical entity from two or more starting materials, shearing or fragmenting a material, separating or purifying a material, combining two or more separate entities into a mixture, and performing a chemical reaction that involves breaking or forming covalent or non-covalent bonds. Obtaining a value or knowledge directly includes performing a process that involves a physical change in a sample or another substance. Examples include performing an analytical process (sometimes referred to herein as a "physical analysis") that involves a physical change in a substance, e.g., a sample, analyte, or reagent; performing an analytical method, e.g., separating or purifying a substance, e.g., an analyte, or a fragment, or other derivative thereof, from another substance; combining an analyte, or a fragment, or other derivative thereof, with another substance, e.g., a buffer, solvent, or reactant; or altering the structure of an analyte, or a fragment, or other derivative thereof, e.g., by cleaving or forming a covalent or non-covalent bond between a first and second atom of the analyte; or altering the structure of a reagent, or a fragment, or other derivative thereof, e.g., by cleaving or forming a covalent or non-covalent bond between a first and second atom of the reagent.

[0026] As used herein, the term "functional" as applied to an allele of a gene that can activate, for example, the MC4R pathway, means an allele that has, for example, at least 5, 10, 20, 30, 40, 50, 70, or 80% of the activity of a reference allele, e.g., a wild-type allele.

[0027] As used herein, the term "non-functional" as applied to an allele, e.g., a gene capable of activating the MC4R pathway, refers to an allele that has less than 5, 10, 20, 30, 40, 50, 70, or 80% of the activity of a reference allele, e.g., a wild-type allele. In one embodiment, a non-functional allele is an allele of a gene other than a functional allele (as the term "functional allele" is defined herein). By way of example, in one embodiment, if a functional allele has at least 20% of the activity of a reference allele, a non-functional allele is an allele that has less than 20% of the activity.

[0028] As used herein, the term "gene capable of activating the MC4R pathway" refers to a gene associated with a phenotype that can be controlled, e.g., improved or alleviated, by regulating MC4R, e.g., activating MC4R, e.g., by an MC4R agonist. In one embodiment, the phenotype is hyperphagia, appetite, unwanted appetite, obesity, weight, body mass, or metabolic syndrome (e.g., diabetes), and the phenotype is, e.g., controlled, e.g., alleviated or ameliorated.

[0029] In one embodiment, the term "genes capable of activating the MC4R pathway" does not include the melanocortin 4 receptor (MC4R) gene. In one embodiment, the term "genes capable of activating the MC4R pathway" does not include POMC. In one embodiment, genes capable of activating the MC4R pathway do not include any one of POMC, proprotein convertase subtilisin / kexin type 1 (PCSK1, also known as PC1 / 3), MAGE-like 2 (MAGEL2), leptin receptor (leptin-R), leptin, 5-hydroxytryptamine (serotonin) receptor 2C, G protein-coupled (5-HT2c receptor), nesient helix-loop-helix 2 (NhHL2, also known as NSCL2), prohormone convertase, carboxypeptidase E (CPE), and single-minded 1 (Sim1). In one embodiment, the genes capable of activating the MC4R pathway do not include any of the genes disclosed in WO2013 / 102047 or WO2017 / 059076, the entire contents of each of which are incorporated herein by reference in their entirety.

[0030] In one embodiment, at least one of the MC4R alleles is functional, e.g., has at least 5, 10, 20, 30, 40, 50, 70, or 80% of the activity of a reference allele, e.g., a wild-type allele, as measured by a functional assay. In one embodiment, one of the MC4R alleles is functional. In one embodiment, both MC4R alleles are functional. In one embodiment, the subject is heterozygous at the MC4R gene, and both alleles are functional. In one embodiment, the subject is homozygous at the MC4R gene for the functional allele.

[0031] In one embodiment, both MC4R alleles are non-functional (a non-functional allele is an allele that is not functional, functional being as defined herein). In one embodiment, the subject is heterozygous in the MC4R gene, where both alleles are non-functional. In one embodiment, the subject is homozygous in the MC4R gene for the non-functional allele.

[0032] In one embodiment, at least one allele of a gene capable of activating the MC4R pathway other than MC4R is functional, e.g., has at least 5, 10, 20, 30, 40, 50, 70, or 80% of the activity of a reference allele, e.g., a wild-type allele, as measured by a functional assay. In one embodiment, one allele of a gene capable of activating the MC4R pathway other than MC4R is functional. In one embodiment, both alleles of a gene capable of activating the MC4R pathway other than MC4R are functional. In one embodiment, the subject is heterozygous in a gene capable of activating the MC4R pathway other than MC4R, and both alleles are functional. In one embodiment, the subject is homozygous in a gene capable of activating the MC4R pathway other than MC4R for a functional allele.

[0033] In one embodiment, both MC4R alleles are non-functional (a non-functional allele is an allele that is not functional, functional being as defined herein). In one embodiment, the subject is heterozygous in the MC4R gene, where both alleles are non-functional. In one embodiment, the subject is homozygous in the MC4R gene for the non-functional allele.

[0034] In one embodiment, an epigenetic modification, e.g., a histone modification, e.g., acetylation or nucleic acid base methylation, e.g., cytosine methylation, is present and is associated with a phenotype of a gene that can activate the MC4R pathway, e.g., hyperphagia, appetite, unwanted appetite, obesity, weight, body mass, or metabolic syndrome (e.g., diabetes).

[0035] In one embodiment, the epigenetic modification is associated with a gene that can activate the MC4R pathway. In one embodiment, the epigenetic modification is associated with MC4R.

[0036] In one embodiment, the epigenetic modification is associated with a gene other than MC4R that can activate the MC4R pathway. In one embodiment, the gene that can activate the MC4R pathway does not include any one of POMC, proprotein convertase subtilisin / kexin type 1 (PCSK1, also known as PC1 / 3), MAGE-like 2 (MAGEL2), leptin receptor (leptin-R), leptin, 5-hydroxytryptamine (serotonin) receptor 2C, G protein-linked (5-HT2c receptor), nesient helix-loop-helix 2 (NhHL2, also known as NSCL2), prohormone convertase, carboxypeptidase E (CPE), and single-minded 1 (Sim1). In one embodiment, the gene that can activate the MC4R pathway does not include any of the genes disclosed in WO2013 / 102047 or WO2017 / 059076, the entire contents of each of which are incorporated herein by reference in their entirety. As used herein, the term "obesity" refers to a subject having a body mass index (BMI) within the range defined as "obese" by the Centers for Disease Control and Prevention (see, e.g., URL.cdc.gov / obesity / defining.html and www.cdc.gov / obesity / childhood- / defining.html; last accessed August 26, 2012) or the National Institutes of Health's "Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults." BMI is obtained by dividing a subject's weight (e.g., in kilograms (kg)) by the square of the subject's height (e.g., in meters (m)). For example, a BMI of 30 kg / m 2 Adults with a BMI above 25.0 to 29.9 kg / m are considered obese. 2 Adults with a BMI between 18.5 and 24.9 kg / m are considered overweight. 2 An adult with a BMI of 18.5 kg / m is considered to be in the normal or healthy weight range.2 An adult with a BMI below 203 pounds is considered underweight. For example, an adult who weighs 203 pounds or more and is 5 feet 9 inches tall is considered obese. For children and teens, obesity refers to a subject having a BMI at or above the 85th-95th percentile for children and teens of the same age and sex.

[0037] A "severely obese" subject, or a subject with "severe obesity," is defined as having a body mass index of 35 kg / m 2 More than, for example, 40 kg / m 2 For example, a severely obese subject is 100% over their ideal (normal, healthy) weight.

[0038] As used herein, "early onset," e.g., as in early onset obesity, means onset (e.g., first occurrence of one or more symptoms of a disorder, e.g., a disorder described herein, e.g., obesity) in a subject before adulthood, e.g., during childhood, e.g., when the subject is 18 years of age or younger (e.g., age 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 year or younger, or during adolescence, e.g., when the child is under 12 years of age, or when the child is under 6 years of age).

[0039] As used herein, the term "metabolic syndrome" refers to a group of conditions that occur together and increase the risk of coronary artery disease, stroke, and type 2 diabetes. According to the American Heart Association and the National Heart, Lung, and Blood Institute, metabolic syndrome is also referred to as syndrome X) when a subject has three or more of the following symptoms: 1) blood pressure of 130 / 85 mmHg or higher; 2) fasting blood sugar (glucose) of 100 mg / dL or more; 3) large waist circumference (abdominal circumference): 40 inches or more for men, 35 inches or more for women; 4) low HDL cholesterol: less than 40 mg / dL for men, less than 50 mg / dL for women; 5) triglycerides of 150 mg / dL or more. Metabolic syndrome can be diagnosed by examining a subject's blood pressure, blood glucose, HDL cholesterol, LDL cholesterol, total cholesterol, and triglyceride levels.

[0040] As used herein, the term "agonist" refers to any chemical compound, either naturally occurring or synthetic, that, upon interacting with (e.g., binding to) its target, e.g., MC4R, results in an increase in MC4R signaling activity above its baseline. Agonists can be superagonists (i.e., compounds capable of producing a maximal response greater than that of the endogenous agonist for the target receptor and thus having greater than 100% efficacy), full agonists (i.e., compounds that elicit a maximal response following receptor occupancy and activation), or partial agonists (i.e., compounds that can activate receptors but are unable to elicit the maximal response of the receptor system).

[0041] As used herein, the terms "treatment," "treat," and "treating" refer to, for example, administering a therapy, e.g., administering a compound described herein (e.g., a compound of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVII), (XX Administering a compound of Formula VIII), (XXIX), (XXX), (XXXI), (XXXII), or (XXXIII) (e.g., as described herein), or a pharmaceutically acceptable salt thereof, means reversing, alleviating, delaying the onset of, or inhibiting the progression of, one or more of the symptoms, signs, or underlying causes of a disease, disorder, or condition (e.g., as described herein). In one embodiment, treating means reducing, reversing, alleviating, or inhibiting the progression of the symptoms of a disease, disorder, or condition. In one embodiment, treating includes alleviating, ameliorating, alleviating, delaying the onset of, or inhibiting the progression of a disease, disorder, or condition. In one embodiment, treating includes reducing, reversing, alleviating, reducing, or delaying the onset of the underlying cause of a disease, disorder, or condition. In some embodiments, "treatment," "treat," and "treating" require that signs or symptoms of a disease, disorder, or condition have developed or been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of a disease or condition, e.g., in prophylactic 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, e.g., to delay or prevent recurrence.Treatment can also be continued after symptoms have resolved, e.g., to delay or prevent recurrence. In some embodiments, treatment includes prevention, while in other embodiments it does not include prevention. The term "treating" refers to achieving one or more of the following results: e.g., reducing weight (e.g., as measured by body mass index (BMI) and / or weight) compared to a control (e.g., weight before treatment, or a predetermined weight); e.g., reducing waist circumference compared to a control (e.g., waist circumference before treatment, or a predetermined waist circumference); e.g., reducing hunger compared to a control (e.g., hunger before treatment or a predetermined hunger level); e.g., increasing resting metabolic rate (REE) compared to a control (e.g., REE before treatment or a predetermined REE); e.g., increasing control levels (e.g., food intake before treatment or a predetermined level) ), improving or ameliorating clinical symptoms or indicators associated with a disorder described herein, such as obesity (e.g., hypothalamic obesity), Prader-Willi syndrome, Smith-Maginis syndrome, type II diabetes, a prediabetic state, a blood level of hemoglobin A1C (Hb1Ac) greater than 6%, hyperinsulinemia, hyperlipidemia, reduced insulin sensitivity, or impaired glucose tolerance; delaying, inhibiting, or preventing the progression of obesity and / or obesity-related symptoms; or partially or completely delaying, inhibiting, or preventing the onset or occurrence of obesity or obesity-related symptoms. Delaying, inhibiting, or preventing the progression of obesity includes, for example, delaying, inhibiting, or preventing the progression to obesity in a subject of normal weight. In embodiments, the control is a value of a parameter measured before treatment with an MC4R agonist described herein, or a predetermined value. The term "treating" further includes partially or completely reducing the risk of coronary artery disease, stroke, and type 2 diabetes associated with metabolic syndrome, as well as improving or ameliorating the clinical symptoms or signs of metabolic syndrome associated with metabolic syndrome, such as any one or more of the five factors listed above.For example, the term "treating" includes slowing, inhibiting, or preventing the progression of parameters associated with metabolic syndrome, including insulin resistance, glucose clearance, and parameters of cardiovascular disease, including heart rate and blood pressure.

[0042] As used herein, "inhibition" or "inhibiting" can include a decrease in a particular parameter, such as those parameters described herein. For example, inhibition of a parameter, e.g., activity, can be at least 5%, 10%, 20%, 30%, 40%, or more and is encompassed by the term. Thus, inhibition need not be 100%.

[0043] "Prophylactic treatment" means treatment prior to the onset of obesity to prevent, inhibit, or reduce its occurrence.

[0044] As used herein, the term "subject" refers to a mammal, e.g., a human. A subject also refers to animals requiring veterinary treatment, such as companion animals (e.g., dogs, cats, etc.), livestock (e.g., cattle, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). In one embodiment, the subject is a pediatric subject (e.g., a subject under 21 years of age or under 18 years of age). In one embodiment, the subject is an adult subject (e.g., a subject 18 years of age or older or 21 years of age or older).

[0045] As used herein, the term "mutation" can refer to an altered nucleic acid sequence of a gene or fragment thereof compared to the wild-type sequence. For example, mutations can include point mutations, frameshift mutations, missense mutations, inversions, deletions, insertions, truncations, and chromosomal translocations. In embodiments, mutations can result in a gene or fragment thereof encoding 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 a gene or fragment thereof encoding a non-functional protein with substantially reduced activity compared to its wild-type activity (e.g., a non-functional protein has less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less of its wild-type activity). For example, a "partial loss-of-function" mutation refers to a mutation that results in a gene or fragment thereof encoding a partially functional protein with reduced activity compared to its wild-type activity (e.g., a partially functional protein has less than 50% but more than 10% of its wild-type activity).

[0046] As used herein, "heterozygous" refers to the presence of two different alleles (having different nucleic acid sequences) in a given gene in a subject. In some embodiments, a "heterozygous mutation" can refer to the presence of a mutation in one allele for a given gene and the absence of a mutation in another 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 can refer to the presence of a mutation (e.g., a loss-of-function mutation or a partial loss-of-function mutation) in one allele for a given gene and a different mutation (e.g., a loss-of-function mutation or a partial loss-of-function mutation) in another allele for the same gene (e.g., two different alleles that are mutated together, e.g., non-functional or partially functional). In embodiments, when a compound heterozygous mutation includes two non-functional alleles, the genotype can be a null genotype or a loss-of-function genotype.

[0047] As used herein, "homozygous" means that there are two identical alleles for a given gene. In some embodiments, "homozygous mutation" means that there are two mutant alleles for a given gene, and these two mutant alleles are identical.

[0048] As used herein, "null genotype" means that two non-functional alleles of a gene are present in a subject.

[0049] As used herein, "unit dosage form" means physically discrete units suited as unitary dosages for the subjects to be treated, each containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect, in association with the required pharmaceutical carrier.

[0050] As used herein, "dose" refers to the quantity or amount of a therapeutic agent. In some embodiments, a dose is an amount administered to a subject in a single administration of one or more unit doses, e.g., a single injection, infusion, or administration. In embodiments, a dose is an amount administered to a subject in multiple administrations of one or more unit doses, e.g., multiple injections, infusions, or administrations. In other embodiments, a dose can refer to the total amount administered to a subject over a given period of time, e.g., per day. In such instances, the dose is typically referred to as a "daily dose," or a dose in terms of number per day.

[0051] As used herein, "hunger" or "hunger level" refers to a subject's appetite, desire to eat food, or perceived need for food. In embodiments, a subject's hunger or hunger level can be quantified by using a scale to obtain a hunger score. In embodiments, the hunger scale assigns higher scores to subjects who experience unbearable hunger more frequently (e.g., most of the time or all the time) and lower scores to subjects who experience unbearable hunger less frequently (e.g., only occasionally or never). See, e.g., Sibilia. Psychological Topics 19 (2010), 2, 341-354. For example, a Likert scale of hunger can be used, assigning a score from 0 to 10 points (0 = no hunger; 10 = severe hunger). In another example, a Likert scale of hunger can be used that assigns a score of 1 to 4 points, where subjects who never experience unbearable hunger are assigned a score of 1, subjects who sometimes experience unbearable hunger are assigned a score of 2, subjects who often experience unbearable hunger are assigned a score of 3, and subjects who always experience unbearable hunger are assigned a score of 4.

[0052] Specific Chemical Definitions Definitions of specific functional groups and chemical terms are set forth in more detail below. Chemical elements are defined in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th The general principles of organic chemistry, as well as specific functional groups and reactivities, are defined in accordance with Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999, and Smith and March, March's Advanced Organic Chemistry, 5 th Edition, 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, 3. rd Edition, Cambridge University Press, Cambridge, 1987.

[0053] 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. The chemical structures and formulas described herein are to be construed in accordance with the standard rules of chemical valency known in the chemical arts. In addition, all publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.

[0054] The nomenclature used to define peptides is that commonly used in the art, with the N-terminal amino group appearing on the left and the C-terminal carboxyl group appearing on the right. Where an amino acid has D- and L-isomeric forms, it is the L-form of the amino acid that is represented unless otherwise specified.

[0055] When a range of values ​​is listed, it is intended to encompass each value and subrange within that range. For example, "C1-C6 alkyl" is intended to include C1, C2, C3, C4, C5, C6, 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 C5-C6 alkyl.

[0056] Compounds useful for practicing the methods described herein may have one or more chiral centers and therefore may exist in multiple stereoisomeric forms. All stereoisomers, and mixtures thereof, are within the scope of the present disclosure. Racemic compounds can be separated using preparative HPLC and columns equipped with chiral stationary phases, or resolved to obtain individual enantiomers using methods known to those skilled in the art. Additionally, chiral intermediate compounds can be resolved and used to prepare the chiral compounds of the present disclosure.

[0057] Compounds useful for practicing the methods described herein may also contain one or more isotopic substitutions. For example, H is: 1 H, 2 H (D or deuterium), and 3 H (T or tritium), and C can be in any isotopic form. 12 C. 13 C, and 14 C can be any isotopic form, including O 16 O and 18 It can be any isotopic form including O, and N is 14 N and 15 N may be any isotopic form, including F. 18 F, 19 It can be any isotopic form containing F, etc.

[0058] As used herein, the term "pharmaceutically acceptable salts" refers to salts of active compounds prepared using relatively non-toxic acids or bases, depending on the specific substituents found in the compounds described herein.When a compound used in the present disclosure contains a relatively acidic functional group, a base addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of the desired base, either directly or in a suitable inert solvent.Examples of pharmaceutically acceptable base addition salts include sodium salts, potassium salts, calcium salts, ammonium salts, organic amino salts, or magnesium salts, or similar salts.When a compound used in the present disclosure contains a relatively basic functional group, an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of the desired acid, either directly or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, as well as salts derived from organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like. Also included are salts of amino acids such as arginate, and salts of organic acids such as glucuronic acid or galacturonic acid (see, e.g., Berge et al., Journal of Pharmaceutical Science 66:1-19 (1977)). Certain compounds used in the present disclosure contain both basic and acidic functionalities, allowing the compounds to be converted into either base or acid addition salts. These salts can be prepared by methods known to those skilled in the art. Other pharmaceutically acceptable carriers known to those of ordinary skill in the art are suitable for use in the present disclosure.

[0059] In addition to salt forms, the present disclosure provides compounds in prodrug form. Prodrugs of the compounds described herein are compounds that easily undergo chemical changes under physiological conditions to produce the compounds of the present invention. Furthermore, 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.

[0060] The compounds useful for carrying out the methods described herein can exist in unsolvated forms as well as solvated forms, including hydrated forms. Generally, solvated forms are equivalent to unsolvated forms and are included within the scope of the present disclosure. The compounds useful for carrying out the methods described herein can exist in multiple crystalline or amorphous forms. Generally, all physical forms are equivalent for the uses contemplated by the present disclosure and are included within the scope of the present disclosure.

[0061] The term "solvate" refers to a form of a compound associated with a solvent, usually by solvolysis. This physical association may involve hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, etc. The compounds described herein may be prepared, for example, in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates, further including both stoichiometric and non-stoichiometric solvates. In certain cases, solvates are capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0062] The term "hydrate" refers to a compound associated with water. Typically, the number of water molecules contained in a hydrate of a compound is in a fixed ratio to the number of compound molecules in the hydrate. Thus, a hydrate of a compound can be represented, for example, by the general formula R·xH2O, where R is the compound and x is a number greater than 0. A given compound may form multiple types of hydrates, including, for example, monohydrates (x is 1), lower hydrates (x is a number greater than 0 and less than 1, e.g., hemihydrate (R·0.5H2O)), and polyhydrates (x is a number greater than 1, e.g., dihydrate (R·2H2O) and hexahydrate (R·6H2O)).

[0063] As used herein, the term "tautomer" refers to interchangeable forms of a particular compound structure, with changes in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the shifting of π electrons and atoms (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of a tautomer is the aci and nitro forms of phenylnitromethane, which are also formed by treatment with acid or base. Tautomers may be suitable for achieving optimal chemical reactivity and biological activity of a compound of interest. [Table 4-1] [Table 4-2] [Table 4-3]

[0064] Unless otherwise specified, all abbreviations for amino acids in this disclosure, with the exception of the N-terminal amino acid (e.g., Ala), refer to the structure -NH-C(R)(R')-CO-, where R and R' are each independently hydrogen, the side chain of the amino acid (e.g., for Ala, R=CH3 and R'=H), or R and R' can be joined to form a ring system.

[0065] For the N-terminal amino acid, the abbreviation is: [ka] This means the structure of

[0066] For example, the designation "NH" as in Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH (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 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH (SEQ ID NO: 107) indicates that the C-terminus is a free acid.

[0067] "-c(Cys-Cys)-" or "-cyclo(Cys-Cys)-" represents the following structure: [ka]

[0068] "-c(Cys-Pen)-", or "-cyclo(Cys-Pen)-" represents the following structure: [ka]

[0069] "-c(Asp-Lys)-", or "-cyclo(Asp-Lys)-", represents the following structure: [ka]

[0070] The following abbreviations are used throughout this disclosure:

[0071] "Hydantoin-(C(O)-(A a -A b ))" refers to the following structure: [ka] wherein the amino acid "A a " has the structure: [ka] It has the amino acid "A b " has the structure: [ka] It has.

[0072] For example, "hydantoin-(C(O)-Arg-A b ))" has the following structure: [ka]

[0073] For example, "hydantoin-(C(O)-(Arg-Gly))" has the following structure: [ka]

[0074] For example, "c[hydantoin]" (C(O)-(Cys-A b ))-A 1 -A 2 -A 3 -A 4 The compound represented as [-Cys]-" has the following structure: [ka] In contrast, "c[hydantoin (C(O)-(A b -Cys))-A 1 -A 2 -A 3 -A 4 The compound represented as [-Cys]-" has the following structure: [ka]

[0075] For further guidance, "c[hydantoin (C(O)-(Asp-A b ))-A 1 -A 2 -A 3 -A 4 -Lys]-" is the compound: [ka] In contrast, "c[hydantoin (C(O)-(Dap-A b ))-A 1 -A 2 -A 3 -A 4 -Asp]-" has the formula: [ka]

[0076] "Acyl" refers to R"-(C(O)-, where R" is H, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, alkenyl, substituted alkenyl, aryl, alkylaryl, or substituted alkylaryl, and is represented in certain embodiments in the general formula as "Ac." Exemplary substituted acyl groups include, but are not limited to, acetyl, trifluoroacetyl, hydroxyacetyl, methoxyacetyl, ethoxyacetyl, propionyl, ethoxypropionyl, isobutyryl, cyanoisobutyryl, hydroxyisobutyryl, carbamoylisobutyryl, 3,3-dimethylbutanoyl, pivaloyl, fluoropivaloyl, difluoropivaloyl, hydroxypivaloyl, mercaptopivaloyl, methylisobutyr ... Examples include -furoyl, 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, tetrahydropyrancarbonyl, and morpholinecarbonyl.

[0077] "Alkyl" means the radical of a straight-chain or branched saturated hydrocarbon group containing one or more carbon atoms, where multiple carbon atoms are present and are joined by single bonds. An alkyl hydrocarbon group can be straight-chained or contain one or more branches. In some embodiments, an alkyl group has 1 to 40 carbon atoms ("C1-C 40 In some embodiments, an alkyl group has 1 to 24 carbon atoms ("C1-C 24 In some embodiments, an alkyl group has 1 to 12 carbon atoms ("C1-C 12In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C1-C8 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 ("C1 alkyl"). Examples of C1-C6 alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8), etc. Each example of an alkyl group can independently be optionally substituted, i.e., unsubstituted (an "unsubstituted alkyl"), or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent (a "substituted alkyl"). In certain embodiments, an alkyl group is an unsubstituted C1 to C8 10 Alkyl (e.g., -CH3). In certain embodiments, the alkyl group is a substituted C1-C6 alkyl.

[0078] "Hydroxyalkyl" means an alkyl group in which one or more hydrogen atoms of the hydrocarbon group have been replaced by one or more hydroxy radicals (e.g., hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, etc.).

[0079] "Substituted alkyl" refers to a hydrocarbon group in which one or more hydrogen atoms have been replaced with a halogen (i.e., fluorine, chlorine, bromine, and iodine), -OH, -CN, -SH, amines (e.g., -NH, -NHCH), -NO, guanidine, urea, amidine, and -(C-C 20 ) alkyl [the -(C1-C 20) alkyl is optionally selected independently for each occurrence from halogen, —CF3, —OCH3, —OCF3, and —(CH2) 0-20 -COOH]. In different embodiments, there are 1, 2, 3, or 4 substituents. -(CH) 0-20 The presence of -COOH leads to the production of alkyl acids. -(CH2) 0-20 Non-limiting examples of alkyl acids containing or consisting of -COOH include 2-norbornaneacetic acid, tert-butyric acid, 3-cyclopentylpropionic acid, and the like.

[0080] As used herein, the term "halogen" or "halo" includes fluoro, chloro, bromo, and iodo.

[0081] As used herein, the term "hydroxy" refers to --OH.

[0082] Guanidine has the general structure (R 1 R 2 N)(R 3 R 4 N)C=NR 5 The central bond in this group is an imine, and the group is structurally related to amidines and ureas.

[0083] "Heteroalkyl" means an acyclic, stable, straight-chain or branched-chain alkyl, or combinations thereof, in which one or more of the carbon atoms in the hydrocarbon group are substituted 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 located at any position in the heteroalkyl group, the nitrogen and sulfur atoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. In different embodiments, one or two heteroatoms are present. 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)-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-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. A "heteroalkyl" may be followed by a particular heteroalkyl group, e.g., -CHO, -NR C R D etc., it will be understood that the term heteroalkyl and -CH2O or -NR C R D are neither redundant nor mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term "heteroalkyl" is used herein to refer to specific heteroalkyl groups, such as, for example, -CHO, -NR C R D should not be construed as excluding

[0084] "Substituted heteroalkyl" refers to a group in which one or more hydrogen atoms of a hydrocarbon group are replaced with a halogen (i.e., fluorine, chlorine, bromine, and iodine), -OH, -CN, -SH, -NH, -NHCH, -NO, and -(C-C 20 ) alkyl [the -(C1-C 20) alkyl is optionally selected independently for each occurrence from halogen, —CF3, —OCH3, —OCF3, and —(CH2) 0-20 -COOH, wherein the heteroalkyl group is substituted with one or more substituents selected from the group consisting of: -COOH, ...

[0085] "Alkenyl" means a hydrocarbon group composed of two or more carbons with one or more carbon-carbon double bonds ("C2-C 24 Alkenyl hydrocarbon groups can be straight-chained or contain one or more branched or cyclic groups. In some embodiments, alkenyl groups have 2 to 10 carbon atoms ("C2-C6"). 10 In 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 carbon-carbon double bonds can be internal (e.g., as in 2-butenyl) or terminal (e.g., 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 C2-C6 alkenyl groups described above. 2~4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), etc. Further examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), etc.

[0086] "Substituted alkenyl" refers to an alkyl group in which one or more hydrogens have been replaced with a halogen (i.e., fluorine, chlorine, bromine, and iodine), -OH, -CN, -SH, -NH, -NHCH, -NO, and -(C-C 20 ) alkyl [C1~20 ) alkyl is optionally selected independently for each occurrence from halogen, —CF3, —OCH3, —OCF3, and —(CH2) 0-20 -COOH, optionally substituted with one or more substituents selected from the group consisting of: In different embodiments, 1, 2, 3, or 4 substituents are present.

[0087] As used herein, the term "alkynyl" refers to the radical of a straight- or branched-chain hydrocarbon group having 2 to 24 carbon atoms and one or more carbon-carbon triple bonds ("C2-C 24 In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C-C 10 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 carbon-carbon triple bonds can be internal (e.g., as in 2-butynyl) or terminal (e.g., 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 independently can be optionally substituted, i.e., unsubstituted (an "unsubstituted alkynyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent (a "substituted alkynyl"). In certain embodiments, an alkynyl group is an unsubstituted C 2~10 In certain embodiments, the alkynyl group is a substituted C 2~6 It is alkynyl.

[0088] "Aryl" refers to an optionally substituted aromatic group ("C6-C6") having at least one ring with a conjugated pi-atom system (e.g., having 6, 10, or 14 pi-electrons shared in a cyclic arrangement), containing up to three conjugated or fused ring systems, and having 6 to 14 ring carbon atoms and zero heteroatoms distributed among the aromatic ring systems. 14 In some embodiments, an aryl group has 6 ring carbon atoms ("C aryl", e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 aryl," e.g., naphthyl, such as 1-naphthyl and 2-naphthyl. In some embodiments, an aryl group has 14 ring carbon atoms ("C 14 Aryl, for example, anthracyl. The aryl group is, for example, C6-C 10 The term "membered" refers to the non-hydrogen ring atoms in the moiety. Aryl includes carbocyclic aryl, heterocyclic aryl, and biaryl groups. Preferably, the aryl is a 5- or 6-membered ring. Preferred atoms in 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 include -(C1-C 20 ) alkyl, -(C1-C 20 ) alkoxy, halogen (i.e., fluorine, chlorine, bromine, and iodine), —OH, —CN, —SH, —NH2, —NO2; halogen, —CF3, —OCF3, and —(CH2) 0-20 -COOH-substituted -(C1-C 20 ) alkyl. In different embodiments, the aryl contains 0, 1, 2, 3, or 4 substituents.

[0089] As used herein, "heteroaryl" refers to a radical of a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having ring carbon atoms and 1 to 4 ring heteroatoms arranged in an aromatic ring system, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, where valence permits. Heteroaryl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more aryl groups, with the point of attachment being at either the aryl or heteroaryl ring; in such cases, the number of ring members refers to the number of ring members in the fused (aryl / heteroaryl) ring system. In bicyclic heteroaryl groups in which one ring does not contain heteroatoms (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be at either ring, i.e., the ring with the heteroatom (e.g., 2-indolyl) or the ring without the heteroatom (e.g., 5-indolyl). Heteroaryl groups may be described, for example, as 6- to 10-membered heteroaryl, where the term "member" refers to the non-hydrogen ring atoms in that moiety. Each instance of a heteroaryl group can independently be optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted heteroaryl").

[0090] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Other exemplary heteroaryl groups include heme and heme derivatives.

[0091] "Alkylaryl" refers to an "alkyl" bonded to an "aryl".

[0092] "(C 1~12The term "hydrocarbon moiety" includes alkyl, alkenyl, and alkynyl, and in the case of alkenyl and alkynyl, C to C 12 exists.

[0093] As used herein, "cycloalkyl" refers to a radical of a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms and 0 heteroatoms in the non-aromatic ring system ("C3-C 10 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-C 10 Cycloalkyl groups may be described, for example, as C4-C7 membered cycloalkyl, where the term "member" refers to the non-hydrogen ring atoms in the moiety. Exemplary C3-C6 cycloalkyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-C8 cycloalkyl groups include, but are not limited to, the aforementioned C3-C6 cycloalkyl groups, as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), cubanyl (C8), bicyclo[1.1.1]pentanyl (C5), bicyclo[2.2.2]octanyl (C8), bicyclo[2.1.1]hexanyl (C6), bicyclo[3.1.1]heptanyl (C7), and the like. 10 The cycloalkyl group may be any of the above-mentioned C3 to C8 cycloalkyl groups, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 As the foregoing examples illustrate, in certain embodiments, a cycloalkyl group is monocyclic ("monocyclic cycloalkyl") or includes fused, bridged, or spiro ring systems, e.g., bicyclic systems ("bicyclic cycloalkyl"), and may be saturated or partially unsaturated. "Cycloalkyl" also includes ring systems in which a cycloalkyl ring, as defined above, is fused with one or more aryl groups (where the point of attachment is on the cycloalkyl ring). In such instances, the number of carbons still refers to the number of carbons in the cycloalkyl ring system. Each instance of a cycloalkyl group independently may be optionally substituted, i.e., unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, a cycloalkyl group is an unsubstituted C3-C6 10 In certain embodiments, the cycloalkyl group is a substituted C-C 10 It is cycloalkyl.

[0094] As used herein, "heterocyclyl" refers to the radical of a 3- to 16-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 16-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, where valence permits. Heterocyclyl groups may be either monocyclic ("monocyclic heterocyclyl") or fused, bridged, or spiro ring systems, e.g., bicyclic systems ("bicyclic heterocyclyl"), and may be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring, as defined above, is fused to one or more cycloalkyl groups (where the point of attachment is on either the cycloalkyl ring or the heterocyclyl ring), or ring systems in which a heterocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups (where the point of attachment is on the heterocyclyl ring). In such instances, the number of ring members still refers to the number of ring members in the heterocyclyl ring system. A heterocyclyl group may be described, for example, as a 3- to 7-membered heterocyclyl, where the term "member" refers to the non-hydrogen ring atoms in that moiety, i.e., carbon, nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. Each instance of heterocyclyl may independently be optionally substituted, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, a heterocyclyl group is an unsubstituted 3- to 16-membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-16 membered heterocyclyl.

[0095] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azirtynyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl (e.g., 2,2,6,6-tetramethylpiperidinyl), tetrahydropyranyl, dihydropyridinyl, tetrahydrothiopyranyl, pyridinonyl (e.g., 1-methylpyridin-2-onyl), and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, pyridazinonyl (2-methylpyridazin-3-onyl), pyrimidinonyl (e.g., 1-methylpyrimidin-2-onyl, 3-methylpyrimidin-4-onyl), dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl.Exemplary 5-membered heterocyclyl groups (also referred to herein as 5,6-bicyclic heterocyclyl rings) fused to a C6 aryl ring include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 5-membered heterocyclyl groups (also referred to herein as 5,5-bicyclic heterocyclyl rings) fused to a heterocyclyl ring include, but are not limited to, octahydropyrrolopyrrolyl (e.g., octahydropyrrolo[3,4-c]pyrrolyl), and the like. Exemplary 6-membered heterocyclyl groups (also referred to as 4,6-membered heterocyclyl rings) fused to a heterocyclyl ring include, but are not limited to, diazaspirononanyl (e.g., 2,7-diazaspiro[3.5]nonanyl). Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as 6,6-bicyclic heterocyclyl rings) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. Exemplary 6-membered heterocyclyl groups fused to a cycloalkyl ring (also referred to herein as 6,7-bicyclic heterocyclyl rings) include, but are not limited to, azabicyclooctanyl (e.g., (1,5)-8-azabicyclo[3.2.1]octanyl). Exemplary 6-membered heterocyclyl groups fused to a cycloalkyl ring (also referred to herein as 6,8-bicyclic heterocyclyl rings) include, but are not limited to, azabicyclononanyl (e.g., 9-azabicyclo[3.3.1]nonanyl).

[0096] As used herein, the term "cyano" or "-CN" refers to a substituent in which a carbon atom is attached to a nitrogen atom by a triple bond, eg, C≡N.

[0097] As used herein, the term "nitro" refers to a substituent in which two oxygen atoms are attached to a nitrogen atom, e.g., --NO.sub.2.

[0098] As used herein, "oxo" refers to carbonyl, i.e., --C(O)--.

[0099] Symbols used herein for compounds of formula (I) or (II) [ka] refers to the point of attachment to another site or functional group within a compound.

[0100] As defined herein, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted. For the avoidance of doubt, unless otherwise stated, the term "substituted," whether preceded by the term "optionally," means substituted with one or more defined groups, e.g., a substituent whose substitution results in a stable compound (e.g., a compound that does not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination, or other reaction). When groups can be selected from multiple alternative groups, the selected groups can be the same or different. For the avoidance of doubt, the term "independently" means that when two or more substituents are selected from multiple possible substituents, the substituents can be the same or different.

[0101] Notation: (amino acid) n " means that an amino acid is repeated n times. For example, the notation "(Pro)2" or "(Arg)3" means that a proline or arginine residue is repeated two or three times, respectively.

[0102] MC4R Hmc4R is a protein encoded by the genome sequence with GenBank accession number CH471077.2. Mutations in the MC4R receptor are associated with severe childhood obesity. The carrier prevalence of MC4R mutations in the early-onset obese population is reported to be approximately 2.5%, with a maximum prevalence of 6% among severely obese children. Humans with MC4R mutations exhibit a phenotype more or less similar to that observed in mice with mutations in the MC4R gene. MC4R-deficient patients exhibit hyperphagia, hyperinsulinemia, increased fat mass, concomitant lean mass, increased bone mineral density, and linear growth velocity, without changes in cortisol, gonadotropin, thyroid, and sex steroid levels. In contrast to MC4R deficiency, hyperphagia and hyperinsulinemia tend to subside as human subjects age. Similar to MC4R knockout mice, the phenotype in heterozygote carriers is moderate compared to homozygote carriers. The hyperphagia observed during the test meal is less severe than that observed in individuals with leptin deficiency. The severity of MC4R dysfunction observed in in vitro assays can predict the amount of food consumed during the test meal by subjects with that particular mutation and correlates with the onset and severity of the obesity phenotype. At least 90 different MC4R mutations are associated with obesity, and it is likely that additional mutations in MC4R that result in similar obesity phenotypes will be discovered.

[0103] Examples of MC4R mutations that cause obesity in humans are described, for example, 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.

[0104] Additional mutations that may potentially cause obesity in humans include R18H, R18L, S36Y, P48S, V50M, F51L, E61K, I69T, D90N, S94R, G98R, I121T, A154D, Y157S, W174C, G181D, F202L, A219, and R18L, 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. V, I226T, G231S, G238D, N240S, C271R, S295P, P299L, E308K, I317V, L325F, and 750DelGA.

[0105] Further examples of mutations that may potentially cause obesity in humans are listed in the Online Mendelian Inheritance in Man (OMIM), a database of human genes and genetic diseases, under accession number 155541 (MC4R) (more precisely, accession numbers 155541.0001-155541.0023), at URL http: / / omim.org / entry / 155541. Representative examples include 4-BP DEL, NT631; 4-BP INS, NT732; TYR35TER; ASP37VAL; SER58CYS; ILE102SER; ASN274SER; 1-BP INS, 112A; 4-BP DEL, 211CTCT; ILE125LYS; ALA175THR; ILE316SER; TYR287TER; ASN97ASP; 15-BP DEL (δ88-92 codons); and SER127LEU. The relevant portions of the OMIM database are incorporated herein by reference. Further exemplary mutations in MC4R are described in Lee. Annals Acad. Med. 38.1 (2009): 34-44.

[0106] In exemplary embodiments, the MC4R mutation results in the maintenance of MC4R signaling activity. Mutations in the genomic sequence encoding MC4R can be detected by methods known to those skilled in the art. For example, genomic sequences can be cloned using nucleotide primers, such as those described 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, and the cloned sequences can be analyzed using commercially available sequencers and software.

[0107] MC4R activity can be measured by methods known to those skilled in the art. For example, cells can be transiently transfected with cloned MC4R DNA, the transfected cells can be contacted with an MC4R agonist (e.g., α-MSH), and the intracellular concentration of Camp, a second messenger of MC4R, can be measured, for example, by an electrochemiluminescence assay as described in Roubert et al., Journal of Endocrinology (2010) 207, pp. 177-183. Reduced MC4R signaling can be confirmed by comparing the intracellular concentration of Camp produced by wild-type MC4R in response to a given agonist with that produced by mutant MC4R.

[0108] MC4R agonists can bind directly or indirectly to MC4R. In one embodiment, the MC4R agonist binds to MC4R in or near the ligand-binding pocket. In one embodiment, the MC4R agonist binds to MC4R in or near the G protein-binding cavity. In one embodiment, the MC4R agonist binds to MC4R in or near the transmembrane domain or extracellular loop, such as TM2, TM3, TM5, TM7, EL2, and / or EL3. Further interactions between MC4R agonists and MC4R may be exemplified in Nat Cell Research (2021) 31:1176-1189, which is incorporated herein by reference.

[0109] Melanocortin-4 receptor (MC4R) pathway genes The melanocortin system, including melanocortins (MCs), agouti, agouti-related protein, and their receptors, integrates hormonal, metabolic, and neural signals to control energy homeostasis and regulate appetite, metabolism, and body weight. MCs, including α-melanocyte-stimulating hormone (α-MSH), β-MSH, γ-MSH, and ACTH, are a family of peptide hormones derived from a precursor protein called proopiomelanocortin (POMC). Activation of the MC4 receptor (MC4R) in the POMC-MC4R pathway increases metabolism and decreases food intake. See, e.g., Fan et al. Nature 1997;385:165-68. The POMC-MC4R pathway contains numerous proteins, including melanocortin (MC), MC4 receptor (MC4R), POMC, proprotein convertase subtilisin / kexin type 1 (PCSK1, also known as PC1 / 3), MAGE-like 2 (MAGEL2), leptin receptor (leptin-R), leptin, 5-hydroxytryptamine (serotonin) receptor 2C, G protein-coupled (5-HT2c receptor), nesient helix-loop-helix 2 (NhHL2, also known as NSCL2), prohormone convertase, carboxypeptidase E (CPE), and single-minded 1 (Sim1), which together contribute to the control of energy homeostasis by, for example, regulating appetite and metabolic rate. MC4R and other components of the POMC-MC4R pathway play important roles in body weight regulation. Mutations in the MC4R gene have been reported to result in early-onset and severe obesity. Other genetic defects in the POMC-MC4R pathway are also thought to likely result in early-onset and severe obesity. These genes are collectively referred to as "genes that can activate the MC4R pathway," and examples are provided below.In one embodiment, the genes capable of activating the MC4R pathway do not include any one of POMC, proprotein convertase subtilisin / kexin type 1 (PCSK1, also known as PC1 / 3), MAGE-like 2 (MAGEL2), leptin receptor (leptin-R), leptin, 5-hydroxytryptamine (serotonin) receptor 2C, G protein-linked (5-HT2c receptor), nesient helix-loop-helix 2 (NhHL2, also known as NSCL2), prohormone convertase, carboxypeptidase E (CPE), and single-minded 1 (Sim1). In one embodiment, the genes capable of activating the MC4R pathway do not include MC4R. In one embodiment, the genes capable of activating the MC4R pathway do not include any of the genes disclosed in WO2013 / 102047 or WO2017 / 059076, the entire contents of each of which are incorporated herein by reference in their entirety. In one embodiment, a compound of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXXII), (XXXIII), (XXXIV), (XXXV), or (XXXVI), or a pharmaceutically acceptable salt, is used to treat a disease, disorder, or condition caused by, for example, a mutation, deletion, or other abnormality in a gene that can activate the MC4R pathway.

[0110] ADP-ribosylation factor-like GTPase 6 (ARL6) ADP-ribosylation factor-like GTPase 6 (ARL6), also known as BBS3, is a member of the ARF-like (ADP-ribosylation factor-like) subfamily of the ARF family of GTP-binding proteins involved in regulating intracellular transport. ARL6 is involved in membrane protein trafficking at the base of ciliary organelles and mediates the recruitment of the BBS-ohmic complex to the plasma membrane. Together with BBS1, ARL6 is required for the correct transport of PKD1 primarily to cilia. Together with the BBS-ohmic complex and LTZL1, ARL6 controls ciliary trafficking of SMO and contributes to Sonic hedgehog (SHH) pathway regulation. ARL6 is thought to regulate ciliary assembly and disassembly, as well as subsequent ciliary signaling events, such as the Wnt signaling cascade. ARL6 isoform 2 may be required for proper retinal function and organization. A vision-specific transcript encoding the long isoform BBS3L has also been described.

[0111] Mutations in the ARL6 gene are associated with Bardet-Biedl syndrome (BBS), a genetically heterogeneous disorder. BBS is a form of Laurence-Moon-Biedl syndrome, characterized by obesity, retinopathy, learning disabilities, polydactyly, genital hypoplasia, and retinitis pigmentosa. (See, e.g., Young et al. Am. J. Med. Genet. 78(5):461-7 (2002)).

[0112] The human ARL6 gene sequence is represented by GenBank accession number NG_008119.2 and is incorporated herein by reference. An exemplary human ARL6 nucleic acid sequence is represented by GenBank accession number NM_001278293.3 and is incorporated herein by reference. An exemplary amino acid sequence of human ARL6 is represented by Q9H0F7 and is incorporated herein by reference.

[0113] Retinoic acid-inducible 1 (RAI1) Retinoic acid-inducible 1 (RAI1) is a transcription factor that regulates circadian clock components: CLOCK, ARNTL / BMAL1, ARNTL2 / BMAL2, PER1 / 3, CRY1 / 2, NR1D1 / 2, and RORA / C. RAI1 positively regulates the transcriptional activity of CLOCK, a core component of the circadian clock. (See, e.g., Williams et al. Am. J. Hum. Genet. 90(6):941-9 (2012)). RAI1 also regulates transcription through chromatin remodeling by interacting with other proteins in chromatin as well as proteins in the basal transcription machinery. RAI1 may be important for embryonic and postnatal development and is thought to be involved in neuronal differentiation.

[0114] Mutations in RAI1 (e.g., resulting in haploinsufficiency) are associated with Smith-Maginis syndrome, a disorder characterized by cognitive and behavioral abnormalities, including self-injurious behavior and sleep disturbances, obesity, and unique craniofacial and skeletal dysmorphisms, which is associated with a deletion involving chromosome 17p11.2 (see, e.g., Slager et al. Nat Genet. 33(4):466-468 (2003)).

[0115] The human RAI1 gene sequence is set forth in GenBank accession number NG_007101.2 and is incorporated herein by reference. An exemplary human RAI1 nucleic acid sequence is set forth in GenBank accession number NM_030665.4 and is incorporated herein by reference. An exemplary amino acid sequence of human RAI1 is set forth in Q7Z5J4-1 and is incorporated herein by reference.

[0116] Steroid receptor coactivator 1 (SRC1) Steroid receptor coactivator 1 (SRC1), also known as nuclear receptor coactivator 1 (NCOA1), is a transcriptional coactivator for steroid and nuclear hormone receptors. SRC1 is a member of the p160 / SRC family and, like other family members, possesses histone acetyltransferase activity and contains a nuclear localization signal as well as Bhlh and PAS domains. SRC1 directly binds to nuclear receptors and stimulates transcriptional activity in a hormone-dependent manner. SRC1 is involved in the coactivation of different nuclear receptors, for example, in response to steroids, retinoids, thyroid hormones, and prostanoids. SRC1 is also involved in the coactivation mediated by the STAT3, STAT5A, STAT5B, and STAT6 transcription factors. SRC1 plays a central role in the generation of multisubunit coactivator complexes that act by chromatin remodeling, possibly by participating in both chromatin remodeling and general transcription factor recruitment. SRC1, together with NCOA2, controls the metabolic balance between white and brown adipose tissue and mediates steroid hormone responses. Alternatively spliced ​​transcript variants encoding different isoforms have also been identified.

[0117] Mutations in SRC1 are associated with obesity. Without wishing to be bound by theory, SRC-1 is thought to control the function of hypothalamic proopiomelanocortin (Pomc) neurons, which regulate feeding and body weight. Rare heterozygous variants of SRC1 have been found in severely obese individuals, resulting in impaired leptin-mediated Pomc reporter activity in cells. (See, e.g., Yang et al. Nat. Commun. 10(1):1718 (2019)).

[0118] The human SRC1 gene sequence is set forth in GenBank Accession No. NG_029014.2 and is incorporated herein by reference. An exemplary human SRC1 nucleic acid sequence is set forth in GenBank Accession No. NM_003743.5 and is incorporated herein by reference. An exemplary amino acid sequence of human SRC1 is set forth in Q15788-1 and is incorporated herein by reference.

[0119] Bardet-Biedl syndrome 19 (BBS19) Bardet-Biedl syndrome 19 (BBS19), also known as intraflagellar transport protein 27 homolog (IFT27), is a small GTPase-like component of intraflagellar transport complex B and is essential for ciliary biogenesis and maintenance. BBS19 promotes the exit of the BBSosome complex from cilia through its interaction with ARL6. BBS19 forms a subcomplex with IFT25 within IFT complex B, preventing the aggregation of GTP-free ARL6, but is not thought to be involved in the entry of the BBSosome complex into cilia (see, for example, Liew et al. Dev. Cell 31(3):265-278 (2014)). BBS19 is also required for Hedgehog signaling. The role of BBS19 in intraflagellar transport has been primarily confirmed in tissues with a high concentration of ciliated cells, such as the kidney and testis. BBS19 is essential for male fertility, spermatogenesis, and sperm flagellation, plays a role in early kidney development, and may be involved in regulating ureteric bud initiation.

[0120] Mutations in the BBS19 gene are associated with Bardet-Biedl syndrome (see, e.g., Aldahmesh et al. Hum. Mol. Genet. 23(12):3307-15 (2014)).

[0121] The human BBS19 gene sequence is set forth in GenBank Accession No. NG_034205.1, which is incorporated herein by reference. An exemplary human BBS19 nucleic acid sequence is set forth in GenBank Accession No. NM_001177701.3, which is incorporated herein by reference. An exemplary human BBS19 amino acid sequence is set forth in Q9BW83-1, which is incorporated herein by reference.

[0122] Bardet-Biedl syndrome 21 (BBS21) The Bardet-Biedl syndrome 21 (BBS21) gene, also known as chromosome 8 open reading frame 37 (C8orf37), encodes a ubiquitously expressed protein of unknown function. High levels of BBS21 mRNA can be found in the brain, heart, and retina. The protein has been shown to colocalize with polyglutamylated tubulin at the base of primary villi in human retinal pigment epithelial cells. Mutations in the BBS21 gene are associated with Bardet-Biedl syndrome, autosomal recessive cone-rod dystrophy (arCRD), and retinitis pigmentosa (see, e.g., Heon et al. Hum. Mol. Genet. 25(11):2283-2294 (2016)).

[0123] The human BBS21 gene sequence is set forth in GenBank Accession No. NG_032804.1, which is incorporated herein by reference. An exemplary human BBS21 nucleic acid sequence is set forth in GenBank Accession No. NM_177965.4, which is incorporated herein by reference. An exemplary amino acid sequence of human BBS21 is set forth in Q96NL8-1, which is incorporated herein by reference.

[0124] Centrosomal protein 290 (CEP290) Centrosomal protein 290 (CEP290), also known as BBS14, encodes a protein containing 13 putative coiled-coil domains, a region homologous to the SMC chromosome segregation ATPase, six KID motifs, three tropomyosin homology domains, and an ATP / GTP binding site motif A. The protein is localized to the centrosome and cilium and has sites for N-glycosylation, tyrosine sulfation, phosphorylation, N-myristoylation, and amidation.

[0125] CEP290 is involved in early and late steps in ciliogenesis, and its association with CCP110 is required for CCP110-mediated inhibition of primary ciliogenesis. CEP290 may play a role in early ciliary development in the disappearance of centriolar satellites and in the transition of primary ciliary vesicles (PCVs) to capped ciliary vesicles (CCVs). CEP290 is also required for the centrosomal recruitment of RAB8A and for targeting centriolar satellite proteins to centrosomes, such as those in PCM1. CEP290 is required for the correct localization of cilia and phototransduction proteins in retinal photoreceptor cells and may play a role in the ciliary transport process. It is required for efficient recruitment of RAB8A to primary cilia. In the ciliary transition zone, CEP290 is part of a structural complex that is required for tissue-specific ciliary development and may regulate ciliary membrane composition. CEP290 is involved in regulating BBSome complex integrity within the complex and, in particular, the presence of BBS2, BBS5, and BBS8 / TTC8, as well as ciliary targeting of selected BBSome cargoes. CEP290 may play a role in controlling entry of the BBSome complex into the cilium.

[0126] Mutations in this gene are associated with several ciliopathy, including Bardet-Biedl syndrome, isolated retinal degeneration, medullary polycystic kidney disease (NPHP), Joubert syndrome, Senior-Loken syndrome (SLSN), and the lethal neonatal Meckel-Gruber syndrome (MKS) (see, e.g., Zhang et al. Hu. Mol. Genet. 23(1):40-51 (2014) and Leitch et al. Nat. Genet. 40(4):443-448 (2008)).

[0127] The human CEP290 gene sequence is set forth in GenBank Accession No. NG_008417.2 and is incorporated herein by reference. An exemplary human CEP290 nucleic acid sequence is set forth in GenBank Accession No. NM_025114.4 and is incorporated herein by reference. An exemplary human CEP290 amino acid sequence is set forth in O15078-1 and is incorporated herein by reference.

[0128] Intraflagellar transport 74 (IFT74) Intraflagellar transport 74 (IFT74) is a core component of intraflagellar transport (IFT), a multiprotein complex involved in transporting ciliary proteins along axonemal microtubules. IFT proteins are found at the base of the ciliary membrane as well as within the cilium, where they aggregate into long arrays between the base and apex of the ciliary membrane. Specifically, IFT74, together with IFT81, forms a tubulin-binding molecule that mediates the transport of tubulin specifically within the cilium. IFT74 binds to β-tubulin via its basic domain and is required for ciliary development.

[0129] Naturally occurring mutations in this gene are associated with Bardet-Biedl syndrome and amyotrophic lateral sclerosis-frontotemporal dementia (see, e.g., Lindstrand et al. Am. J. Hum. Genet. 99(2):318-336 (2016)).

[0130] The human IFT74 gene sequence is set forth in GenBank Accession No. NG_053083.1, which is incorporated herein by reference. An exemplary human IFT74 nucleic acid sequence is set forth in GenBank Accession No. NM_001099222.2, which is incorporated herein by reference. An exemplary amino acid sequence of human IFT74 is set forth in Q96LB3-1, which is incorporated herein by reference.

[0131] Leucine zipper transcription factor-like 1 (LZTFL1) Leucine zipper transcription factor-like 1 (LZTFL1), also known as BBS17, encodes a ubiquitously expressed protein that localizes to the cytoplasm. This protein interacts with the Bardet-Biedl syndrome (BBS) protein and regulates protein trafficking to the ciliary membrane through interaction with the BBS protein complex. LZTFL1 regulates the ciliary localization of the BBS-Omega complex and, together with the BBS-Omega complex, controls SMO ciliary trafficking and contributes to the regulation of the Sonic Hedgehog (SHH) pathway.

[0132] Nonsense mutations in this gene are associated with a form of Bardet-Biedl syndrome (see, e.g., Deffert et al. Am. J. Med. Genet. A. 143A(2):208-213 (2007)). LZTFL1 may also function as a tumor suppressor, possibly by regulating epithelial to mesenchymal cell transition by interacting with E-cadherin and the actin cytoskeleton. Alternative splicing of LZTFL1 results in multiple transcript variants.

[0133] The human LZTFL1 gene sequence is represented by GenBank accession number NG_033917.1 and is incorporated herein by reference. An exemplary human LZTFL1 nucleic acid sequence is represented by GenBank accession number NM_020347.4 and is incorporated herein by reference. An exemplary human LZTFL1 amino acid sequence is represented by Q9NQ48-1 and is incorporated herein by reference.

[0134] MKS transition zone complex subunit 1 (MKS1) MKS transition zone complex subunit 1 (MKS1), also known as BBS13, is a component of the structural complex, a complex that localizes to the transition zone of primary cilia and acts as a barrier to prevent the diffusion of transmembrane proteins between the cilium and the plasma membrane. MKS1 localizes to the basal body and is involved in the movement of centrosomes to the apical cell surface during early ciliary development. It is required for the formation of primary cilia in ciliated epithelial cells and is required for ciliary structure and functions, including regulating centrosome duplication, thereby controlling length and proper number. MKS1 is also required for cell branching morphology.

[0135] Mutations in this gene result in Meckel syndrome type 1 and Bardet-Biedl syndrome type 13. (See, e.g., Xing et al. PloS One 9(3):e90599(2014)). Multiple transcript variants encoding different isoforms have been identified for this gene.

[0136] The human MKS1 gene sequence is set forth in GenBank Accession No. NG_013032.1, which is incorporated herein by reference. An exemplary human MKS1 nucleic acid sequence is set forth in GenBank Accession No. NM_017777.4, which is incorporated herein by reference. An exemplary amino acid sequence of human MKS1 is set forth in Q9NXB0-1, which is incorporated herein by reference.

[0137] Tripartite motif-containing 32 (TRIM32) Tripartite motif-containing 32 (TRIM32), also known as BBS11, is a member of the tripartite motif (TRIM) family. The protein encoded by the TRIM32 gene contains three zinc-binding domains: RING, B-box type 1, and B-box type 2, as well as a coiled-coil region. The protein encoded by TRIM32 is localized to the cytoplasm and nucleus, where it interacts with the activation domain of the HIV-1 Tat protein. The TRIM32 protein also has E3 ubiquitin ligase activity and has been shown to ubiquitinate DTNBP1 (dysbindin) to promote its degradation. The TRIM32 protein can also ubiquitinate BBS2.

[0138] Mutations in TRIM32 are associated with muscular dystrophy, limb-girdle syndrome, autosomal recessive 8, and Bardet-Biedl syndrome (see, e.g., Chiang et al. Proc. Natl. Acad. Sci. USA 103(16):3287-92 (2006)).

[0139] The human TRIM32 gene sequence is set forth in GenBank Accession No. NG_011619.1, which is incorporated herein by reference. An exemplary human TRIM32 nucleic acid sequence is set forth in GenBank Accession No. NM_012210.4, which is incorporated herein by reference. An exemplary amino acid sequence of human TRIM32 is set forth in Q13049-1, which is incorporated herein by reference.

[0140] WD repeat-containing planar cell polarity effector (WDPCP) WD repeat-containing planar cell polarity effector (WDPCP), also known as BBS15, is a cytoplasmic WD40 repeat protein. WDPCP has been suggested to act as a planar cell polarity protein, playing an important role in collective cell movement and ciliogenesis by mediating septin localization. Together with FUZ, WDPCP has been suggested to function as a core component of the CPLANE (Ciliogenesis and Planar Polarity Effector) complex, which is involved in the recruitment of peripheral IFT-A proteins to the basal body.

[0141] Mutations in this gene are associated with Bardet-Biedl syndrome and may also play a role in Meckel-Gruber syndrome (see, e.g., Kim et al. Science 329(5997):1337-40(2010)). Alternative splicing results in multiple transcript variants.

[0142] The human WDPCP gene sequence is set forth in GenBank accession number NG_028144.2 and is incorporated herein by reference. An exemplary human WDPCP nucleic acid sequence is set forth in GenBank accession number NM_001042692.3 and is incorporated herein by reference. An exemplary human WDPCP amino acid sequence is set forth in O95876-1 and is incorporated herein by reference.

[0143] Ribosomal protein S6 kinase A3 (RPS6KA3) Ribosomal protein S6 kinase A3 (RPS6KA3) is a member of the RSK (ribosomal S6 kinase) family of serine / threonine kinases that acts downstream of ERK (MAPK1 / ERK2 and MAPK3 / ERK1) signaling to mediate mitotic and stress-induced activation of the transcription factors CREB1, ETV1 / ER81, and NR4A1 / NUR77, regulate translation through RPS6 and EIF4B phosphorylation, and mediate cell proliferation, survival, and differentiation by regulating Mtor signaling and suppressing the proapoptotic function of BAD and DAPK1. In fibroblasts, RPS6KA3 is required for EGF-stimulated phosphorylation of CREB1 and histone H3 at Ser-10, leading to the subsequent transcriptional activation of several immediate-early genes. RPS6KA3 phosphorylates and activates the NR4A1 / NUR77 and ETV1 / ER81 transcription factors and the cofactor CREBBP in response to mitogenic stimuli (EGF and PMA). During insulin-driven signaling, RPS6KA3 indirectly regulates the transcription of several genes by phosphorylating GSK3B at Ser-9 and inhibiting its activity. RPS6KA3 phosphorylates RPS6 in response to serum or EGF through an mTOR-independent mechanism, promoting translation initiation by promoting the assembly of the preinitiation complex. In response to insulin, RPS6KA3 phosphorylates EIF4B, increasing its affinity for the EIF3 complex and stimulating cap-dependent translation. RPS6KA3 participates in the Mtor nutrient perception pathway by directly phosphorylating TSC2 at Ser-1798 (potentially inhibiting TSC2's ability to suppress Mtor signaling) and mediates the phosphorylation of RPTOR (which may regulate Mtorc1 activity and promote rapamycin-sensitive signaling independently of the PI3K / AKT pathway). RPS6KA3 mediates cell survival by phosphorylating the pro-apoptotic proteins BAD and DAPK1 and suppressing their pro-apoptotic function. RPS6KA3 promotes hepatic stellate cell survival by phosphorylating CEBPB in response to the hepatotoxin carbon tetrachloride (CCl4).RPS6KA3 is also involved in cell cycle control by phosphorylating the CDK inhibitor CDKN1B, which promotes its association with 14-3-3 proteins and prevents its nuclear translocation and G1 progression inhibition. In LPS-stimulated dendritic cells, RPS6KA3 is involved in TLR4-induced macropinocytosis, and in myeloma cells, RPS6KA3 acts as an effector of FGFR3-mediated transforming signaling after direct phosphorylation by FGFR3 at Tyr-529. RPS6KA3 negatively regulates EGF-induced MAPK1 / 3 phosphorylation by phosphorylating SOS1. RPS6KA3 phosphorylates SOS1 at Ser-1134 and Ser-1161 (which creates YWHAB and YWHAE binding sites and contributes to the negative regulation of MAPK1 / 3 phosphorylation) and EPHA2 at Ser-897, and the RPS6KA-EPHA2 signaling pathway controls cell migration.

[0144] Mutations in this gene are associated with Coffin-Lowry syndrome (CLS), a rare X-linked semi-dominant syndrome characterized by severe psychomotor retardation, facial dysmorphism, digital abnormalities, and progressive skeletal deformities (see, e.g., Delaunoy et al. Clin. Genet. 70(2):161-6 (2006)).

[0145] The human RPS6KA3 gene sequence is represented by GenBank accession number NG_007488.1 and is incorporated herein by reference. An exemplary human RPS6KA3 nucleic acid sequence is represented by GenBank accession number NM_004586.3 and is incorporated herein by reference. An exemplary amino acid sequence of human RPS6KA3 is represented by P51812-1 and is incorporated herein by reference.

[0146] 5-hydroxytryptamine receptor 2C (HTR2C) The 5-hydroxytryptamine receptor 2C (HTR2C) is a seven-transmembrane G protein-coupled receptor for 5-hydroxytryptamine (serotonin). HTR2C also functions as a receptor for various drugs and psychoactive substances, including the ergot alkaloid derivatives 1-2,5-dimethoxy-4-iodophenyl-2-aminopropane (DOI) and lysergic acid diethylamide (LSD). Ligand binding causes conformational changes that trigger signaling through guanine nucleotide-binding proteins (G proteins) and modulate the activity of downstream effectors. β-arrestin family members inhibit G protein-mediated signaling and mediate the activation of alternative signaling pathways. Signaling modulates the activity of phosphatidylinositol 3-kinase and downstream signaling cascades, resulting in the uptake of Ca from intracellular stores. 2+ The phosphatidylinositol-calcium second messenger system, which promotes the release of ions, is activated. HTR2C also regulates neuronal activity by activating short-term transient receptor potential calcium channels in the brain, thereby regulating the activation of proopiomelanocortin neurons and the release of CRH, which in turn regulates the release of corticosterone. HTR2C plays a role in regulating appetite and feeding behavior, responding to anxiogenic stimuli and stress, and also plays a role in insulin sensitivity and glucose homeostasis.

[0147] HTR2C mRNA undergoes multiple RNA editing events, in which genomically encoded adenosine residues are converted to inosine. RNA editing is predicted to alter the structure of the second intracellular loop, resulting in the generation of an alternative protein form with reduced ability to interact with G proteins. Abnormalities in HTR2C RNA editing have been detected in suicide victims suffering from depression. Furthermore, naturally occurring variations in the promoter and 5' non-coding and coding regions of HTR2C may show statistically significant associations with psychiatric and behavioral disorders. Alternative splicing results in multiple distinct transcript variants. Mutations in HTR2C are associated with hyperphagia, hyperactivity, and obesity. (See, e.g., Xu et al. Neuron. 60(4):582-9 (2008)).

[0148] The human HTR2C gene sequence is represented by GenBank accession number NG_012082.2 and is incorporated herein by reference. An exemplary human HTR2C nucleic acid sequence is represented by GenBank accession number NM_001256760.2 and is incorporated herein by reference. An exemplary amino acid sequence of human HTR2C is represented by P28335-1 and is incorporated herein by reference.

[0149] Kinase inhibitor of Ras2 (KSR2) Kinase suppressor of Ras2 (KSR2) is an intracellular scaffolding protein involved in multiple signaling pathways. In particular, KSR2 is a position-regulating scaffold that links MEK to RAF. KSR2 has been shown to have very low protein kinase activity and can phosphorylate MAP2K1 at several Ser and Thr residues with very low efficiency in vitro. KSR2 functions as a MAP2K1 / MEK1-dependent allosteric activator of BRAF. Upon binding to MAP2K1 / MEK1, KSR2 dimerizes with BRAF and promotes BRAF-mediated phosphorylation of MAP2K1 / MEK1 (see, e.g., Lavoie et al. Nature 554:549-553 (2018)). Interaction with BRAF enhances KSR2-mediated phosphorylation of MAP2K1 in vitro. KSR2 blocks MAP3K8 kinase activity and MAP3K8-mediated signaling. KSR2 also functions as a negative regulator of MAP3K3-mediated activation of the ERK, JNK, and NF-κB pathways, inhibiting MAP3K3-mediated interleukin-8 production.

[0150] Mutations in KSR2 are associated with childhood hyperphagia, slow heart rate, reduced basal metabolic rate, and severe insulin resistance, suggesting that KSR2 is an important regulator of energy intake, metabolism, and substrate utilization in humans (see, e.g., Pearce et al. Cell. 155(4):765-77 (2013)).

[0151] The human KSR2 gene sequence is represented by GenBank accession number NC_000012.12 and is incorporated herein by reference. An exemplary human KSR2 nucleic acid sequence is represented by GenBank accession number NM_173598.6 and is incorporated herein by reference. An exemplary human KSR2 amino acid sequence is represented by Q6VAB6-1 and is incorporated herein by reference.

[0152] Prokineticin 2 (PROK2) The prokineticin 2 (PROK2) gene encodes a protein expressed in the suprachiasmatic nucleus (SCN) circadian clock that may function as an output component of the circadian clock. A secreted form of the encoded protein may also function as a chemoattractant for neural progenitor cells in the olfactory bulb. Proteins from other vertebrates that are similar to the PROK2 gene product have been isolated based on their homology to snake venom. Secretions from frog skin have been shown to have various functions.

[0153] Mutations in PROK2 are associated with hypogonadotropic hypogonadism type 4, with or without anosmia and Kallmann syndrome. Multiple transcript variants encoding different isoforms have been found for this gene. (See, e.g., Dode et al. PloS Genet. 2(10):e175 (2006)).

[0154] The human PROK2 gene sequence is set forth in GenBank Accession No. NG_008275.1, which is incorporated herein by reference. An exemplary human PROK2 nucleic acid sequence is set forth in GenBank Accession No. NM_001126128.2, which is incorporated herein by reference. An exemplary amino acid sequence of human PROK2 is set forth in Q9HC23-1, which is incorporated herein by reference.

[0155] Ras-related protein Rab-23 (RAB23) The Ras-related protein Rab-23 (RAB23) is a small GTPase of the Ras superfamily. Small GTPases, Rabs, are involved in regulating diverse cellular functions associated with intracellular membrane trafficking, including autophagy and immune responses to bacterial infections. Rabs cycle between an inactive GDP-bound form and an active GTP-bound form, which can recruit a diverse array of downstream effectors to membranes that are directly responsible for vesicle formation, migration, tethering, and fusion. In conjunction with SUFU, the protein encoded by RAB23 prevents the nuclear import of GLI1, thereby inhibiting its transcription factor activity. RAB23 also regulates GLI1 during chondrocyte differentiation, GLI3 proteolytic processing, and GLI2 and GLI3 transcription factor activity. RAB23 also mediates defense against pathogens, such as S. aureus, by playing a role in the assembly of autophagic vacuoles and promoting their subsequent capture by autophagosomes emerging from lysosomes. RAB23 may play a role in central nervous system development by attenuating Sonic hedgehog signaling.

[0156] Mutations in RAB23 are associated with cancer and Carpenter syndrome, a pleiotropic disorder with autosomal recessive inheritance, the cardinal features of which include craniosynostosis, polysyndactyly, obesity, and heart defects. (See, e.g., Jenkins et al. Am. J. Hum. Genet. 80(6):1162-70(2007)). Alternative splicing results in multiple transcript variants.

[0157] The human RAB23 gene sequence is represented by GenBank accession number NG_012170.1 and is incorporated herein by reference. An exemplary human RAB23 nucleic acid sequence is represented by GenBank accession number NM_016277.5 and is incorporated herein by reference. An exemplary human RAB23 amino acid sequence is represented by Q9ULC3-1 and is incorporated herein by reference.

[0158] Melanocortin 2 receptor accessory protein 2 (MRAP2) Melanocortin 2 receptor accessory protein 2 (MRAP2) is a G protein-coupled receptor accessory protein that regulates melanocortin receptor signaling and is involved in energy homeostasis. The encoded protein has been shown to interact with all known melanocortin receptors and can regulate both receptor trafficking and activation in response to ligands. MRAP2 is thought to play a central role in the control of energy homeostasis and body weight regulation by increasing the ligand sensitivity of MC4R and MC4R-mediated production of Campylobacter 4 (CAMP). MRAP2 can also act as a negative regulator of MC2R (e.g., by competing with MRAP for binding to MC2R and impairing corticotropin (ACTH) binding to MC2R). MRAP2 can also regulate the activity of other melanocortin receptors (MC1R, MC3R, and MC5R). MRAP2 has been implicated in metabolic regulation in rodents, particularly via the melanocortin-4 receptor.

[0159] Defects in MRAP2 are associated with obesity (e.g., monogenic hyperphagia, hyperglycemia, and hypertension) in both children and adults (see, e.g., Baron et al. Nat. Med. 25(11):1733-1738 (2019)).

[0160] The human MRAP2 gene sequence is set forth in GenBank Accession No. NG_051944.1, which is incorporated herein by reference. An exemplary human MRAP2 nucleic acid sequence is set forth in GenBank Accession No. NM_138409.4, which is incorporated herein by reference. An exemplary amino acid sequence of human MRAP2 is set forth in Q96G30-1, which is incorporated herein by reference.

[0161] AF4 / FMR2 Family Member 4 (AFF4) AF4 / FMR2 family member 4 (AFF4) is a component of the positive transcription elongation factor b (P-TEFb) complex, a core component of the super elongation complex (SEC), which is required to increase the catalytic rate of RNA polymerase II transcription by suppressing transient polymerase pausing at multiple sites along the DNA. In the SEC complex, AFF4 functions as a central scaffold that recruits other factors through direct interaction with ELL proteins (e.g., ELL, ELL2, or ELL3) and the P-TEFb complex. During infection with the HIV-1 virus, the SEC complex is recruited by the viral Tat protein to stimulate viral gene expression.

[0162] Chromosomal abnormalities involving ATF4 have been found in acute lymphoblastic leukemia (ALL). Missense mutations in ATF4 are associated with CHOPS syndrome (C for cognitive impairment and coarse facies, H for heart defects, O for obesity, P for pulmonary involvement, and S for short stature and skeletal dysplasia). (See, e.g., Izumi et al. Nat. Genet. 47(4):338-44(2015)).

[0163] The human AFF4 gene sequence is represented by GenBank accession number NG_030340.1 and is incorporated herein by reference. An exemplary human AFF4 nucleic acid sequence is represented by GenBank accession number NM_014423.4 and is incorporated herein by reference. An exemplary amino acid sequence of human AFF4 is represented by Q9UHB7-1 and is incorporated herein by reference.

[0164] Adenylate cyclase 3 (ADCY3) Adenylate cyclase 3 (ADCY3) is a membrane-bound enzyme that catalyzes the formation of the second messenger cyclic adenosine monophosphate (Camp). ADCY3 catalyzes the formation of the signaling molecule Camp in response to G protein signaling and, through its function in Camp biosynthesis, participates in the signaling cascade triggered by olfactory receptors. ADCY3 is required for odorant perception, normal sperm motility, and normal male fertility. ADCY3 also plays a role in regulating insulin levels and body fat accumulation in response to a high-fat diet. ADCY3 is widely expressed in various human tissues and may be involved in numerous physiological and pathophysiological metabolic processes. Two transcript variants encoding distinct isoforms have been identified for ADCY3.

[0165] Loss-of-function mutations in ADCY4 are associated with severe monogenic obesity (see, e.g., Saeed et al. Nat. Genet. 50(2):175-179 (2018)).

[0166] The human ADCY3 gene sequence is set forth in GenBank accession number NC_000002.12 and is incorporated herein by reference. An exemplary human ADCY3 nucleic acid sequence is set forth in GenBank accession number NM_001320613.2 and is incorporated herein by reference. An exemplary amino acid sequence of human ADCY3 is set forth in O60266-1 and is incorporated herein by reference.

[0167] TUB bipartite transcription factor (TUB) TUB bipartite transcription factor (TUB) is a member of the Tubby family of bipartite transcription factors that function in signal transduction from heterotrimeric G protein-coupled receptors. The crystal structure has been determined for a similar protein in mouse, which functions as a membrane-bound transcriptional regulator that translocates to the nucleus in response to phosphoinositide hydrolysis. TUB binds to membranes containing phosphatidylinositol 4,5-bisphosphate and has been shown to bind DNA in vitro. TUB may contribute to transcriptional regulation in the nucleus and may be involved in the hypothalamic control of body weight. TUB contributes to the stimulation of apoptotic retinal pigment epithelial (RPE) cells and phagocytosis of macrophages. Two transcript variants encoding distinct isoforms have been identified for this gene.

[0168] Mutations in TUB are associated with obesity and retinal dystrophy (e.g., characterized by obesity, night blindness, reduced visual acuity, and electrophysiological features of rod-cone dystrophy) (see, e.g., Borman et al. Hum. Mutat. 35(3):289-93 (2014)).

[0169] The human TUB gene sequence is set forth in GenBank Accession No. NG_029912.1, incorporated herein by reference. An exemplary human TUB nucleic acid sequence is set forth in GenBank Accession No. NM_003320.4, incorporated herein by reference. An exemplary human TUB amino acid sequence is set forth in P50607-1, incorporated herein by reference.

[0170] Orthopedic Homeobox (OTP) Orthopedic homeobox (OTP) is a member of the homeodomain (HD) family. HD family proteins are helix-turn-helix transcription factors that play an important role in cell fate specification. OTP may function during brain development, particularly in the differentiation of hypothalamic neuroendocrine cells. OTP is also thought to be involved in mammalian energy homeostasis and behavior.

[0171] Disruption of OTP is associated with obesity, wasting, kwashiorkor, and anxiety (see, e.g., Moir et al. Mol. Metab. 6(11):1419-1428 (2017)).

[0172] The human OTP gene sequence is set forth in GenBank Accession No. NC_000005.10 and is incorporated herein by reference. An exemplary human OTP nucleic acid sequence is set forth in GenBank Accession No. NM_032109.3 and is incorporated herein by reference. An exemplary amino acid sequence of human OTP is set forth in Q5XKR4-1 and is incorporated herein by reference.

[0173] G protein-coupled receptor 101 (GPR101) G protein-coupled receptor 101 (GPR101) is an orphan G protein-coupled receptor of largely unknown function. The encoded protein is a member of a family of proteins containing seven transmembrane domains that transduce extracellular signals via heterotrimeric G proteins.

[0174] Diseases associated with GPR101 include growth hormone-secreting pituitary adenoma type 2 and chromosome Xq26.3 duplication syndrome. Neuronal GLP1R has been shown to mediate the weight and appetite-reducing effects of liraglutide, but is not required for its glucose-lowering effect. (See, for example, Sisley et al. J. Clin. Invest. 124(6):2456-63(2014)).

[0175] The human GPR101 gene sequence is represented by GenBank accession number NG_016367.1 and is incorporated herein by reference. An exemplary human GPR101 nucleic acid sequence is represented by GenBank accession number NM_054021.2 and is incorporated herein by reference. An exemplary amino acid sequence of human GPR101 is represented by Q96P66-1 and is incorporated herein by reference.

[0176] T-Box transcription factor 3 (TBX3) T-box transcription factor 3 (TBX3) is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in regulating developmental processes. TBX3 is a transcriptional repressor and is thought to play a role in the anterior / posterior axis of the forelimb in tetrapods. TBX3 acts as a negative regulator of PML function in cellular senescence. TBX3 may also play a role in limb patterning. Alternative splicing of this gene results in three transcript variants encoding distinct isoforms.

[0177] Mutations that disrupt the DNA-binding domain of TBX3 are associated with ulno-mammary syndrome (UMS), a pleiotropic disorder that affects the development of limbs, apocrine glands, teeth, hair, and genitalia (see, e.g., Bamshad et al. Am. J. Hum. Genet. 64(6):1550-62 (1999)).

[0178] The human TBX3 gene sequence is set forth in GenBank Accession No. NG_008315.1, which is incorporated herein by reference. An exemplary human TBX3 nucleic acid sequence is set forth in GenBank Accession No. NM_016569.4, which is incorporated herein by reference. An exemplary human TBX3 amino acid sequence is set forth in O15119-1, which is incorporated herein by reference.

[0179] In embodiments of any of the methods described herein, the method includes treating a subject having a mutation in a gene listed in Table 1 below. In embodiments, the methods described herein include using an MC4R agonist described herein to treat a subject having a mutation in a gene that can activate the MC4R pathway, e.g., as listed in Table 1. Table 1 lists exemplary genes, alleles, transcripts, and proteins, but may include other genes, alleles, transcripts, and proteins. [Table 1]

[0180] Additional genes that can activate the MC4R pathway Additional genes capable of activating the MC4R pathway that are useful in the methods disclosed herein are listed below.

[0181] Acyl-CoA binding domain containing 7 (ACBD7), also known as BA455B2.2, is associated with food intake, metabolism, and body weight in preclinical models (see, e.g., Lanfray et al. Elife. 15;5:e11742 (2016)).

[0182] Agouti-related neuropeptide (AGRP), also known as ASIP2, is associated with hyperphagia and obesity (see, e.g., Carroll et al. Clin. Dermatol. 22(4):345-9 (2004)).

[0183] Cell adhesion molecule 1 (CADM1), also known as TSLC1 or IGSF4, is associated with obesity (see, e.g., Rathjen et al. Nat. Neurosci. 20(8):1096-1103 (2017)).

[0184] Cell adhesion molecule 2 (CADM2), also known as IGSF4D, is associated with obesity (see, e.g., Li et al. Hum. Genet. 132(7):793-801 (2013)).

[0185] Cocaine- and amphetamine-regulated transcript protein (CARTPT), also known as CART, is associated with obesity (see, e.g., Asnicar et al. Endocrinology. 42(10):4394-400 (2001)).

[0186] Coiled-coil domain-containing 28B (CCDC28B) is associated with Bardet-Biedl syndrome (see, e.g., Novas et al. Sic. Rep. 14;8(1):3019 (2018)).

[0187] Cholecystokinin (CCK), also known as preprocholecystokinin, is associated with obesity and body mass index (see, e.g., Namjou et al. Front. Genet. 3;4:268 (2013)).

[0188] Cannabinoid receptor 1 (CNR1), also known as CNR, is associated with obesity and body fat mass and distribution (see, e.g., Russo et al. J. Endocrinol. Metab. 92(6):2382-6 (2007)).

[0189] CREB-binding protein (CREBBP), also known as RSTS, is associated with Rubinstein-Tibi syndrome (see, e.g., Stevens et al. Am. J. Med. Genet. A. 155A(7):1680-4 (2011)).

[0190] CREB3 Regulatory Factor (CREBRF), also known as C5orf41, is associated with obesity and diabetes (see, e.g., Hanson et al. Diabetologia. 62(9):1647-1652 (2019)).

[0191] Cullin 4B (CUL4B), also known as KIAA0695, MRXHF2, MRXS15, MRXSC, and SFM2, is associated with X-linked syndromic mental retardation 15 (Cabezas type) (see, e.g., Tarpey et al. Am. J. Hum. Genet. 80(2):345-52 (2007)).

[0192] DNA methyltransferase 3 alpha (DNMT3A), also known as HESJAS and TBRS, encodes a protein involved in de novo methylation (see, e.g., Xie S. et al. Gene 236(1):87-95 (1999)).

[0193] Dual specificity tyrosine phosphorylation-regulated kinase 1B (DYRK1B), also known as minibrain-associated kinase, is associated with abdominal obesity and metabolic syndrome 3 (see, e.g., Keramati et al. N. Engl. J. Med. 15;370(20):1909-1919 (2014)).

[0194] Ectonucleotide pyrophosphatase / phosphodiesterase 1 (ENPP1), also known as NPPS, M6S1, and PDNP1, is associated with obesity (see, e.g., Valli-Jaakola et al. Obesity. 16(9):2113-9 (2008)).

[0195] E1A-binding protein P300 (EP300), also known as histone acetyltransferase P300, is associated with Rubinstein-Tibi syndrome (see, e.g., Stevens et al. Am. J. Med. Genet. A. 155A(7):1680-4 (2011)).

[0196] FMRP translation regulator 1 (FMR1), also known as POF1 and POF, is associated with fragile X syndrome (see, e.g., Raspa et al. Am. J. Intelelct. Devv. Disabil. 115(6):482-95 (2010)).

[0197] FTO α-ketoglutarate-dependent dioxygenase (FTO), also known as FTO α-ketoglutarate-dependent dioxygenase, is associated with obesity-related traits, including body mass index, hip circumference, and weight (see, e.g., Scuteri et al. PloS. Genet. 3(7):e115 (2007)).

[0198] Ghrelin and obestatin prepropeptide (GHRL), also known as prepro appetite-regulating hormone, are associated with obesity (see, e.g., J. Clin. Endocrinol. Metab. 87(8):4005-8 (2002)).

[0199] The gastric inhibitory polypeptide receptor (GIPR), also known as GIP-R and PGQTL2, is associated with body mass index and energy intake and metabolic pathways in obesity (see, e.g., Turcot et al. Nat. Genet. 50(1):26-41 (2018)).

[0200] The glucagon-like peptide 1 receptor (GLP1R), also known as GLP-1, is associated with feeding and weight regulation. (See, e.g., Sisley et al. J. Clin. Invest. 124(6):2456-63 (2014)).

[0201] Inositol polyphosphate-5-phosphatase E (INPP5E), also known as JBTS1, is associated with Joubert syndrome and MORM syndrome, an autosomal recessive congenital disorder characterized by mental retardation, truncal obesity, retinal dystrophy, and micropenis (see, e.g., Jacoby et al. Nat. Genet. 41(9):1027-31 (2009)).

[0202] Insulin (INS), also known as IDDM2 and IDDM1, is associated with body mass index and obesity (see, e.g., Antunez-Ortiz et al. Biomed. Res. Int. 2017:2432957 (2017)).

[0203] Insulin-inducible gene 2 (INSIG2), also known as insulin-inducible protein 2, is associated with feedback regulation of lipid synthesis and obesity in children (see, e.g., Kaulfers et al. PloS One 10(1):e0116340 (2015)).

[0204] Insulin receptor substrate 1 (IRS1), also known as HIRS-1, is associated with susceptibility to obesity, type II diabetes, and insulin resistance (see, e.g., Clausen et al. Lancet. 346(8972):397-402 (1995)).

[0205] Insulin receptor substrate 4 (IRS4), also known as Pp160, CHNG9, PY160, and Py160, is associated with obesity, hyperglycemia, and insulin resistance (see, e.g., Sadagurski et al. Mol. Metab. 23;3(1):55-63 (2013)).

[0206] The insulin gene enhancer protein (ISL1), also known as Islet-1 and Isl-1, is a member of the LIM / homeodomain family of transcription factors, and mutations in this gene are associated with, among other things, adult-onset diabetes (see, e.g., Tanizawa Y et al. Diabetes (1994)).

[0207] Methyl-CpG-binding protein 2 (MeCP2), also known as AUTSX3, MRXS13, MRX16, RTS, and RTT, encodes a nuclear protein associated with the development of Rett syndrome, a progressive neurodevelopmental disorder. Amir, RE et al. Nat Genet 23(2):185-8(1999).

[0208] Neuropilin 1 (NRP1), also known as CD304 and BDCA4, encodes one of two neuropilins involved in signaling pathways that control cell migration. NRP1 is associated with cerebral arteriopathy, autosomal dominant, and neuroma (see, e.g., Soker, S. et al. Cell 92(6):735-745).

[0209] Neuropilin 2 (NRP2), also known as NPN2, NP2, and PRO2714, may play a role in cardiovascular development, axon guidance, and tumorigenesis (see, e.g., Chen, H. et al. Neuron 19(3):547-549 (1997)).

[0210] RPGRIP1L-like (RPGRIP1L), also known as FTM, PPP1R134, CORS3, MKS5, JBTS7, and KIAA1005, has been found to interact with nephrocystin-4. Defects in this gene are associated with Joubert syndrome type 7 and Meckel syndrome type 5 (Nagase, T et al DNA Res 6(1):63-70(1999)).

[0211] Plexin A1 (PLXNA1), also known as NOV and PLXN1, is associated with hereditary congenital facial paresis and medullary cystic kidney disease (see, e.g., Maestrini, E. et al. Proc Natl Acad Sci USA 93(2):674-678 (1996)).

[0212] Plexin A2 (PLXNA2), also known as OCT, KIAA0463, and FLJ11751, is a member of the Plexin-A family that is thought to be involved in signal transduction from semaphorin-3A and semaphorin-3B (see also, e.g., Coric, V. et al. Depress Anxiety 27(5):417-425 (2010)).

[0213] Plexin A3 (PLXNA3), also known as XAP-6, is involved in cytoskeletal reorganization and apoptosis. This gene has been shown to be important for axon pathfinding in the developing nervous system and is associated with tumor progression (see, e.g., Maestrini, L. et al. Proc Natl Acad Sci USA 93(2):674-678 (1996)).

[0214] Plexin A4 (PLXNA4), also known as FAYV2820, KIAA1550, and PRO34003, is associated with various signaling pathways, particularly those involving semaphorin-3A and semaphorin-3B (see, e.g., Imboden, MJ Allergy Clin Immunol 129(5):1218-1228 (2012)).

[0215] Potassium channel tetramerization domain-containing 15 (KCTD15), also known as BTB / POZ domain-containing protein KCTD15, is associated with body mass index and childhood obesity (see, e.g., Zhao et al. Obesity 17(12):2254-7(2009)).

[0216] Kinase D interacting substrate 220 (KIDINS220), also known as ARMS, KIAA1250, and SINO, is associated with spastic paraplegia, intellectual disability, nystagmus, and obesity (see, e.g., Josifova et al. Hum. Mol. Genet. 25(11):2158-2167 (2016)).

[0217] Melanin-concentrating hormone receptor 1 (MCHR1), also known as GPR24, is associated with the regulation of feeding and body weight (see, e.g., Marsh et al. Proc. Natl. Acad. Sci. USA 5;99(5):3240-5 (2002)).

[0218] Methionine sulfoxide reductase A (MSRA), also known as PMSR, has been associated with several obesity-related traits in children (see, e.g., Albuquerque et al. J. Hum. Genet. 59(6):307-13 (2014)).

[0219] Necdin (NDN), a MAGE family member also known as PWCR, is associated with Prader-Willi syndrome (see, e.g., Jay et al. Nat. Genet. 17(3):357-61 (1997)).

[0220] Nerve growth regulator 1 (NEGR1), also known as neurotractin, IGLON4, DMML2433, KILON, and Ntra, is associated with body mass index (see, e.g., Zhao et al. Obesity. 17(12):2254-7 (2009)).

[0221] Neuroligin 2 (NLGN2), also known as KIAA1366, is associated with anxiety, autism, intellectual disability, bulimia, and obesity (see, e.g., Am. J. Med. Genet. A. 173(1):213-216 (2017)).

[0222] Neuropeptide Y (NPY), also known as PYY4, is associated with obesity (see, e.g., van Rossum et al. Int. J. Obes. 30(10):1522-8 (2006)).

[0223] Nuclear receptor subfamily 0 group B member 2 (NR0B2), also known as SHP1, is associated with mild early-onset obesity (see, e.g., Nishigori et al. PNAS. 16;98(2):575-80 (2001)).

[0224] Neurotrophic receptor tyrosine kinase 2 (NTRK2), also known as Trk-B, is associated with severe obesity and developmental delay (e.g., NTRK2-deficient obesity) (see, e.g., Yeo et al. Nat. Neurosci. 7(11):1187-9 (2004)).

[0225] The opioid receptor Mu1 (OPRM1), also known as MOR1, MOP, LMOR, OPRM, and HMOP, is associated with the metabolic and MC4R pathways (see, e.g., Olszewski et al. Neuroreport 12(8):1727-1730 (2001)).

[0226] Pericentrin (PCNT), also known as kendrin and PCNT2, is associated with Majewski osteogenic primordial dwarfism type II (see, e.g., Rauch et al. Science. 8;319(5864):816-9(2008)).

[0227] Pleckstrin homology domain-interacting protein (PHIP), also known as WDR11, Ndrp, DCAF14, and BRWD2. (See, e.g., Webster et al. Cold Spring Harb Mol Case Stud 2(6):a001172 (2016)).

[0228] Proprotein convertase subtilisin / kexin type 2 (PCSK2), also known as NEC2, is associated with glucose homeostasis, feeding, and ultimately body mass (see, e.g., Anini et al. Int. J. Obes. 34(11):1599-607 (2010)).

[0229] PHD finger protein 6 (PHF6), also known as BFLS and BORJ, is associated with Beresson-Forssmann-Lehmann syndrome, a syndrome characterized by moderate to severe mental retardation, epilepsy, hypogonadism, hypometabolism, obesity with marked gynecomastia, swelling of the facial subcutaneous tissue, narrow palpebral fissures, and large but non-malformed ears (see, e.g., Lower et al. Nat. Genet. 32(4):661-5 (2002)).

[0230] Promelanin-concentrating hormone (PMCH), also known as MCH and PpMCH, is associated with the regulation of feeding and body weight (see, e.g., Shimada et al. Nature. 396(6712):670-4 (1998)).

[0231] Peroxisome proliferator-activated receptor gamma (PPARG), also known as NR1C3, PPARG1, PPARG2, CIMT1, and GLM1, is associated with obesity in children and adolescents (see, e.g., Ochoa et al. Int. J. Obes. Relat. Metab. Disord. 28 Suppl 3:S37-41 (2004)).

[0232] Peptide YY (PYY), also known as peptide tyrosine tyrosine, is associated with feeding regulation and obesity (see, e.g., Ahituv et al. Hum. Mol. Genet. 1;15(3):387-91 (2006)).

[0233] Syndecan 3 (SDC3), also known as SDCN, is associated with energy balance, obesity, body mass index, and LHDL cholesterol (see, e.g., Chang et al. Int. J. Endocrinol. 30;2018:9282598 (2018)).

[0234] Endoplasmic reticulum export factor of SEC16 homolog B (SEC16B), also known as LZTR2, is associated with body mass index (see, e.g., Felix et al. Hum. Mol. Genet. 15;25(2):389-403 (2016)).

[0235] Solute carrier family 6 member 14 (SLC6A14), also known as BMIQ11, is associated with body mass index and obesity (see, e.g., Suviolahti et al. J. Clin. Invest. 112(11):1762-72 (2003)).

[0236] Small nuclear ribonucleoprotein polypeptide N (SNRPN), also known as PWCR, is associated with Prader-Willi syndrome (see, e.g., Kuslich et al. Am. J. Hum. Genet. 64(1):70-6 (1999)).

[0237] Thyroid hormone receptor beta (THRB), also known as ERBA2 and PRTH, is associated with the regulation of food intake and body weight (see, e.g., Amorim et al. J. Endocrinol. 203(2):291-9 (2009)).

[0238] Transient receptor potential cation channel subfamily C member 5 (TRPC5), also known as PPP1R159, TRP-5, and HTRP5 (see, e.g., Sossey-Alaoui, K et al. Genomics 60(3):330-3340(1999)).

[0239] Transmembrane protein 18 (TMEM18), also known as lncND, is associated with body mass index and weight control (see, e.g., Willer et al. Nat. Genet. 41(1):25-34 (2009)).

[0240] Transmembrane protein 67 (TMEM67), also known as MKS3, is associated with Bardet-Biedl syndrome (see, e.g., Leitch et al. Nat. Genet. 40(4):443-8 (2008)).

[0241] Transport protein particle complex 9 (TRAPPC9), also known as NIBP, is associated with autosomal recessive mental retardation 13. (See, e.g., Marangi et al. Eur. J. Hum. Genet. 21(2):229-32 (2013)).

[0242] Thermogenin, SLC25A7, and uncoupling protein 1 (UCP1), also known as UCP, are associated with obesity (see, e.g., Ramos et al. BMC Med. Genet. 7;13:101 (2012)).

[0243] Uncoupling protein 3 (UCP3), also known as SLC25A9, is associated with metabolic fuel partitioning and obesity (see, e.g., Argyropoulos et al. J. Clin. Invest. 1;102(7):1345-51 (1998)).

[0244] Vacuolar protein sorting 13 homolog B (VPS13B), also known as CHS1 and COH1, is associated with Cohen syndrome, an autosomal recessive disorder with variable clinical manifestations characterized by mental retardation, postnatal microcephaly, facial dysmorphism, pigmentary retinopathy, myopia, and cyclic neutropenia (see, e.g., Seifert et al. J. Med. Genet. 43(5):e22 (2006)).

[0245] In one embodiment, genes that can activate the MC4R pathway include POMC, PCSK1, LEPR, LEP, SDCCAG8, SH2B1, CPE, ALMS1, BBS1, BBS2, BBS4, BBS5, BBS6, BBS7, BBS8, BBS9, BBS10, BBS12, BBS18, BBS20, GNAS, MC3R, NHLH2, SIM1, BDNF, NTRK2, MAGEL2, or a 16p11.2 deletion.

[0246] How to use Disclosed herein are methods for treating and / or preventing diseases, disorders, or conditions with an MC4R agonist, such as a compound of any one of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXXII), (XXXIII), (XXXIV), (XXXV), or (XXXVI), or a pharmaceutically acceptable salt thereof. Exemplary diseases or disorders can include obesity or obesity-related disorders (e.g., hypothalamic obesity), metabolic disorders (e.g., hyperphagia, congenital hyperinsulinism), cancer, neurological disorders, cardiovascular disorders, pulmonary disorders, integumentary disorders, sexual disorders, urinary disorders, or symptoms thereof.

[0247] In some embodiments, 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, such as Beckwith-Wiedemann syndrome, hyperinsulinemic hyperammonemia (HIHA) syndrome, Sotos syndrome, Turner syndrome, Costello syndrome, or Kabuki syndrome.

[0248] In some embodiments, the disease, disorder, or condition is obesity, e.g., hypothalamic obesity. In some embodiments, the disease, disorder, or condition is diabetes, e.g., type 1 diabetes or type 2 diabetes, or stage 1 diabetes or prediabetic syndrome. In some embodiments, the disease, disorder, or condition is a genetic or epigenetic disorder, e.g., Prader-Willi syndrome, Alström syndrome, Bardet-Biedl syndrome, or Smith-MaGinnis syndrome. In some embodiments, the disease, disorder, or condition is Prader-Willi syndrome. In some embodiments, the disease, disorder, or condition is Alström syndrome. In some embodiments, the disease, disorder, or condition is Bardet-Biedl syndrome. In some embodiments, the metabolic disorder is Smith-MaGinnis syndrome. In one embodiment, the disease, disorder, or condition is ischemia. In one embodiment, any one of obesity (e.g., hypothalamic obesity), diabetes, or a genetic or epigenetic disorder, e.g., Prader-Willi syndrome, Alström syndrome, Bardet-Biedl syndrome, or Smith-MaGinnis syndrome, is selected from the group consisting of a compound represented by Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXXII), (XXXIII), (XXXIV), (XXXV), or (XXXVI), or a pharmaceutically acceptable salt thereof.

[0249] In some embodiments, the disease, disorder, or condition is alopecia or baldness. In one embodiment, the disease, disorder, or condition is a behavioral or mental disorder. In some embodiments, the methods described herein directly or indirectly reduce or alleviate at least one symptom of a disease, disorder, or condition (e.g., a disease or disorder described herein).

[0250] In some embodiments, the methods described herein are capable of treating or alleviating at least one symptom of a disease, disorder, or condition, e.g., an increase in waist circumference of at least 2 cm compared to a baseline (e.g., waist circumference in a subject before the onset of a metabolic disorder), elevated blood pressure compared to a baseline (e.g., blood pressure in a subject before the onset of a metabolic disorder), hyperglycemia or increased fasting blood glucose compared to a baseline (e.g., fasting blood glucose in a subject before the onset of a metabolic disorder), increased thirst (e.g., increased thirst compared to a baseline, such as the level of thirst in a subject before the onset of a metabolic disorder), increased fatigue (e.g., increased fatigue compared to a baseline, such as the level of fatigue in a subject before the onset of a metabolic disorder), or increased urination (e.g., increased urination compared to a baseline, such as the frequency or volume of urination in a subject before the onset of a metabolic disorder).

[0251] In some embodiments, the methods described herein prevent or slow the onset of a disease, disorder, or condition, such as hypothalamic obesity.

[0252] In some embodiments, the subject has a co-morbidity, such as obesity, bulimia or bulimia-related syndrome, unwanted appetite, hypoglycemia, hyperglycemia, hyperlipidemia, hypercholesterolemia, or hypertriglyceridemia. In some embodiments, the metabolic disorder is hyperinsulinemia, such as chronic hyperinsulinemia (CHI). In some embodiments, the metabolic disorder is prediabetes, type I diabetes, or type II diabetes. In some embodiments, the metabolic disorder is a diabetic condition.

[0253] In some embodiments, the subject has undergone surgical intervention, e.g., bariatric surgery. In some embodiments, the subject has undergone brain surgery, e.g., hypothalamic surgery. In some embodiments, the subject has a brain tumor, e.g., a craniopharyngioma, germinoma, glioma, hamartoma, or pituitary adenoma.

[0254] In some embodiments, the methods described herein can treat metabolic disorders.In some embodiments, the methods described herein can cause counterregulatory response to hypoglycemia in subjects with diabetes, for example, type I diabetes or type II diabetes.In some embodiments, the methods described herein can be used in combination with a second drug, for example, sulfonylurea, before bolus administration to restore normal insulin levels in subjects, such as subjects with diabetes, for example, type I diabetes or type II diabetes.

[0255] In some embodiments, the disease, disorder, or condition is cancer. In some embodiments, the cancer is a gastrointestinal cancer, such as esophageal cancer, gastric cancer, pancreatic cancer, liver cancer, gallbladder cancer, colorectal cancer, anal cancer, or gastrointestinal carcinoid tumor. In some embodiments, the gastrointestinal cancer is esophageal cancer. In some embodiments, the gastrointestinal cancer is gastric cancer. In some embodiments, the gastrointestinal cancer is pancreatic cancer. In some embodiments, the gastrointestinal cancer is pancreatic cancer, and the pancreatic cancer is insulinoma. In some embodiments, the gastrointestinal cancer is liver cancer. In some embodiments, the gastrointestinal cancer is gallbladder cancer. In some embodiments, the gastrointestinal cancer is colorectal cancer. In some embodiments, the gastrointestinal cancer is anal cancer. In some embodiments, the gastrointestinal cancer is a gastrointestinal cancer.

[0256] In some embodiments, the disease, disorder, or condition is a neurological disorder, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, migraine (e.g., chronic migraine), epilepsy, and epilepsy-related syndromes.

[0257] In some embodiments, the methods described herein directly or indirectly reduce or alleviate at least one symptom of a disease, disorder, or condition (e.g., a neurological disease or neurological disorder described herein). In some embodiments, the methods directly or indirectly reduce or alleviate pain or assist in pain management, i.e., the methods described herein function directly or indirectly in the relief of pain from a disease, disorder, or condition (e.g., a neurological disorder).

[0258] In some embodiments, the methods described herein directly or indirectly alleviate the symptoms of a disease, disorder, or condition (e.g., a neurological disorder). In some embodiments, the methods described herein provide neuroprotection in a subject in need thereof (e.g., a subject with a neurological disorder, e.g., Alzheimer's disease, Parkinson's disease, or multiple sclerosis).

[0259] In some embodiments, the disease, disorder, or condition is a cardiovascular disease, such as ischemia, ischemia-reperfusion injury, hypertension, coronary artery spasm, intraocular pressure, or peripheral vascular disease. In some embodiments, the cardiovascular disorder is angina pectoris, heart failure, ventricular septal defect, atrial fibrillation, arrhythmia, coronary artery disease, or myocardial stunning. In some embodiments, the methods described herein provide cardioprotection in a subject in need thereof (e.g., a subject with a cardiovascular disorder, such as angina pectoris, heart failure, ventricular septal defect, atrial fibrillation, arrhythmia, coronary artery disease, or myocardial stunning). In some embodiments, the disease, disorder, or condition is a pulmonary disorder, such as pulmonary hypertension or asthma.

[0260] In some embodiments, the disease, disorder, or condition is an integumentary disorder, e.g., a disorder of hair, skin, and nails, among others. In some embodiments, the disease or disorder is alopecia, baldness, e.g., male pattern baldness, or a disorder of hair follicle growth. In some embodiments, the disease, disorder, or condition is a sexual disorder, e.g., male impotence. In some embodiments, the disease, disorder, or condition is a urinary disorder, e.g., detrusor hypersensitivity.

[0261] In one embodiment, the subject is a mammal, e.g., a human. In one embodiment, the subject is an adult (e.g., 18 years of age or older) or a child (e.g., under 18, 12, 10, 8, 6, 4, or 2 years of age). In one embodiment, the subject has previously been treated for a disease, disorder, or condition (e.g., obesity or a metabolic disorder). For example, the subject may be a bariatric surgery patient.

[0262] obesity The present disclosure features a method for treating a subject with obesity, such as non-genetic obesity. In one embodiment, the obesity is hypothalamic obesity. In one embodiment, the obesity is caused by a disease, disorder, or condition associated with a gene that can activate the MC4R pathway. In one embodiment, the disease, disorder, or condition is characterized by a mutation (e.g., a substitution mutation, a deletion mutation, or a polymorphism) in a gene that can activate the MC4R pathway. In embodiments, the method includes administering to the subject an MC4R agonist or composition described herein, e.g., a compound of any one of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXXII), (XXXIII), (XXXIV), (XXXV), or (XXXVI), or a pharmaceutically acceptable salt thereof (e.g., as described herein).

[0263] Hypothalamic obesity is a form of obesity caused by physical or genetic damage to the hypothalamus, resulting in symptoms such as uncontrollable hunger, rapid and / or excessive weight gain, and a low metabolic rate. Causes of this condition include the presence of tumors, intracranial swelling, head trauma, radiation therapy, brain surgery, or the presence of certain genetic mutations. For example, hypothalamic obesity can be caused by craniopharyngioma, a rare non-cancerous tumor. Removal of this tumor can damage the hypothalamus, leading to the symptoms of hypothalamic obesity. Genetic mutations in the LEP, LEPR, POMC, MC4R, and CART genes can also lead to this disease (see, for example, Kim et al. Ann Pediatr Endocrinol Metab (2013) 18(4):161-167). Hypothalamic obesity is also associated with reduced α-MSH levels (see, e.g., Roth et al. Metabol Clin Exper (2010) 59:186-194). In one embodiment, a compound of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXXII), (XXXIII), (XXXIV), (XXXV), or (XXXVI), or a pharmaceutically acceptable salt thereof, is used in a method of treating a subject having (e.g., diagnosed with) hypothalamic obesity. In one embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is used in a method of treating a subject having (e.g., diagnosed as having) hypothalamic obesity. In one embodiment, a compound of formula (II), or a pharmaceutically acceptable salt thereof, is used in a method of treating a subject having (e.g., diagnosed as having) hypothalamic obesity.In one embodiment, a compound of formula (III), or a pharmaceutically acceptable salt thereof, is used in a method of treating a subject having (e.g., diagnosed with) hypothalamic obesity. In one embodiment, a compound of formula (IV), or a pharmaceutically acceptable salt thereof, is used in a method of treating a subject having (e.g., diagnosed with) hypothalamic obesity. In one embodiment, a compound of formula (V), or a pharmaceutically acceptable salt thereof, is used in a method of treating a subject having (e.g., diagnosed with) hypothalamic obesity. In one embodiment, a compound of formula (VI), or a pharmaceutically acceptable salt thereof, is used in a method of treating a subject having (e.g., diagnosed with) hypothalamic obesity. In one embodiment, a compound of formula (VII), or a pharmaceutically acceptable salt thereof, is used in a method of treating a subject having (e.g., diagnosed with) hypothalamic obesity. In one embodiment, a compound of formula (VIII), or a pharmaceutically acceptable salt thereof, is used in a method of treating a subject having (e.g., diagnosed with) hypothalamic obesity. In one embodiment, a compound of formula (IX), or a pharmaceutically acceptable salt thereof, is used in a method of treating a subject having (e.g., diagnosed with) hypothalamic obesity. In one embodiment, a compound of formula (X), or a pharmaceutically acceptable salt thereof, is used in a method of treating a subject having (e.g., diagnosed with) hypothalamic obesity. In one embodiment, a compound of formula (XI), or a pharmaceutically acceptable salt thereof, is used in a method of treating a subject having (e.g., diagnosed with) hypothalamic obesity. In one embodiment, a compound of formula (XII), or a pharmaceutically acceptable salt thereof, is used in a method of treating a subject having (e.g., diagnosed with) hypothalamic obesity. In one embodiment, a compound of formula (XIII), or a pharmaceutically acceptable salt thereof, is used in a method of treating a subject having (e.g., diagnosed with) hypothalamic obesity. In one embodiment, a compound of formula (XIV), or a pharmaceutically acceptable salt thereof, is used in a method of treating a subject having (e.g., diagnosed with) hypothalamic obesity.In one embodiment, a compound of formula (XV), or a pharmaceutically acceptable salt thereof, is used in a method of treating a subject having (e.g., diagnosed with) hypothalamic obesity. In one embodiment, a compound of formula (XVI), or a pharmaceutically acceptable salt thereof, is used in a method of treating a subject having (e.g., diagnosed with) hypothalamic obesity. In one embodiment, a compound of formula (XVII), or a pharmaceutically acceptable salt thereof, is used in a method of treating a subject having (e.g., diagnosed with) hypothalamic obesity. In one embodiment, a compound of formula (XVIII), or a pharmaceutically acceptable salt thereof, is used in a method of treating a subject having (e.g., diagnosed with) hypothalamic obesity. In one embodiment, a compound of formula (XIX), or a pharmaceutically acceptable salt thereof, is used in a method of treating a subject having (e.g., diagnosed with) hypothalamic obesity. In one embodiment, a compound of formula (XX), or a pharmaceutically acceptable salt thereof, is used in a method of treating a subject having (e.g., diagnosed with) hypothalamic obesity. In one embodiment, a compound of formula (XXI), or a pharmaceutically acceptable salt thereof, is used in a method of treating a subject having (e.g., diagnosed with) hypothalamic obesity. In one embodiment, a compound of formula (XXII), or a pharmaceutically acceptable salt thereof, is used in a method of treating a subject having (e.g., diagnosed with) hypothalamic obesity. In one embodiment, a compound of formula (XXIII), or a pharmaceutically acceptable salt thereof, is used in a method of treating a subject having (e.g., diagnosed with) hypothalamic obesity. In one embodiment, a compound of formula (XXVI), or a pharmaceutically acceptable salt thereof, is used in a method of treating a subject having (e.g., diagnosed with) hypothalamic obesity. In one embodiment, a compound of formula (XXV), or a pharmaceutically acceptable salt thereof, is used in a method of treating a subject having (e.g., diagnosed with) hypothalamic obesity. In one embodiment, a compound of formula (XXVI), or a pharmaceutically acceptable salt thereof, is used in a method of treating a subject having (e.g., diagnosed with) hypothalamic obesity.In one embodiment, a compound of Formula (XXVII), or a pharmaceutically acceptable salt thereof, is used in a method of treating a subject having (e.g., diagnosed with) hypothalamic obesity. In one embodiment, a compound of Formula (XXVIII), or a pharmaceutically acceptable salt thereof, is used in a method of treating a subject having (e.g., diagnosed with) hypothalamic obesity. In one embodiment, a compound of Formula (XXIX), or a pharmaceutically acceptable salt thereof, is used in a method of treating a subject having (e.g., diagnosed with) hypothalamic obesity. In one embodiment, a compound of Formula (XXX), or a pharmaceutically acceptable salt thereof, is used in a method of treating a subject having (e.g., diagnosed with) hypothalamic obesity. In one embodiment, a compound of Formula (XXXI), or a pharmaceutically acceptable salt thereof, is used in a method of treating a subject having (e.g., diagnosed with) hypothalamic obesity. In one embodiment, a compound of Formula (XXXII), or a pharmaceutically acceptable salt thereof, is used in a method of treating a subject having (e.g., diagnosed with) hypothalamic obesity. In one embodiment, a compound of formula (XXXIII), or a pharmaceutically acceptable salt thereof, is used in a method of treating a subject having (e.g., diagnosed with) hypothalamic obesity. In one embodiment, a compound of formula (XXIV), or a pharmaceutically acceptable salt thereof, is used in a method of treating a subject having (e.g., diagnosed with) hypothalamic obesity. In one embodiment, a compound of formula (XXV), or a pharmaceutically acceptable salt thereof, is used in a method of treating a subject having (e.g., diagnosed with) hypothalamic obesity. In one embodiment, a compound of formula (XXVI), or a pharmaceutically acceptable salt thereof, is used in a method of treating a subject having (e.g., diagnosed with) hypothalamic obesity.

[0264] an MC4R agonist or composition described herein, e.g., a compound of any one of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXXII), (XXXIII), (XXXIV), (XXXV), or (XXXVI); or Further diseases, disorders, or conditions treatable by administering a pharmaceutically acceptable salt thereof include 5p3 microduplication syndrome, Angelman syndrome, Chudley-Lowry syndrome, Cornelia de Lange syndrome, Laron syndrome, Kleefstra syndrome / 9q34.3, Camera-Margot-Cohen syndrome, Clark and Baraitser XLMR syndrome, DiGeorge syndrome, velopharyngeal artery syndrome, conotruncal dysfacies syndrome, 22q11.2 deletion syndrome, rapid-onset obesity with hypothalamic dysfunction (ROHHAD), rapid-onset obesity with hypothalamic dysfunction, hypoventilation, autonomic nervous system dysregulation, and neural crest tumors (ROHHAD NET), Shashi XLMR syndrome, mental retardation, epileptic seizures, hypogonadism and genital dysplasia, microcephaly, and obesity (MEHMO) syndrome, mandibular prognathism with eye and skin anomalies (MOMES) syndrome, and MOMO syndrome. Additional diseases, disorders, or conditions that can be treated by administering an MC4R agonist, such as an MC4R agonist described herein, include those summarized in Kaur et al (2017) Obesity Reviews 18:603-634.

[0265] Outcome In embodiments, the methods described herein result in one or more outcomes including, for example, reduced weight (e.g., body weight), reduced hunger, no detectable decrease in metabolic rate (e.g., resting metabolic rate), increased metabolic rate (e.g., resting metabolic rate), reduced daily / weekly / monthly food intake, reduced waist circumference, no detectable increase in blood pressure, or reduced blood pressure in a subject compared to a control.

[0266] In embodiments, the control is a measurement of a parameter in a subject prior to administration of (treatment with) an MC4R agonist, e.g., a compound of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXXII), (XXXIII), (XXXIV), (XXXV), or (XXXVI), or a pharmaceutically acceptable salt thereof, for use in a method of treating a subject with (e.g., diagnosed as having) hypothalamic obesity. In embodiments, the control is a predetermined value, e.g., the value of a parameter, in an average obese human population of approximately the same age and sex as the subject, or the value of the parameter measured in the subject at a previous time (e.g., at a previous visit to a doctor, medical institution, or laboratory, etc.).

[0267] In embodiments, the outcome (e.g., a decrease, increase, undetectable decrease, or undetectable increase in a given parameter) is measured in a subject 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more weeks after initiation of treatment with an MC4R agonist. In other embodiments, the outcome (e.g., a decrease, increase, undetectable decrease, or undetectable increase in a given parameter) is measured in a subject over a defined period of time during the course of treatment (e.g., over 1-2 weeks, 2-4 weeks, 4-6 weeks, 6-8 weeks, 8-12 weeks, or 12-16 weeks).

[0268] In embodiments, the methods described herein result in a reduction in weight (e.g., body weight) in a subject compared to a control (e.g., the subject's weight before treatment, or a predetermined value, e.g., the average weight of a population of obese humans of approximately the same age and sex as the subject not receiving the therapeutic intervention, or a previous measurement, e.g., the subject's weight at a previous visit). In embodiments, the reduction is about 1 kg to 3 kg after 1 week of treatment, about 1 kg to 6 kg after 2 weeks of treatment, about 2 kg to 12 kg after 4 weeks of treatment, about 4 kg to 24 kg after 8 weeks of treatment, or about 8 kg to 48 kg after 16 weeks of treatment. In embodiments, the reduction is at a rate of loss of about 1 to 2 kg / week, e.g., about 2 kg / week, over a period of, e.g., 1 to 2 weeks or more of treatment, 2 to 4 weeks or more of treatment, 4 to 8 weeks or more of treatment, 8 to 16 weeks or more of treatment, or 16 to 32 weeks or more of treatment.

[0269] Measurement of weight, eg, body weight, can be performed using methods standard in the art.

[0270] In embodiments, the methods described herein result in a decrease in hunger in the subject compared to a control (e.g., the subject's hunger level before treatment, or a predetermined hunger level, e.g., the average hunger level of an obese human population of approximately the same age and sex as the subject, or a previous measurement, e.g., the subject's hunger level at a previous visit). In embodiments, the methods described herein result in the elimination of hunger in the subject.

[0271] In embodiments, hunger ranges from 0 to 10 and is measured by a scale such as the Likert hunger scale described herein. In embodiments, the methods described herein result in a decreased hunger score in the subject compared to a control (e.g., the subject's hunger level before treatment, or a predetermined hunger level, e.g., the average hunger level of an obese population of approximately the same age and sex as the subject, or a previous measurement, e.g., the subject's hunger level at a previous visit). In embodiments, the methods described herein result in a lower score, e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 points lower, on the Likert hunger scale compared to a control (e.g., the subject's hunger level before treatment, or a predetermined hunger level, e.g., the average hunger level of an obese population of approximately the same age and sex as the subject, or a previous measurement, e.g., the subject's hunger level at a previous visit). In embodiments, the methods described herein result in a score of 0 on the Likert hunger scale after treatment.

[0272] In embodiments, the reduction in hunger is measured / observed after 1-2 weeks or more of treatment, after 2-4 weeks or more of treatment, after 4-8 weeks or more of treatment, or after 8-16 weeks or more of treatment.

[0273] REE is an indicator of a subject's basal metabolic rate and can be measured using methods such as those described in Chen et al. J. Clin. Endocrinol. Metab. 100.4 (2015):1639-45. In embodiments, REE can be measured by placing the subject in a whole-room indirect calorimeter (also called a metabolic chamber) after a predetermined time period after treatment (e.g., 3, 4, 5, 6, or 7 days, or 1, 2, 3, 4 weeks or more). In embodiments, REE is measured over a 30-minute measurement period, and, in some cases, REE values ​​from several 30-minute periods are averaged to generate an average REE. In embodiments, REE can be measured after a 10-12-hour fasting period in a thermoneutral state (e.g., approximately 25°C), in which the subject is awake and free from psychological or physical stress. In embodiments, REE is measured in units of energy per unit time (e.g., kcal / h or kcal / day). In embodiments, REE is measured relative to lean body mass (kg) in a subject (e.g., REE / kg lean body mass), for example, as described in the Examples.

[0274] In embodiments, the methods described herein do not result in a change or decrease in metabolic rate, e.g., resting metabolic rate (REE), in a subject over an hourly, daily (e.g., 24-hour period), weekly (e.g., 7 days), or monthly (e.g., 30-day period) period compared to a control REE (e.g., the REE in the subject before treatment, or a predetermined REE, e.g., the average REE normalized to the subject's weight for a population of obese humans of similar age and sex, or the REE of the subject at a previous measurement, e.g., at a previous visit), e.g., measured 3, 4, 5, 6, 7 days, or 1, 2, 3, 4 or more weeks after treatment.

[0275] In embodiments, the methods described herein do not result in a detectable change or detectable decrease in metabolic rate, e.g., resting metabolic rate (REE) per kg of lean body mass, in a subject over an hourly, daily (e.g., 24-hour period), weekly (e.g., 7 days), or monthly (e.g., 30-day period) period compared to a control REE (e.g., the REE in the subject before treatment, or a predetermined REE, e.g., the average REE of an obese human population of similar age and sex, or the REE of the subject at a previous measurement, e.g., at a previous visit), e.g., measured 3, 4, 5, 6, 7 days, or 1, 2, 3, 4 or more weeks after treatment.

[0276] In embodiments, the methods described herein result in an increase in metabolic rate, e.g., resting metabolic rate (REE), in a subject over an hourly, daily (e.g., 24-hour period), weekly (e.g., 7 days), or monthly (e.g., 30-day period) period compared to a control REE (e.g., the REE in the subject before treatment, or a predetermined REE, e.g., the average REE normalized to the subject's weight for a population of obese humans of similar age and sex, or the REE of the subject at a previous measurement, e.g., at a previous visit), e.g., measured 3, 4, 5, 6, 7 days, or 1, 2, 3, 4 or more weeks after treatment.

[0277] In embodiments, the increase in REE in a subject is at least 20 kcal / day (e.g., at least 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150 kcal / day or more), e.g., when measured 3, 4, 5, 6, 7 days, or 1, 2, 3, 4 weeks or more after treatment.

[0278] In embodiments, the increase in REE in the subject is at least 2% (e.g., at least 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% or more) compared to the REE in the subject before treatment, e.g., when measured 3, 4, 5, 6, 7 days, or 1, 2, 3, 4 weeks or more after treatment.

[0279] In embodiments, the REE in a subject (e.g., an adult subject) after treatment with an MC4R agonist (e.g., 3, 4, 5, 6, 7 days, or 1, 2, 3, 4 weeks or more after treatment) is, for example, at least 1800 kcal / day (e.g., 1800, 1825, 1850, 1875, 1900, 1925, 1950, 1975, 2000, 2025, 2050, 2100, 2150, 2200, 2250, 2300, 2400 kcal / day or more) for an adult subject. In embodiments, the REE in a subject (e.g., a pediatric subject) after treatment with an MC4R agonist (e.g., 3, 4, 5, 6, 7 days, or 1, 2, 3, 4 weeks or more after treatment) is at least 200 kcal / day (e.g., at least 200, 225, 250, 275, 300, 325, 350, 375, 400, 450, 500 kcal / day or more), e.g., for pediatric patients.

[0280] In embodiments, the methods described herein result in a reduction in food intake by the subject compared to a control (e.g., the subject's food intake before treatment, e.g., a predetermined food intake, e.g., the food intake of an average obese human population, or a previous measurement, e.g., the subject's food intake at a previous visit), e.g., when food intake is measured as daily food intake or over a 24-hour or week period. In embodiments, the reduction is, for example, for an adult subject, at least 100 kilocalories, e.g., at least 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 1000 kilocalories or more, e.g., for daily food intake or over a 24-hour, week, or 30-day, or longer, period. In embodiments, mean food intake can be reduced from baseline by about 100 kcal / kg / day or more to about 90, 80, 70, 60, 50, 40, 30, 20, or 10 kcal / kg / day or less after treatment with an MC4R agonist, e.g., setomelanotide, in pediatric subjects, e.g., at about 1 year of age. In embodiments, mean food intake can be reduced from baseline by about 40 kcal / kg / day or more to about 35, 30, 20, or 10 kcal / kg / day or less after treatment with an MC4R agonist, e.g., setomelanotide, in pediatric subjects, e.g., during late adolescence.

[0281] Food intake can be measured by standard methods, for example, as described in Rutishauser. Pub. Health Nutr. 8.7A (2005):1100-07.

[0282] In embodiments, the methods described herein result in a decrease in the subject's waist circumference when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more weeks after initiation of treatment, compared to a control (e.g., the subject's waist circumference before treatment, or a previous measurement, e.g., waist circumference at a previous visit).

[0283] In embodiments, the reduction in waist circumference is at least 2 cm (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10 cm or more) in a subject (e.g., an adult subject) compared to a control (e.g., the subject's waist circumference before treatment, or a predetermined waist circumference, e.g., the waist circumference of an average obese human population of similar age and sex, or a previous measurement, e.g., the subject's waist circumference at a previous visit) when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 weeks or more after initiation of treatment.

[0284] In embodiments, waist circumference is measured using standard methods. In embodiments, waist circumference is the largest circumference around a central cross section of a subject, e.g., around the subject's abdomen. In other embodiments, waist circumference is measured around the natural waist (e.g., between the lowest rib and the top of the hip bone), the navel, or the narrowest point of the central cross section.

[0285] In embodiments, the methods described herein do not result in a detectable increase in the subject's blood pressure (e.g., diastolic and / or systolic blood pressure) when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more weeks after initiation of treatment, compared to a control blood pressure (e.g., the subject's blood pressure before treatment, or a predetermined blood pressure, e.g., the blood pressure of an average obese human population of similar age and sex, or a previous measurement, e.g., the subject's blood pressure at a previous visit).

[0286] In embodiments, the methods described herein result in a detectable decrease in the subject's blood pressure (e.g., diastolic and / or systolic blood pressure) when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more weeks after initiation of treatment, compared to a control blood pressure (e.g., the subject's blood pressure before treatment, or a predetermined blood pressure, e.g., the blood pressure of an average obese human population of similar age and sex, or a previous measurement, e.g., the subject's blood pressure at a previous visit).

[0287] In embodiments, the reduction in blood pressure, e.g., systolic blood pressure, is at least 3 mmHg (e.g., at least 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7 mmHg or more) compared to the subject's blood pressure before treatment, when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more weeks after initiation of treatment.

[0288] In embodiments, the reduction in blood pressure, e.g., diastolic blood pressure, is at least 4 mmHg (e.g., at least 4, 7, 7.5, 8, 8.5, 9, 9.5, 10 mmHg or more) compared to the subject's blood pressure before treatment, when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 weeks or more after initiation of treatment.

[0289] In embodiments, the methods described herein do not result in adverse effects on heart rate or blood pressure.

[0290] Patient Selection According to any of the methods described herein, in certain embodiments, the subject is administered an MC4R agonist, e.g., an MC4R agonist described herein, e.g., an MC4R agonist represented by Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), The subject is obese prior to administration of any one of compounds (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXXII), (XXXIII), (XXXIV), (XXXV), or (XXXVI), or a pharmaceutically acceptable salt thereof, when the MC4R agonist is prescribed, or at the time of initial administration of the MC4R agonist. In embodiments, the subject is a severely obese pediatric or adult patient, e.g., prior to administration of an MC4R agonist described herein, e.g., when the MC4R agonist is prescribed, or at the time of initial administration of the MC4R agonist. In embodiments, the subject is bulimic, e.g., prior to administration of an MC4R agonist described herein, e.g., when the MC4R agonist is prescribed, or at the time of initial administration of the MC4R agonist.

[0291] In embodiments, the subject (e.g., an adult subject) is administered a blood pressure of 25 kg / m prior to administration of the MC4R agonist, e.g., when the MC4R agonist is prescribed or at the time of the first administration. 2 or 30 kg / m 2 More than (e.g., ≥ 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 kg / m 2 have a body mass index (BMI) of 18.2 or higher.

[0292] In embodiments, the subject (e.g., a pediatric subject) has a body mass index (BMI) above the 85th to 95th percentile prior to administration of the MC4R agonist, e.g., when the MC4R agonist is prescribed or at the time of first administration.

[0293] In embodiments, the subject weighs at least about 5 kg, e.g., at least about 5 kg, 10 kg, 20 kg, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200, 205, 210, 215, 220 kg or more, e.g., prior to administration of the MC4R agonist, e.g., when the MC4R agonist is prescribed or at the time of the first administration. In embodiments, the subject weighs at least 20 kg, at least 60 kg, or at least 100 kg, e.g., prior to administration of the MC4R agonist, e.g., when the MC4R agonist is prescribed or at the time of the first administration.

[0294] In embodiments, the subject is undergoing an intervention in the digestive system. For example, the subject may be undergoing gallbladder surgery, intestinal surgery, stomach surgery (e.g., bariatric surgery), or other life-sustaining treatment. In one embodiment, the subject is undergoing gastric bypass surgery. In one embodiment, the subject is undergoing surgery that results in a restriction of the total amount of food that can be held or processed in, for example, the stomach, small intestine, large intestine, or colon at one time.

[0295] In one embodiment, the subject has undergone surgery, for example, tumor resection surgery.

[0296] In one embodiment, the subject has a proliferative brain disease. The proliferative brain disease may include a benign tumor, a benign lesion, or a malignant tumor, such as cancer. In one embodiment, the proliferative brain disease is present in the hypothalamus. In one embodiment, the proliferative brain disease is present in the hypothalamic paraventricular nucleus, the hypothalamic ventromedial nucleus, or the hypothalamic arcuate nucleus.

[0297] In one embodiment, the proliferative brain disease is a benign brain tumor or benign brain lesion. Representative types of benign tumors or brain lesions include meningiomas, pituitary adenomas, craniopharyngiomas, schwannomas, nasopharyngeal angiofibromas, choroid plexus tumors, dysembryoplastic neuroepithelial tumors, neurofibromas, hemangioblastomas, chondromas, giant cell tumors, osteomas, arachnoid cysts, colloid cysts, dermoid cysts, epidermoid cysts, fibrous dysplasia, Rathke's cyst, and petrous apex lesions. In one embodiment, the proliferative brain disease is a craniopharyngioma.

[0298] In one embodiment, the subject has a malignant tumor or cancer, such as a cancer of the central or peripheral nervous system. In one embodiment, the cancer is in the hypothalamus. In one embodiment, the cancer is in the hypothalamic paraventricular nucleus, the hypothalamic ventromedial nucleus, or the hypothalamic arcuate nucleus. In one embodiment, the subject has brain cancer. Representative brain cancers include glioblastoma, oligodendroglioma, and astrocytoma. In one embodiment, the cancer comprises astrocytoma.

[0299] In embodiments, the subject is an adult, e.g., 18 years of age or older, e.g., 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70 years of age or older.

[0300] In embodiments, the subject is a pediatric subject, e.g., 18 years of age or younger (e.g., 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 year of age or younger).

[0301] In embodiments, the subject has or has been identified as having a defect, eg, a genetic defect or mutation, in a gene that can turn on the MC4R pathway. In embodiments, the subject is diagnosed with a gene encoding ARL6, RAI1, SRC1, BBS19, BBS21, CEP290, IFT74, LZTFL1, MKS1, TRIM32, WDPCP, RPS6KA3, HTR2C, KSR2, PROK2, RAB23, MRAP2, AFF4, ADCY3, TUB, OTP, GPR101, TBX3, ACBD7, AGRP, CADM1, CADM2, CARTPT, CCDC28B, CCK, CNR1, CREBBP, CREBRF, CUL4B, DYRK1B, ENPP1, EP300, FMR1, FTO, GHRL, GIPR, GLP1R, INPP5E, INS, INSIG2, IRS1, IRS4, KCTD15, KIDIN The subject has or has been identified as having a mutation in a gene selected from the group consisting of S220, MCHR1, MSRA, NDN, NEGR1, NLGN2, NPY, NR0B2, NTRK2, PCNT, PCSK2, PHF6, PMCH, PPARG, PYY, SDC3, SEC16B, SLC6A14, SNRPN, THRB, TMEM18, TMEM67, TRAPPC9, UCP1, UCP3, VPS13B, NRP1, NRP2, PLXNA1, PLXNA2, PLXNA3, PLXNA4, SEMA3A, SEMA3B, SEMA3D, SEMA3E, SEMA3F, SEMA3G, DNMT3A, RPGRIP1L, ISL1, or MeCP2 genes. In an embodiment, the subject has a disease or disorder associated with a gene in Table 1. In embodiments, the subject has, or is identified as having, a loss of function mutation in one or more genes in Table 1.

[0302] In embodiments, the methods herein can include identifying or selecting subjects having a defect, e.g., a genetic defect, or mutation, in one or more genes listed in Table 1. In embodiments, the methods herein can include obtaining knowledge of a genotype, a given sequence, or a mutation. In embodiments, the methods herein are directed to the use of a gene encoding a gene encoding a gene encoding a gene encoding a gene encoding a gene for which the gene is intended, for example, ARL6, RAI1, SRC1, BBS19, BBS21, CEP290, IFT74, LZTFL1, MKS1, TRIM32, WDPCP, RPS6KA3, HTR2C, KSR2, PROK2, RAB23, MRAP2, AFF4, ADCY3, TUB, OTP, GPR101, TBX3, ACBD7, AGRP, CADM1, CADM2, CARTPT, CCDC28B, CCK, CNR1, CREBBP, CREBRF, CUL4B, DYRK1B, ENPP1, EP300, FMR1, FTO, GHRL, GIPR, GLP1R, INPP5E, INS, INSIG2, IRS1, IRS4, KCTD15, KIDINS 220, MCHR1, MSRA, NDN, NEGR1, NLGN2, NPY, NR0B2, NTRK2, PCNT, PCSK2, PHF6, PMCH, PPARG, PYY, SDC3, SEC16B, SLC6A14, SNRPN, THRB, TMEM18, TMEM67, TRAPPC9, UCP1, UCP3, or VPS13B, NRP1, NRP2, PLXNA1, PLXNA2, PLXNA3, PLXNA4, SEMA3A, SEMA3B, SEMA3D, SEMA3E, SEMA3F, SEMA3G, DNMT3A, RPGRIP1L, ISL1, or MeCP2 genes.In embodiments, the MC4R agonist may be, for example, ARL6, RAI1, SRC1, BBS19, BBS21, CEP290, IFT74, LZTFL1, MKS1, TRIM32, WDPCP, RPS6KA3, HTR2C, KSR2, PROK2, RAB23, MRAP2, AFF4, ADCY3, TUB, OTP, GPR101, TBX3, ACBD7, AGRP, CADM1, CADM2, CARTPT, CCDC28B, CCK, CNR1, CREBBP, CREBRF, CUL4B, DYRK1B, ENPP1, EP300, FMR1, FTO, GHRL, GIPR, GLP1R, INPP5E, INS, INSIG2, IRS1, IRS4, KCTD15, KIDINS220, MCHR1 , MSRA, NDN, NEGR1, NLGN2, NPY, NR0B2, NTRK2, PCNT, PCSK2, PHF6, PMCH, PPARG, PYY, SDC3, SEC16B, SLC6A14, SNRPN, THRB, TMEM18, TMEM67, TRAPPC9, UCP1, UCP3, or VPS13B, NRP1, NRP2, PLXNA1, PLXNA2, PLXNA3, PLXNA4, SEMA3A, SEMA3B, SEMA3D, SEMA3E, SEMA3F, SEMA3G, DNMT3A, RPGRIP1L, ISL1, or MeCP2 genes.

[0303] In embodiments, identifying or selecting subjects having a particular genotype or predetermined sequence, e.g., mutation, in a gene can include gaining knowledge about the particular genotype or predetermined sequence, e.g., mutation. Such knowledge can be obtained in a number of ways, as detailed in the section "Definitions."

[0304] In some embodiments, the sequence is obtained, for example, by possessing the nucleotide sequence, e.g., by "directly obtaining" or "indirectly obtaining" the sequence. "Directly obtaining a sequence" refers to performing a process to obtain the sequence (e.g., performing a synthesis or analytical method), such as performing a sequencing method (e.g., a next-generation sequencing (NGS) method). "Indirectly obtaining" a sequence refers to receiving information or knowledge of the sequence or receiving the sequence from another party or source (e.g., a third-party laboratory that directly obtained the sequence). The obtained sequence does not need to be a complete sequence. For example, sequencing at least one nucleotide or obtaining information or knowledge identifying a genotype or a predetermined sequence, e.g., a mutation, as disclosed herein, as present in a subject constitutes obtaining a sequence.

[0305] In embodiments, the sequence can be obtained directly. Directly obtaining a sequence includes performing a process that involves a physical change in a physical substance, such as a starting material, such as a tissue sample, e.g., a blood sample or tissue biopsy, or biological tissue, or analyzing an isolated nucleic acid (e.g., DNA or RNA) sample. Exemplary changes include creating a physical entity from two or more starting materials, shearing or fragmenting a substance such as genomic DNA fragments, separating or purifying a substance (e.g., isolating a nucleic acid sample from tissue), combining two or more separate entities into a mixture, or performing a chemical reaction that involves breaking or forming a covalent or non-covalent bond. Directly obtaining a value includes performing a process that involves a physical change in a sample or another substance, as described above.

[0306] In some embodiments, obtaining knowledge of a particular genotype or predetermined sequence, e.g., a mutation, can include obtaining a sample in which the genotype or predetermined sequence, e.g., a mutation, is measured. The term "obtaining a sample," as used herein, refers to obtaining a sample, e.g., a tissue sample or a nucleic acid sample, by "directly obtaining" or "indirectly obtaining" the sample. "Directly obtaining a sample" means performing a process to obtain the sample (e.g., performing a physical method such as surgery or extraction). "Indirectly obtaining a sample" refers to receiving a sample from another party or source (e.g., a third-party laboratory that directly obtained the sample). Directly obtaining a sample includes performing a process that involves a physical change in a physical material, e.g., a starting material, e.g., a tissue, e.g., a tissue in a human patient or a tissue previously isolated from a patient. Exemplary changes include creating a physical entity from a starting material, dissecting or scraping tissue, separating or purifying a substance (e.g., a sample tissue or nucleic acid sample), combining two or more separate entities into a mixture, and performing a chemical reaction that involves breaking or forming a covalent or non-covalent bond. Directly obtaining a sample includes, for example, performing a process that involves a physical change in the sample or another substance, as described above.

[0307] Also provided herein in some aspects are methods of assessing a subject's likelihood of responding to, e.g., an MC4R agonist, e.g., an MC4R agonist described herein, e.g., a compound of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXXII), (XXXIII), (XXXIV), (XXXV), or (XXXVI), or a pharmaceutically acceptable salt thereof. In some embodiments, the method includes obtaining information about the subject's genotype. In embodiments, the methods include obtaining information about the presence or absence of a defect, e.g., a genetic defect, in one or more genes listed in Table 1 in a subject.

[0308] In embodiments, a subject may be identified as having a defect, e.g., a genetic defect, e.g., a mutation, in one or more of the genes listed in Table 1 using the methods described herein.

[0309] In embodiments, identification of a subject having a defect, e.g., a genetic defect, e.g., a mutation, indicates that the subject is likely to respond (e.g., experience improvement in one or more symptoms) to an MC4R agonist, e.g., an MC4R agonist described herein, e.g., a compound of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXXII), (XXXIII), (XXXIV), (XXXV), or (XXXVI), or a pharmaceutically acceptable salt thereof. In embodiments, symptomatic improvement can include outcomes described herein. For example, symptomatic improvement can include, for example, a reduction in weight (e.g., body weight), a reduction in hunger, no detectable decrease in metabolic rate (e.g., resting metabolic rate), an increase in metabolic rate (e.g., resting metabolic rate), a reduction in daily / weekly / monthly eating, or a reduction in waist circumference, for example, compared to a control.

[0310] In embodiments, identification of a subject having a defect, e.g., a genetic defect, e.g., a mutation, can be achieved by comparing the subject to an MC4R agonist, e.g., an MC4R agonist described herein, e.g., an MC4R agonist of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), or a combination thereof, with a mutation in one or more of the genes listed in Table 1 (e.g., obese subjects of similar age and / or pre-treatment weight, etc.), e.g., wild-type obese subjects. (XXV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXXII), (XXXIII), (XXXIV), (XXXV), or (XXXVI), or a pharmaceutically acceptable salt thereof. In embodiments, a subject that is likely to respond is more likely to have one or more improved symptoms, e.g., a symptom described herein, compared to, for example, a control, e.g., a subject lacking a genetic defect in one or more genes listed in Table 1 (e.g., an obese subject of similar age and / or pre-treatment weight, etc.), e.g., a wild-type obese subject. In embodiments, subjects who are likely to have a greater response are more likely to have a greater improvement in a symptom, e.g., a symptom described herein, e.g., a greater weight loss, a greater decrease in waist circumference, a greater increase in resting metabolic rate, a greater decrease in food intake, a greater decrease in hunger, compared to a control, e.g., a subject lacking a genetic defect in one or more of the genes listed in Table 1 (e.g., an obese subject of similar age and / or pre-treatment weight), e.g., a wild-type obese subject.

[0311] In embodiments, the methods described herein further comprise providing a report identifying the presence or absence of the genetic defect, and optionally a discriminator, for the subject. In embodiments, the report provides recommendations for potential treatment options, the likelihood of effectiveness of the treatment options, and / or recommendations / instructions for administration of a treatment option (e.g., an MC4R agonist, e.g., an MC4R agonist described herein, e.g., a compound of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXXII), (XXXIII), (XXXIV), (XXXV), or (XXXVI), or a pharmaceutically acceptable salt thereof).

[0312] MC4R agonists This specification describes a method for treating a disease, disorder, or condition in a subject, comprising administering a melanocortin 4 receptor (MC4R) agonist to the subject. Examples of naturally occurring MC4R agonists include α-MSH, β-MSH, γ-MSH, and adrenocorticotropic hormone (ACTH), or functional fragments thereof. Examples of synthetic MC4R agonists are described in detail below.

[0313] In some embodiments, the MC4R agonist can be any known agonist of MC4R. In some exemplary embodiments, the MC4R agonist is not adrenocorticotropic hormone or a fragment thereof. Exemplary MC4R agonists include WO2011104378; WO2011104379; WO201060901; WO200887189, WO200887188, WO200887187, WO200887186; US20110065652; WO2010144341; WO2010144344; WO201065799; WO201065800; WO201065801; WO201065802; WO201037081; WO2009152079; WO200915 1383; US20100311648; US20100280079; WO201081666; WO201034500; WO200910299; WO2008116665; WO201052256; WO201052255; WO201126015; US20100120783; WO201096854; US20100190793; WO201025142; WO2014144260; WO2017059075; and WO201015972. Further examples of MC4R agonists can be found in U.S. Patent Nos. 8,263,608; 8,247,530; 8,114,844; and 7,968,548, the entire teachings of which are incorporated herein by reference.

[0314] In some embodiments, the MC4R agonist is a compound of any one of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXXII), (XXXIII), (XXXIV), (XXXV), or (XXXVI), as described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the MC4R agonist is not a compound of any one of formulas (I) or (II), as described herein, or a pharmaceutically acceptable salt thereof. In one embodiment, the MC4R agonist is not a compound of formula (I). In one embodiment, the MC4R agonist is not a compound of formula (II).

[0315] In one exemplary embodiment, the agonist of MC4R is not the tripeptide D-Phe-Arg-Trp (SEQ ID NO: 560) or a pharmaceutical salt thereof. In another example, the agonist is any peptide that does not include SEQ ID NO: 560, or a pharmaceutical salt thereof. In yet another example, the MC4R agonist is not the acetylated tripeptide Ac-D-Phe-Arg-Trp-NH (SEQ ID NO: 561) or a pharmaceutical salt thereof.

[0316] This specification describes a method for treating a disease, disorder, or condition in a subject, comprising administering a melanocholine 4 receptor (MC4R) agonist to the subject. Examples of naturally occurring MC4R agonists include α-MSH, β-MSH, γ-MSH, and adrenocorticotropic hormone (ACTH), or functional fragments thereof. Examples of synthetic MC4R agonists are described in detail below.

[0317] In some embodiments, the MC4R agonist can be any known agonist of MC4R. In some exemplary embodiments, the MC4R agonist is not adrenocorticotropic hormone or a fragment thereof. Exemplary MC4R agonists include WO2011104378; WO2011104379; WO201060901; WO200887189, WO200887188, WO200887187, WO200887186; US20110065652; WO2010144341; WO2010144344; WO201065799; WO201065800; WO201065801; WO201065802; WO201037081; WO2009152079; WO200915 1383; US20100311648; US20100280079; WO201081666; WO201034500; WO200910299; WO2008116665; WO201052256; WO201052255; WO201126015; US20100120783; WO201096854; US20100190793; WO201025142; WO2014144260; WO2017059075; and WO201015972. Further examples of MC4R agonists can be found in U.S. Patent Nos. 8,263,608; 8,247,530; 8,114,844; and 7,968,548, the entire teachings of which are incorporated herein by reference.

[0318] In some embodiments, the MC4R agonist is a compound of any one of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXXII), (XXXIII), (XXXIV), (XXXV), or (XXXVI), as described herein, or a pharmaceutically acceptable salt thereof.

[0319] In some embodiments, the MC4R agonist is a compound of formula (I): (R 2 R 3 )-A 1 -c(A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 )-A 10 -R 1 (I) or a pharmaceutically acceptable salt thereof, wherein A 1 Acc, HN-(CH2) m -C(O), L-amino acids or D-amino acids, or deleted; A 2 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Asp, or Glu; A 3 is Gly, Ala, β-Ala, Gaba, Aib, a D-amino acid, or is deleted; A 4 is His, 2-Pal, 3-Pal, 4-Pal, Taz, 2-Thi, 3-Thi, or (X 1 , X 2 , X 3 , X 4 , X 5 ) Phe; A 5are D-Phe, D-1-Nal, D-2-Nal, D-Trp, D-Bal, D-(X 1 , X 2 , X 3 , X 4 , X 5 )Phe, L-Phe or D-(Et)Tyr; A 6 is Arg, hArg, Dab, Dap, Lys, Orn, or HN-CH((CH2) n -N(R 4 R 5 ))-C(O);A 7 is Trp, 1-Nal, 2-Nal, Bal, Bip, D-Trp, D-2-Nal, D-Bal, or D-Bip; A 8 is Gly, D-Ala, Acc, Ala, 13-Ala, Gaba, Apn, Ahx, Aha, HN-(CH2) s -C(O) or deleted; A 9 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Dab, Dap, Orn, or Lys; A 10 Acc, HN-(CH2) t -C(O), L-amino acids or D-amino acids, or deleted; R 1 is OH or NH2; R 2 and R 3 Each of H, (C1 to C 30 ) alkyl, (C1-C 30 ) heteroalkyl, (C1-C 30 ) Acyl, (C2-C 30 ) alkenyl, (C2-C 30 ) alkynyl, aryl (C1-C 30 ) Alkyl, aryl (C1-C 30 ) Acyl, Substituted (C1-C 30 ) Alkyl, substituted (C1-C 30 ) Heteroalkyl, substituted (C1-C 30 ) Acyl, Substituted (C2-C 30 ) Alkenyl, substituted (C2-C 30 ) alkynyl, substituted aryl (C1-C 30 ) alkyl and substituted aryl (C1-C30 ) acyl; R 4 and R 5 Each of H, (C1 to C 40 ) alkyl, (C1-C 40 ) heteroalkyl, (C1-C 40 ) Acyl, (C2-C 40 ) alkenyl, (C2-C 40 ) alkynyl, aryl (C1-C 40 ) Alkyl, aryl (C1-C 40 ) Acyl, Substituted (C1-C 40 ) Alkyl, substituted (C1-C 40 ) Heteroalkyl, substituted (C1-C 40 ) Acyl, Substituted (C2-C 40 ) Alkenyl, substituted (C2-C 40 ) alkynyl, substituted aryl (C1-C 40 ) Alkyl, substituted aryl (C1-C 40 ) Acyl, (C1-C 40 m is, for each occurrence, independently 1, 2, 3, 4, 5, 6, or 7; n is, for each occurrence, independently 1, 2, 3, 4, 5, 6, or 7; s is, for each occurrence, independently 1, 2, 3, 4, 5, 6, or 7; t is, for each occurrence, independently 1, 2, 3, 4, 5, 6, or 7; X', X 2 , X 3 , X 4 , and X 5 are, independently for each occurrence, H, F, Cl, Br, I, -(C1-C 10 ) Alkyl, substituted (C1-C 10 ) Alkyl, (C2-C 10 ) Alkenyl, substituted (C2-C 10 ) alkenyl, (C2-C 10 ) alkynyl, substituted (C2-C 10 ) alkynyl, aryl, substituted aryl, OH, NH2, NO2, or CN.

[0320] In some embodiments, with respect to Formula (I), R 4 (C1-C40 ) Acyl, aryl (C1-C 40 ) acyl, substituted (C1-C 40 ) acyl, substituted aryl (C1-C 40 ) acyl, (C1-C 40 ) alkylsulfonyl, or -C(NH)-NH, when R 5 is H, or (C1-C 40 ) alkyl, (C1-C 40 ) heteroalkyl, (C2-C 40 ) alkenyl, (C2-C 40 ) alkynyl, aryl (C1-C 40 ) alkyl, substituted (C1-C 40 ) alkyl, substituted (C1-C 40 ) heteroalkyl, substituted (C2-C 40 ) alkenyl, substituted (C2-C 40 ) alkynyl, or substituted aryl (C1-C 40 ) alkyl.

[0321] In some embodiments, with respect to Formula (I), R 2 (C1-C 30 ) Acyl, aryl (C1-C 30 ) acyl, substituted (C1-C 30 ) acyl, or substituted aryl (C1-C 30 ) acyl, R 3 is H, (C1-C 30 ) alkyl, (C1-C 30 ) heteroalkyl, (C2-C 30 ) alkenyl, (C2-C 30 ) alkynyl, aryl (C1-C 30 ) alkyl, substituted (C1-C 30 ) alkyl, substituted (C1-C 30 ) heteroalkyl, substituted (C2-C 30 ) alkenyl, substituted (C2-C 30 ) alkynyl, or substituted aryl (C1-C 30 ) alkyl.

[0322] In some embodiments, with respect to formula (I), A 3 or A8 Either or both of these must be present in the compound.

[0323] In some embodiments, with respect to formula (I), A 2 If is Cys, D-Cys, hCys, D-hCys, Pen, or D-Pen, then A 9 is Cys, D-Cys, hCys, D-hCys, Pen, or D-Pen.

[0324] In some embodiments, with respect to formula (I), A 2 If is Asp or Glu, A 9 is Dab, Dap, Orn, or Lys.

[0325] In some embodiments, with respect to formula (I), A 8 is Ala or Gly, A 1 is not NIe.

[0326] In some embodiments, with respect to formula (I), A 1 If is missing, R 2 and R 3 cannot both be H.

[0327] In some embodiments, with respect to formula (I), A 1 is A6c, Arg, D-Arg, Cha, D-Cha, hCha, Chg, D-Chg, Gaba, Ile, Leu, hLeu, Met, β-hMet, 2-Nal, D-2-Nal, Nip, Nle, Oic, Phe, D-Phe, hPhe, hPro, Val, or is deleted; A 2 is Asp, Cys, D-Cys, hCys, D-hCys, Glu, Pen, or D-Pen; A 3 is D-Abu, Aib, Ala, β-Ala, D-Ala, D-Cha, Gaba, D-Glu, Gly, D-Ile, D-Leu, D-Tle, D-Val, or is deleted; A 4 is His or 3-Pal; A 5is D-Bal, D-1-Nal, D-2-Nal, D-Phe, D-Trp, or D-(Et)Tyr; A 6 is Arg or hArg; A 7 are Bal, Bip, 1-Nal, 2-Nal, Trp, and D-Trp; A 8 is A6c, D-Ala, Aha, Ahx, Ala, β-Ala, Apn, Gaba, Gly, or is deleted; A 9 is Cys, D-Cys, hCys, D-hCys, Lys, Pen, or D-Pen; A 10 is Thr or deleted, and A 3 or A 8 At least one of the genes is deleted, but not both.

[0328] In some embodiments, the compound of formula (I) is a compound disclosed in International Patent Application Publication No. WO2007 / 008704, which is incorporated by reference herein in its entirety.

[0329] In some embodiments, the compound of formula (I) is selected from: (SEQ ID NO: 1)Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-β-Ala-Lys)-NH2; (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; (SEQ ID NO: 4)D-Phe-c(Cys-His-D-Phe-Arg-Trp-Ala-D-Cys)-Thr-NH2; (SEQ ID NO: 5)D-Phe-c(Cys-His-D-Phe-Arg-Trp-β-Ala-D-Cys)-Thr-NH2; (SEQ ID NO: 6)D-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-D-Cys)-Thr-NH2; (Layout No. 7) Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH2; (Layout No. 8) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Apn-Lys)-NH2; (Allocation number 9)Ac-A6c-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; (Allocation number 10)Ac-D-2-Nal-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; (Allocation number 11)Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; (Allocation number 12)Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; (Allocation number 13)Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (Layout No. 14) Ac-Nle-c(Cys-β-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (Allocation number 15)Ac-Nle-c(Cys-Gaba-His-D-Phe-Arg-Trp-Cys)-NH2; (Layout No. 16) Ac-Nle-c(Cys-Aib-His-D-Phe-Arg-Trp-Cys)-NH2; (Layout No. 17) Ac-Nle-c(Cys-Gly-His-D-Phe-Arg-Trp-Cys)-NH2; (Allocation number 18)Ac-Nle-c(D-Cys-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (Allocation number 19)Ac-Nle-c(D-Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (Allocation number 20)Ac-Nle-c(D-Cys-β-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (Allocation number 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-β-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-β-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: 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; (SEQ ID NO: 48)Ac-β-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; (Layout No. 50) Ac-Cha-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2; (Layout No. 51) Ac-hCha-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2; (Layout No. 52) Ac-Leu-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2; (Layout No. 53) Ac-hLeu-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2; (Layout No. 54) Ac-Phe-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2; (Allocation number 55)Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-D-Ala-Lys)-NH2; (Layout No. 56) Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-β-Ala-Lys)-NH2; (Allocation number 57)Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Gaba-Lys)-NH2; (Layout No. 58) Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Aha-Lys)-NH2; (Allocation number 59)Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Apn-Lys)-NH2; (Layout No. 60) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Apn-Cys)-NH2; (Allocation number 61)Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Gaba-Cys)-NH2; (Allocation number 62)Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Ahx-Cys)-NH2; (Allocation number 63)Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-β-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-1-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; (SEQ ID NO: 71)Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-1-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; (Allocation number 78)Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; (Allocation number 79)D-Phe-c(Cys-His-D-Phe-hArg-Trp-β-Ala-D-Cys)-Thr-NH2; (Layout No. 80)D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-Thr-NH2; (Layout No. 81)D-Phe-c(Cys-His-D-Phe-Arg-Bip-β-Ala-D-Cys)-Thr-NH2; (Layout No. 82)D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-NH2; (Layout No. 83)D-Phe-c(Cys-His-D-Phe-hArg-Bip-β-Ala-D-Cys)-Thr-NH2; (Layout No. 84)D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-β-Ala-D-Cys)-Thr-NH2; (Layout No. 85) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH2; (Allocation number 86)Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Trp-Lys)-NH2; (Allocation number 87)Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal-Lys)-NH2; (Allocation number 88)Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-OH; (Layout No. 89) Ac-Nle-c(Cys-D-Abu-His-D-Phe-Arg-Trp-Cys)-NH2; (Layout No. 90) Ac-Nle-c(Cys-D-Val-His-D-Phe-Arg-Trp-Cys)-NH2; (Allocation number 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: 104) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; (SEQ ID NO: 105) Phe-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: 107)Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH; (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-β-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-β-Ala-Lys)-OH; (SEQ ID NO: 116)Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Ahx-Cys)-OH; (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-β-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; (Layout No. 121) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Apn-Lys)-OH; (Allocation number 122)Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; (Layout number 123)Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; (Allocation number 124)Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; (Allocation number 125)Ac-D-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; (Layout No. 126) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; (Allocation number 127)Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; (Layout No. 128) Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; (Allocation number 129)Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Gaba-Cys)-OH; (Allocation number 130)Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Ahx-Cys)-OH; (Allocation number 131)Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-β-Ala-Cys)-OH; (Allocation number 132)Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-D-Ala-Cys)-OH; (Allocation number 133)Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-OH; (Allocation number 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-1-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; (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; (SEQ ID NO: 143) Ac-D-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2; (SEQ ID NO: 144) Ac-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2; (SEQ ID NO: 145) Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 146) Ac-D-Arg-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-NH; and (SEQ ID NO: 147)Ac-Arg-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-NH2, or a pharmaceutically acceptable salt thereof. In various 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 setomelanotide, 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: [ka]

[0330] In some embodiments, the MC4R agonist is a compound of formula (Ia): HA 1 -c(A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 )-A 10 -NH2(Ia) or a pharmaceutically acceptable salt thereof, wherein: A 1 is Phe, D-Phe, or Nle; A 2 is Cys; A 3 is deleted; A 4 is His; A 5 is D-Phe or D-(Et)Tyr; A 6 is Arg or hArg; A 7 is Trp or Bip; A 8 is Ala, β-Ala, Gaba, or Apn; A 9 is D-Cys; A 10 is Thr or is deleted.

[0331] In some embodiments, the compound of Formula (Ia) is selected from: (SEQ ID NO: 4)D-Phe-c(Cys-His-D-Phe-Arg-Trp-Ala-D-Cys)-Thr-NH2; (SEQ ID NO: 5)D-Phe-c(Cys-His-D-Phe-Arg-Trp-β-Ala-D-Cys)-Thr-NH2; (SEQ ID NO: 6)D-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-D-Cys)-Thr-NH2; (SEQ ID NO: 79)D-Phe-c(Cys-His-D-Phe-hArg-Trp-β-Ala-D-Cys)-Thr-NH2; (SEQ ID NO: 80)D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-Thr-NH2; (SEQ ID NO: 81)D-Phe-c(Cys-His-D-Phe-Arg-Bip-β-Ala-D-Cys)-Thr-NH2; (SEQ ID NO: 82)D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-NH2; (SEQ ID NO: 83)D-Phe-c(Cys-His-D-Phe-hArg-Bip-β-Ala-D-Cys)-Thr-NH2; (SEQ ID NO: 84)D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-β-Ala-D-Cys)-Thr-NH2; (SEQ ID NO: 85) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH; and (SEQ ID NO: 105) Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2.

[0332] In some embodiments, the MC4R agonist is a compound of formula (Ib): Ac-A 1 -c(A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 )-A 10 -NH2(Ib) or a pharmaceutically acceptable salt thereof, wherein: A 1 is Nle, A6c, D-2-Nal, Cha, Oic, Chg, hCha, D-Cha, D-hCha, Nip, hPro, hLeu, Phe, D-Phe, D-Chg, hPhe, β-hMet, Gaba, Leu, Ile, Val, 2-Nal, Arg or D-Arg; A 2 is Asp, Cys, D-Cys, or Pen; A 3 is D-Ala, β-Ala, Gaba, Aib, Gly, Ala, D-Glu, D-Abu, D-Val, D-Ile, D-Leu, D-Tle, D-Cha, or is deleted; A 4 is His or 3-Pal; A 5 is Phe, D-Phe, or D-2-Nal; A 6 is Arg; A 7 is Trp, 1-Nal, 2-Nal, Bal, or D-Trp; A 8 is β-Ala, A6c, Ahx, Apn, Gaba, Ala, Aha, D-Ala, or is deleted; A 9 is Lys, Cys, D-Cys, or Pen; A10 is missing, A 2 and A 9 are chosen in pairs to form disulfide or lactam bridges.

[0333] In some embodiments, the compound of Formula (Ib) is selected from: (SEQ ID NO: 1)Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-β-Ala-Lys)-NH2; (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; (SEQ ID NO: 7)Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH2; (SEQ ID NO: 8)Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Apn-Lys)-NH2; (SEQ ID NO: 9) Ac-A6c-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; (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; (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-β-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 15) Ac-Nle-c(Cys-Gaba-His-D-Phe-Arg-Trp-Cys)-NH2; (Layout No. 16) Ac-Nle-c(Cys-Aib-His-D-Phe-Arg-Trp-Cys)-NH2; (Layout No. 17) Ac-Nle-c(Cys-Gly-His-D-Phe-Arg-Trp-Cys)-NH2; (Allocation number 18)Ac-Nle-c(D-Cys-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (Allocation number 19)Ac-Nle-c(D-Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (Allocation number 20)Ac-Nle-c(D-Cys-β-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (Allocation number 21)Ac-Nle-c(D-Cys-Gaba-His-D-Phe-Arg-Trp-Cys)-NH2; (Layout No. 22) Ac-Nle-c(D-Cys-Aib-His-D-Phe-Arg-Trp-Cys)-NH2; (Allocation number 23)Ac-Nle-c(D-Cys-Gly-His-D-Phe-Arg-Trp-Cys)-NH2; (Allocation number 24)Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2; (Allocation number 25)Ac-Nle-c(Cys-β-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2; (Allocation number 26)Ac-Nle-c(Cys-Gaba-His-D-Phe-Arg-Trp-D-Cys)-NH2; (Layout No. 27) Ac-Nle-c(Cys-Aib-His-D-Phe-Arg-Trp-D-Cys)-NH2; (Allocation number 28)Ac-Nle-c(Cys-Gly-His-D-Phe-Arg-Trp-D-Cys)-NH2; (Allocation number 29)Ac-Nle-c(D-Cys-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2; (Allocation number 30)Ac-Nle-c(D-Cys-D-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2; (Allocation number 31)Ac-Nle-c(D-Cys-β-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2; (Allocation number 32)Ac-Nle-c(D-Cys-Gaba-His-D-Phe-Arg-Trp-D-Cys)-NH2; (Allocation number 33)Ac-Nle-c(D-Cys-Aib-His-D-Phe-Arg-Trp-D-Cys)-NH2; (Layout No. 34) Ac-Oic-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; (Allocation number 35)Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; (Allocation number 36)Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; (Allocation number 37)Ac-D-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; (Allocation number 38)Ac-D-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; (Allocation number 39)Ac-Nip-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; (Layout No. 40) Ac-hPro-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; (Layout No. 41)Ac-hLeu-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; (Layout No. 42) Ac-Phe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; (Allocation number 43)Ac-D-Phe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; (Allocation number 44)Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; (Allocation number 47)Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; (Allocation number 48)Ac-β-hMet-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; (Allocation number 49)Ac-Gaba-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; (Layout No. 50) Ac-Cha-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2; (Layout No. 51) Ac-hCha-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2; (Layout No. 52) Ac-Leu-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2; (Layout No. 53) Ac-hLeu-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2; (Layout No. 54) Ac-Phe-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2; (Allocation number 55)Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-D-Ala-Lys)-NH2; (Layout No. 56) Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-β-Ala-Lys)-NH2; (Allocation number 57)Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Gaba-Lys)-NH2; (Layout No. 58) Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Aha-Lys)-NH2; (Allocation number 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-β-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-1-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-1-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-β-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: 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; (SEQ ID NO: 143) Ac-D-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2; (SEQ ID NO: 144) Ac-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2; (SEQ ID NO: 145) Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 146) Ac-D-Arg-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-NH; and (SEQ ID NO: 147)Ac-Arg-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-NH2.

[0334] In some embodiments, the MC4R agonist is a compound of formula (Ic): Ac-Nle-c(A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 )-A 10 -NH2(Ic) or a pharmaceutically acceptable salt thereof, wherein: A 2 is Asp, Cys, D-Cys, or Pen; A 3 is D-Ala, β-Ala, Gaba, Aib, Gly, Ala, Aib, Dl-Glu, D-Abu, D-Val, D-Ile, D-Leu, D-Tle, D-Cha, or is deleted; A4 is His or 3-Pal; A 5 is D-Phe, D-2-Nal, or Phe; A 6 is Arg; A 7 are Trp, D-Trp, 2-Nal, 1-Nal, and Bal; A 8 is β-Ala, A6c, Ahx, Apn, Gaba, D-Ala, Aha, Ala, or is deleted; A 9 is Lys, Cys, D-Cys or Pen; A 10 is missing, A 2 and A 9 are chosen in pairs to form disulfide or lactam bridges.

[0335] In some embodiments, the compound of Formula (Ic) is selected from: (SEQ ID NO: 1)Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-β-Ala-Lys)-NH2; (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; (SEQ ID NO: 7)Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH2; (SEQ ID NO: 8)Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Apn-Lys)-NH2; (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; (Layout No. 14) Ac-Nle-c(Cys-β-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (Allocation number 15)Ac-Nle-c(Cys-Gaba-His-D-Phe-Arg-Trp-Cys)-NH2; (Layout No. 16) Ac-Nle-c(Cys-Aib-His-D-Phe-Arg-Trp-Cys)-NH2; (Layout No. 17) Ac-Nle-c(Cys-Gly-His-D-Phe-Arg-Trp-Cys)-NH2; (Allocation number 18)Ac-Nle-c(D-Cys-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (Allocation number 19)Ac-Nle-c(D-Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (Allocation number 20)Ac-Nle-c(D-Cys-β-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (Allocation number 21)Ac-Nle-c(D-Cys-Gaba-His-D-Phe-Arg-Trp-Cys)-NH2; (Layout No. 22) Ac-Nle-c(D-Cys-Aib-His-D-Phe-Arg-Trp-Cys)-NH2; (Allocation number 23)Ac-Nle-c(D-Cys-Gly-His-D-Phe-Arg-Trp-Cys)-NH2; (Allocation number 24)Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2; (Allocation number 25)Ac-Nle-c(Cys-β-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2; (Allocation number 26)Ac-Nle-c(Cys-Gaba-His-D-Phe-Arg-Trp-D-Cys)-NH2; (Layout No. 27) Ac-Nle-c(Cys-Aib-His-D-Phe-Arg-Trp-D-Cys)-NH2; (Allocation number 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-β-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-β-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-β-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-1-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-1-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-β-Ala-Lys)-NH2; (SEQ ID NO: 111) Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Gaba-Cys)-NH; and (SEQ ID NO: 112) Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Ahx-Cys)-NH2.

[0336] In some embodiments, the MC4R agonist is a compound of formula (Id): HD-Phe-c(A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 )-A 10 -NH2(Id) or a pharmaceutically acceptable salt thereof, wherein: A 2 is Cys; A 3 is deleted; A 4 is His; A 5 is D-Phe or D-(Et)Tyr; A 6 is Arg or hArg; A 7 is Trp or Bip; A 8 is Ala, β-Ala, or Gaba; A 9 is D-Cys; A 10 is Thr.

[0337] In some embodiments, the compound of formula (Id) is selected from: (SEQ ID NO: 4)D-Phe-c(Cys-His-D-Phe-Arg-Trp-Ala-D-Cys)-Thr-NH2; (SEQ ID NO: 5)D-Phe-c(Cys-His-D-Phe-Arg-Trp-β-Ala-D-Cys)-Thr-NH2; (SEQ ID NO: 6)D-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-D-Cys)-Thr-NH2; (SEQ ID NO: 79)D-Phe-c(Cys-His-D-Phe-hArg-Trp-β-Ala-D-Cys)-Thr-NH2; (SEQ ID NO: 80)D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-Thr-NH2; (SEQ ID NO: 81)D-Phe-c(Cys-His-D-Phe-Arg-Bip-β-Ala-D-Cys)-Thr-NH2; (SEQ ID NO: 82)D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-NH2; (SEQ ID NO: 83)D-Phe-c(Cys-His-D-Phe-hArg-Bip-β-Ala-D-Cys)-Thr-NH2; and (SEQ ID NO: 84)D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-β-Ala-D-Cys)-Thr-NH2.

[0338] In some embodiments, the MC4R agonist is a compound of formula (II): [ka] or a pharmaceutically acceptable salt thereof [wherein X 1 teeth [ka] and X 2 teeth [ka] and;A 1 is Asp, Cys, D-Cys, Dab, Dap, Glu, Lys, Orn, Pen, or D-Pen; A 2 is an L-amino acid or a D-amino acid; A 3 His, 2-Pal, 3-Pal, 4-Pal, (X 1 , X 2 , X 3 , X 4 , X 5) Phe, Taz, 2-Thi or 3-Thi; A 4 is D-Bal, D-1-Nal, D-2-Nal, D-Phe or D-(X 1 , X 2 , X 3 , X 4 , X 5 ) Phe; A 5 is Arg, hArg, Dab, Dap, Lys, or Orn; A 6 are Bal, 1-Nal, 2-Nal, (X 1 , X 2 , X 3 , X 4 , X 5 ) Phe or Trp; A 7 is Asp, Cys, D-Cys, Dab, Dap, Glu, Lys, Orn, Pen, or D-Pen; R 1 is H, (C1~C 10 ) alkyl or substituted (C1-C 10 ) alkyl; R 2 and R 3 are each independently H, (C1 to C 10 ) alkyl, (C1-C 10 )heteroalkyl, aryl(C1-C5) alkyl, substituted (C1-C 10 ) Alkyl, substituted (C1-C 10 ) heteroalkyl or substituted aryl(C1-C5) alkyl, or R 2 and R 3 may be fused together to form a cyclic moiety; R 4 is OH, NH2, CO2H or C(O)NH2; R 5 and R 6 are each independently H, (C1 to C 10 ) alkyl, (C1-C 10 )heteroalkyl, aryl(C1-C5) alkyl, substituted (C1-C 10 ) Alkyl, substituted (C1-C 10 ) heteroalkyl or substituted aryl(C1-C5) alkyl, or R 5 and R 6 may be fused together to form a cyclic moiety; R 7and R 8 are each independently H, (C1 to C 10 ) alkyl, (C1-C 10 )heteroalkyl, aryl(C1-C5) alkyl, substituted (C1-C 10 ) Alkyl, substituted (C1-C 10 ) heteroalkyl or substituted aryl(C1-C5) alkyl; or R 7 and R 8 may be fused together to form a cyclic moiety; R 9 is H, (C1~C 10 ) alkyl or substituted (C1-C 10 ) alkyl; and n is, independently for each occurrence, 0, 1, 2, 3, 4, 5, 6, or 7], or a pharmaceutically acceptable salt thereof.

[0339] In some embodiments of Formula (II), A 1 is Cys; A 2 is D-Ala, Asn, Asp, Gln, Glu, or D-Phe; A 3 is His;A 4 is D-2-Nal or D-Phe; A 5 is Arg;A 6 is Trp; and A 7 is Cys or Pen; R', R 2 , R 3 , and R 9 each independently is H; R 4 is C(O)NH2; R 5 and R 6 Each of these is independently H, (C1 to C 10 ) Heteroalkyl, substituted (C1-C 10 ) alkyl or substituted (C1-C 10 ) heteroalkyl, or R 5 and R 6 may be fused together to form a cyclic moiety; R 7 and R 8 Each of these is independently H, (C1 to C 10 ) alkyl, (C1-C 10 ) Heteroalkyl, substituted (C1-C10 ) alkyl, or substituted (C1-C 10 ) heteroalkyl; or a pharmaceutically acceptable salt thereof.

[0340] In some embodiments, the compound of formula (II) is selected from: (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; (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)-NH; and (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.

[0341] In some embodiments, the compound of formula (II) is described in WO2008 / 147556 or International Patent Application No. PCT / US08 / 06675, each of which is incorporated by reference herein in its entirety.

[0342] 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), also known as RM-511, or a pharmaceutically acceptable salt thereof. 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: [ka]

[0343] In some embodiments, the MC4R agonist is a compound of formula (III): [ka] or a pharmaceutically acceptable salt thereof, wherein X is -CH2-SS-CH2-, -C(CH3)2-SS-CH2-, -CH2-SSC(CH3)2-, -C(CH3)2-SSC(CH3)2-, -(CH2)2-SS-CH2-, -CH2-SS-(CH2)2-, -(CH2)2-SS-(CH2)2-, -C(CH3)2-SS-(CH2)2-, -(CH2)2-SSC(CH3)2-, -(CH2) t -C(O)-NR 8 -(CH2) r - and -(CH2) r -NR 8 -C(O)-(CH2) t - selected from the group consisting of; R 2 are each independently H, (C1 to C 10 ) alkyl or substituted (C1-C 10 ) alkyl; R 3 is -OH or -NH; R 4 and R 5 are each independently H, (C1 to C 10 ) alkyl or substituted (C1-C 10 ) alkyl; X 1 teeth [ka] and;A 1 are His, 2-Pal, 3-Pal, 4-Pal, (X 1 , X 2 , X 3 , X 4 , X 5 ) Phe, Taz, 2-Thi, 3-Thi, or deleted; A 2 is D-Bal, D-1-Nal, D-2-Nal, D-Phe, or D-(X 1 , X 2 , X 3 , X4 , X 5 ) Phe; A 3 is Arg, hArg, Dab, Dap, Lys, or Orn; A 4 are Bal, 1-Nal, 2-Nal, (X 1 , X 2 , X 3 , X 4 , X 5 ) Phe, or Trp; R 6 and R 7 are independently expressed as H, (C1 to C 10 )heteroalkyl, aryl(C1-C5) alkyl, substituted (C1-C 10 ) Alkyl, substituted (C1-C 10 )heteroalkyl, or substituted aryl(C1-C5)alkyl, provided that R 6 and R 7 may be joined together to form a ring; R 8 is H, (C1~C 10 ) alkyl, or substituted (C1-C 10 ) alkyl; r, for each occurrence, is independently 1, 2, 3, 4, or 5; and t, for each occurrence, is independently 1 or 2.

[0344] Compounds according to the above formula are those in which X 1 but [ka] The compound may comprise a compound selected from the group consisting of:

[0345] Compounds of formula (III) are disclosed in International Patent Publication No. WO2008 / 147556 or International Patent Application No. PCT / US08 / 06675, each of which is incorporated by reference herein in its entirety.

[0346] In some embodiments, the compound of formula (III) is selected from: (SEQ ID NO: 187) c[hydantoin(C(O)-(Cys-D-Ala))-His-D-Phe-Arg-Trp-Cys]-NH2; (SEQ ID NO: 188) c[hydantoin(C(O)-(hCys-D-Ala))-His-D-Phe-Arg-Trp-Cys]-NH2; (SEQ ID NO: 189) c[hydantoin(C(O)-(Cys-D-Ala))-His-D-2-Nal-Arg-Trp-Cys]-NH2; (SEQ ID NO: 190) c[hydantoin(C(O)-(hCys-D-Ala))-His-D-2-Nal-Arg-Trp-Cys]-NH2; (SEQ ID NO: 191) c[hydantoin (C(O)-(Asp-D-Ala))-His-D-Phe-Arg-Trp-Lys]-NH2; (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; (SEQ ID NO: 194) c[hydantoin (C(O)-(Asp-D-Ala))-His-D-Phe-Arg-Trp-Dap]-NH2; (SEQ ID NO: 195) c[hydantoin(C(O)-(Asp-His))-D-2-Nal-Arg-Trp-Lys]-NH2; (SEQ ID NO: 196) c[hydantoin(C(O)-(Asp-His))-D-Phe-Arg-Trp-Lys]-NH2; (SEQ ID NO: 197) c[hydantoin(C(O)-(Asp-A3c))-D-Phe-Arg-Trp-Lys]-NH2; (SEQ ID NO: 198) c[hydantoin(C(O)-(Asp-A5c))-D-Phe-Arg-Trp-Lys]-NH2; (SEQ ID NO: 199) c[hydantoin(C(O)-(Asp-A6c))-D-Phe-Arg-Trp-Lys]-NH2; (SEQ ID NO: 200) c[hydantoin(C(O)-(Asp-A3c))-D-2-Nal-Arg-Trp-Lys]-NH2; (SEQ ID NO: 201) c[hydantoin(C(O)-(Asp-A5c))-D-2-Nal-Arg-Trp-Lys]-NH2; (SEQ ID NO: 202) c[hydantoin(C(O)-(Asp-A6c))-D-2-Nal-Arg-Trp-Lys]-NH2; (SEQ ID NO: 203) c[hydantoin (C(O)-(Asp-Aic))-D-Phe-Arg-Trp-Lys]-NH2; (SEQ ID NO: 204) c[hydantoin (C(O)-(Asp-Apc))-D-Phe-Arg-Trp-Lys]-NH2; (SEQ ID NO: 205) c[hydantoin (C(O)-(Asp-Aic))-D-2-Nal-Arg-Trp-Lys]-NH2; (SEQ ID NO: 206) c[hydantoin (C(O)-(Asp-Apc))-D-2-Nal-Arg-Trp-Lys]-NH2; (SEQ ID NO: 207) c[hydantoin (C(O)-(Glu-D-Ala))-His-D-Phe-Arg-Trp-Orn]-NH2; (SEQ ID NO: 208) c[hydantoin(C(O)-(Glu-D-Ala))-His-D-Phe-Arg-Trp-Dab]-NH2; (SEQ ID NO: 209) c[hydantoin (C(O)-(Glu-D-Ala))-His-D-Phe-Arg-Trp-Dap]-NH2; (SEQ ID NO: 210) c[hydantoin (C(O)-(Glu-D-Ala))-His-D-Phe-Arg-Trp-Lys]-NH2; (SEQ ID NO: 211) c[hydantoin (C(O)-(Glu-His))-D-Phe-Arg-Trp-Dap]-NH; and (SEQ ID NO: 212) c[hydantoin (C(O)-(Glu-His))-D-Phe-Arg-Trp-Lys]-NH or a pharmaceutically acceptable salt thereof.

[0347] In some embodiments, the MC4R agonist is a compound of formula (IV): (R 2 R 3 )-A 1 -c(A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 )-NH2(IV) or a pharmaceutically acceptable salt thereof, wherein A 1 is Nle or deleted, and A 2 is Cys or Asp; A 3 is Glu or D-Ala; A 4 is His;A 5 is D-Phe; A 6 is Arg;A 7 is Trp, 2-Nal, or Bal; A 8 is Gly, Ala, D-Ala, 3-Ala, Gaba, or Apn; A 9 is Cys or Lys; R 2 and R 3 are each independently selected from the group consisting of H or (C1-C6) acyl.

[0348] In an exemplary embodiment of Formula (IV), (I) R 2 is (C1-C6) acyl, R 3 is H; (II) A 2 If is Cys, A 9 is Cys.

[0349] Exemplary MC4R agonists of formula (IV) are disclosed in International Patent Application Publication No. WO2007 / 008704, which is incorporated herein by reference in its entirety.

[0350] In some embodiments, the compound of formula (IV) is selected from: (SEQ ID NO: 213) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gly-Cys)-NH2; (SEQ ID NO: 214)Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-D-Ala-Cys)-NH2; (SEQ ID NO: 215)Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-β-Ala-Cys)-NH2; (SEQ ID NO: 216)Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; (SEQ ID NO: 217) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Apn-Cys)-NH2; (SEQ ID NO: 218)Ac-c(Cys-Glu-His-D-Phe-Arg-Trp-Ala-Cys)-NH2; (SEQ ID NO: 219)Ac-c(Cys-Glu-His-D-Phe-Arg-2-Nal-Ala-Cys)-NH2; (SEQ ID NO: 220) Ac-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Ala-Cys)-NH2; (SEQ ID NO: 221)Ac-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Ala-Cys)-NH2; (SEQ ID NO: 222) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Ala-Cys)-NH; and (SEQ ID NO: 223)Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal-Ala-Lys)-NH2, or a pharmaceutically acceptable salt thereof.

[0351] In some embodiments, the MC4R agonist is a compound of formula (V): (R 2 R 3 )-B 1 -A 1 -c(A 2 -A 3 -A 4 -A5 -A 6 -A 7 -A 8 -A 9 )-A 10 -A 11 -A 12 -A 13 -B 2 -B 3 -R 1 (V) or a pharmaceutically acceptable salt thereof, 1 is a peptide moiety containing 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids (at least 5 amino acids independently selected from the group consisting of L-Arg, D-Arg, L-hArg, and D-hArg), or B 1 is optionally deleted; A 1 Acc, HN-(CH2) m -C(O), L-amino acids or D-amino acids, or deleted; A 2 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Asp, or Glu; A 3 is Gly, Glu, Ala, β-Ala, Gaba, Aib, a D-amino acid, or is missing; A 4 is His, 2-Pal, 3-Pal, 4-Pal, Taz, 2-Thi, 3-Thi or (X', X 2 , X 3 , X 4 , X 5 ) Phe; A 5 are D-Phe, D-1-Nal, D-2-Nal, D-Trp, D-Bal, D-(X 1 , X 2 , X 3 , X 4 , X 5 ) Phe, D-(Et)Tyr, D-Dip, D-Bip or D-Bpa; A 6 is Arg, hArg, Dab, Dap, Lys, Orn or HN-CH((CH2) n -N(R 4 R 5 ))-C(O);A 7is 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; A 8 is Gly, D-Ala, Acc, Ala, β-Ala, Gaba, Apn, Ahx, Aha, HN-(CH2) s -C(O) or deleted; A 9 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Dab, Dap, Orn, or Lys; A 10 Acc, HN-(CH2) t -C(O), Pro, hPro, 3-Hyp, 4-Hyp, Thr, an L-amino acid or a D-amino acid, or is deleted; A 11 is Pro, hPro, 3-Hyp, 4-Hyp, or deleted; A 12 is Lys, Dab, Dap, Arg, hArg, or is deleted; A 13 is Asp, Glu, or is deleted; B 2 is a peptide moiety containing 1, 2, 3, 4, or 5 amino acids or is deleted, and B 3 is a peptide moiety containing 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids (at least 5 amino acids independently selected from the group consisting of L-Arg, D-Arg, L-hArg, and D-hArg), or is deleted; R 1 is OH or NH2; R 2 and R 3 are independently calculated for each occurrence, H, (C1 to C 30 ) alkyl, (C1-C 30 ) heteroalkyl, (C1-C 30 ) Acyl, (C2-C 30 ) alkenyl, (C2-C 30 ) alkynyl, aryl (C1-C 30 ) Alkyl, aryl (C1-C 30 ) Acyl, Substituted (C1-C 30 ) Alkyl, substituted (C1-C 30) Heteroalkyl, substituted (C1-C 30 ) Acyl, Substituted (C2-C 30 ) Alkenyl, substituted (C2-C 30 ) alkynyl, substituted aryl (C1-C 30 ) Alkyl and substituted aryl (C1-C 30 ) acyl; R 4 and R 5 are independently calculated for each occurrence, H, (C1 to C 40 ) alkyl, (C1-C 40 ) heteroalkyl, (C1-C 40 ) Acyl, (C2-C 40 ) alkenyl, (C2-C 40 ) alkynyl, aryl (C1-C 40 ) Alkyl, aryl (C1-C 40 ) Acyl, Substituted (C1-C 40 ) Alkyl, substituted (C1-C 40 ) Heteroalkyl, substituted (C1-C 40 ) Acyl, Substituted (C2-C 40 ) Alkenyl, substituted (C2-C 40 ) alkynyl, substituted aryl (C1-C 40 ) Alkyl, substituted aryl (C1-C 40 ) Acyl, (C1-C 40 ) alkylsulfonyl or C(NH)—NH; n, for each occurrence, is independently 1, 2, 3, 4, or 5; m, for each occurrence, is independently 1, 2, 3, 4, 5, 6, or 7; s, for each occurrence, is independently 1, 2, 3, 4, 5, 6, or 7; t, for each occurrence, is independently 1, 2, 3, 4, 5, 6, or 7; X 1 , X 2 , X 3 , X 4 and X 5 are, independently for each occurrence, H, F, Cl, Br, I, -(C1-C 10 ) Alkyl, substituted (C1-C 10 ) Alkyl, (C2-C 10 ) Alkenyl, substituted (C2-C 10 ) alkenyl, (C2-C 10 ) alkynyl, substituted (C2-C10 ) alkynyl, aryl, substituted aryl, OH, NH2, NO2 or CN.

[0352] In some embodiments of Formula (V), (I)R 4 (C1-C 40 ) Acyl, aryl (C1-C 40 ) acyl, substituted (C1-C 40 ) acyl, substituted aryl (C1-C 40 ) acyl, (C1-C 40 ) alkylsulfonyl, or C(NH)—NH, when R 5 is H, (C1-C 40 ) alkyl, (C1-C 40 ) heteroalkyl, (C2-C 40 ) alkenyl, (C2-C 40 ) alkynyl, aryl (C1-C 40 ) alkyl, substituted (C1-C 40 ) alkyl, substituted (C1-C 40 ) heteroalkyl, substituted (C2-C 40 ) alkenyl, substituted (C2-C 40 ) alkynyl, or substituted aryl (C1-C 40 ) alkyl; (II)R 2 (C1-C 30 ) Acyl, aryl (C1-C 30 ) acyl, substituted (C1-C 30 ) acyl or substituted aryl (C1-C 30 ) acyl, R 3 is H, (C1-C 30 ) alkyl, (C1-C 30 ) heteroalkyl, (C2-C 30 ) alkenyl, (C2-C 30 ) alkynyl, aryl (C1-C 30 ) alkyl, substituted (C1-C 30 ) alkyl, substituted (C1-C 30 ) heteroalkyl, substituted (C2-C 30 ) alkenyl, substituted (C2-C 30) Alkynyl or substituted aryl (C1-C 30) alkyl; (III)B 1 and B 2 none of the following amino acid sequences contain 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; (IV)B 1 Or B 2 must be present in the compound; (V)A 2 If is Cys, D-Cys, hCys, D-hCys, Pen, or D-Pen, then A 9 is Cys, D-Cys, hCys, D-hCys, Pen, or D-Pen; and (VI)A 2 If is Asp or Glu, A 9 is Dab, Dap, Orn, or Lys.

[0353] In some embodiments of Formula (V), B 1は、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-Gl n-(Lys)2-(Arg)5、Arg-Gln-(Arg)7、Arg-Gln-(Arg)8、(Arg)2-Gln-(Arg)6、(Arg)2-Gln-(Ar g)7、(Arg)3-Gln-(Arg)5、(Arg)3-Gln-(Arg)6、(Arg)4-Gln-(Arg)4、(Arg)4-Gln-(Arg)5、(A rg)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)s-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-(L ys)2-(Arg)2-Gln-(Arg)3、Tyr-Gly-Arg-(Lys)2-(Arg)2-Gln-(Arg)3-Doc B 2 は、β-Ala、β-Ala-Gly、β-Ala-Tyr、β-Ala-Tyr-Gly、(β-Ala)2、(β-Ala)2-Gly、(β-Ala)2-Tyr、(β-Ala)2-Tyr-G ly、Doc、Doc-Gly、Doc-Tyr、Doc-Tyr-Gly、(Doc)2、(Doc )2-Gly、(Doc)2-Tyr、Doc)2-Tyr-Gly; B 3are 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) s , (Arg)2-Lys-(Arg)2-Gln-(Arg)3, (Arg)2-Gln-(Arg)6, (Arg)2-Gln-(Arg)7, (Arg)3-Gl n-(Arg)5, (Arg)3-Gln-(Arg)6, (Arg)4-Gln-(Arg)4, (Arg)4-Gln-(Arg)5, (Arg)5, (Arg) s -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) s -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; A 1 is A6c, Cha, hCha, Chg, D-Chg, hChg, Gaba, hLeu, Met, β-hMet, D-2-Nal, Nip, Nle, Oic, Phe, D-Phe, hPhe, hPro, or is deleted; A 2 is Cys; A 3 is D-Abu, Aib, Ala, β-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 is deleted; A 4is H; A 5 are D-Bal, D-1-Nal, D-2-Nal, D-Phe, D-(X 1 , X 2 , X 3 , X 4 , X 5 )Phe, D-Trp, or D-(Et)Tyr; A 6 is Arg or hArg; A 7 is Bal, Bip, 1-Nal, 2-Nal, Trp, or D-Trp; A 8 is A5c, A6c, Aha, Ahx, Ala, β-Ala, Apn, Gaba, Gly, or is deleted; A 9 is Cys, D-Cys, hCys, D-hCys, Lys, Pen, or is D-Pen; A 10 is Pro, Thr, or deleted; A 11 is Pro or deleted; A 12 is Arg, Lys, or is deleted; A 13 is Asp or is deleted; R 2 and R 3 each is independently H or acyl; or a pharmaceutically acceptable salt thereof.

[0354] In some embodiments, the compound of Formula (V) is selected from: (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; (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; (SEQ ID NO: 226) Nle-c(Asp-His-D-2-Nal-Arg-Trp-Lys)-β-Ala-Tyr-Gly-Arg-(Lys)2-(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO: 227) Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Lys)-β-Ala-Tyr-Gly-Arg-(Lys)2-(Arg)2-Gln-(Arg)3-NH2; (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; (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; (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; (SEQ ID NO: 231) Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Lys)-(β-Ala)2-Tyr-Gly-Arg-(Lys)2-(Arg)2-Gln-(Arg)3-NH2; (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; (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-β-Ala-Tyr-Gly-Arg-(Lys)2-(Arg)2-Gln-(Arg)3-NH2; (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-NH2; (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; (SEQ ID NO: 237) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala-Tyr-Gly-Arg-(Lys)2-(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO: 238) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 239) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 240) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 241) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala-Tyr-Gly-Arg-(Lys)2-Arg-Gln-(Arg)4-NH2; (SEQ ID NO: 242) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala-Tyr-Gly-Arg-(Lys)2-Gln-(Arg)5-NH2; (SEQ ID NO: 243) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala-Tyr-Gly-Arg-Lys-Gln-Lys-(Arg)5-NH2; (SEQ ID NO: 244) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala-Tyr-Gly-Arg-(Lys)2-(Arg)4-Gln-Arg-NH2; (SEQ ID NO: 245) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala-Tyr-Aib-Arg-(Lys)2-(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO: 246) Ac-c(Cys-Glu-His-D-2-Nal-Arg-1-Nal-Ala-Cys)-(Pro)2-Arg-Asp-β-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 247) Ac-c(Cys-Glu-His-D-2-Nal-Arg-1-Nal-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 248) Ac-c(Cys-Glu-His-D-2-Nal-Arg-1-Nal-Ala-Cys)-(Pro)2-Lys-Asp-β-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-β-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 250) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 251) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala-(Arg)6-Gln-(Arg)3-NH2; (SEQ ID NO: 252) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Arg-Asp-β-Ala-(Arg)6-Gln-(Arg)3-NH2; (SEQ ID NO: 253) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Arg-Asp-β-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 254) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala-(Arg)6-Gln-(Arg)3-NH2; (SEQ ID NO: 255) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala-Tyr-Gly-Arg-(Lys)2-(Arg)3-Gln-(Arg)2-NH2; (SEQ ID NO: 256) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala-Tyr-Gly-Arg-Gln-(Lys)2-(Arg)5-NH2; (SEQ ID NO: 257) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala-Tyr-Gly-Arg-(Lys)2-(Arg)5-Gln-NH2; (SEQ ID NO: 258) Ac-c(Cys-Glu-His-D-2-Nal-Arg-1-Nal-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala-Tyr-Gly-Arg-(Lys)2-(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO: 259) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala-Tyr-Gly-Arg-(Lys)2-(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO: 260) Ac-c(Cys-Glu-His-D-2-Nal-Arg-1-Nal-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala-(Arg)2-Lys-(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO: 261) Ac-c(Cys-Glu-His-D-2-Nal-Arg-1-Nal-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala-Arg-Lys-(Arg)3-Gln-(Arg)3-NH2; (SEQ ID NO: 262) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala-(Arg)2-Lys-(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO: 263) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-β-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-β-Ala-Gly-(Arg)2-Lys-(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO: 265) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala-Gly-Arg-Lys-(Arg)3-Gln-(Arg)3-NH2; (SEQ ID NO: 266) Ac-c(Cys-Glu-His-D-2-Nal-Arg-1-Nal-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala-Tyr-Gly-(Arg)2-Lys-(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO: 267) Ac-c(Cys-Glu-His-D-2-Nal-Arg-1-Nal-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala-Tyr-Gly-Arg-Lys-(Arg)3-Gln-(Arg)3-NH2; (SEQ ID NO: 268) Ac-c(Cys-Glu-His-D-2-Nal-Arg-1-Nal-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala-Gly-(Arg)2-Lys-(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO: 269) Ac-c(Cys-Glu-His-D-2-Nal-Arg-1-Nal-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala-Gly-Arg-Lys-(Arg)3-Gln-(Arg)3-NH2; (SEQ ID NO: 270) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala-(Arg)2-Lys-(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO: 271) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala-Arg-Lys-(Arg)3-Gln-(Arg)3-NH2; (SEQ ID NO: 272) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala-Tyr-Gly-Arg-Lys-(Arg)3-Gln-(Arg)3-NH2; (SEQ ID NO: 273) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala-(Arg)2-Lys-(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO: 274) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala-Arg-Lys-(Arg)3-Gln-(Arg)3-NH2; (SEQ ID NO: 275) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala-Tyr-Gly-(Arg)2-Lys-(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO: 276) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala-Tyr-Gly-Arg-Lys-(Arg)3-Gln-(Arg)3-NH2; (SEQ ID NO: 277) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala-Gly-(Arg)2-Lys-(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO: 278) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala-Gly-Arg-Lys-(Arg)3-Gln-(Arg)3-NH2; ​​​​​​(SEQ ID NO: 282) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Arg-Asp-β-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 283) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 284) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Arg-Asp-β-Ala-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 285) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 286) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Arg-Asp-β-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 287) Ac-c(Cys-Glu-His-D-2-Nal-Arg-1-Nal-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 288) Ac-c(Cys-Glu-His-D-2-Nal-Arg-1-Nal-Ala-Cys)-(Pro)2-Arg-Asp-β-Ala-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 289) Ac-c(Cys-Glu-His-D-2-Nal-Arg-1-Nal-Ala-Cys)-(Pro)2-Arg-Asp-β-Ala-(Arg)6-Gln-(Arg)3-NH2; (SEQ ID NO: 290) Ac-c(Cys-Glu-His-D-2-Nal-Arg-1-Nal-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 291) Ac-c(Cys-Glu-His-D-2-Nal-Arg-1-Nal-Ala-Cys)-(Pro)2-Arg-Asp-β-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 292) Ac-c(Cys-Glu-His-D-2-Nal-Arg-1-Nal-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 293) Ac-c(Cys-Glu-His-D-2-Nal-Arg-1-Nal-Ala-Cys)-(Pro)2-Arg-Asp-β-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 294) Ac-c(Cys-Glu-His-D-2-Nal-Arg-1-Nal-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala-Tyr-Gly-(Arg)6-Gln-(Arg)3-NH2; (SEQ ID NO: 295) Ac-c(Cys-Glu-His-D-2-Nal-Arg-1-Nal-Ala-Cys)-(Pro)2-Arg-Asp-β-Ala-Tyr-Gly-(Arg)6-Gln-(Arg)3-NH2; (SEQ ID NO: 296) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Arg-Asp-β-Ala-(Arg)6-Gln-(Arg)3-NH2; (SEQ ID NO: 297) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 298) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Arg-Asp-β-Ala-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 299) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 300) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Arg-Asp-β-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 301) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala-Tyr-Gly-(Arg)6-Gln-(Arg)3-NH2; (SEQ ID NO: 302) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Arg-Asp-β-Ala-Tyr-Gly-(Arg)6-Gln-(Arg)3-NH2; (SEQ ID NO: 303) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 304) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Arg-Asp-β-Ala-Tyr-Gly-(Arg)·5-Gln-(Arg)4-NH2; (SEQ ID NO: 305) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 306) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Arg-Asp-β-Ala-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 307) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Arg-Asp-β-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 308) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-β-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-β-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 310) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala-Tyr-Gly-(Arg)6-Gln-(Arg)3-NH2; (SEQ ID NO: 311) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Arg-Asp-β-Ala-Tyr-Gly-(Arg)6-Gln-(Arg)3-NH2; (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; (SEQ ID NO: 313) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-β-Ala-Tyr-Gly-Arg-(Lys)2-Arg-Gln-(Arg)4-NH2; (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; (SEQ ID NO: 315) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-β-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 316) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-β-Ala-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 317) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-β-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 318) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-β-Ala-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 319) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-β-Ala-Tyr-Gly-(Arg)2-Lys-(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO: 320) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-β-Ala-Tyr-Gly-Arg-Lys-(Arg)3-Gln-(Arg)3-NH2; (SEQ ID NO: 321) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-β-Ala-Gly-(Arg)2-Lys-(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO: 322) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-β-Ala-Gly-Arg-Lys-(Arg)3-Gln-(Arg)3-NH2; (SEQ ID NO: 323) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-β-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)-β-Ala-Arg-Lys-(Arg)3-Gln-(Arg)3-NH2; (SEQ ID NO: 325) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(β-Ala)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 326) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(β-Ala)2-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 327) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(β-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (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; (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; (SEQ ID NO: 331) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(Doc)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 332) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(Doc)2-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 333) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 334) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-β-Ala-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 335) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-β-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 336) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(β-Ala)2-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 337) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(β-Ala)2-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 338) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(β-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 339) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-Doc-(Arg)5-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-NH2; (SEQ ID NO: 341) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 342) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(Doc)2-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 343) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(Doc)2-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 344) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 345) Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-β-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 346) Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-β-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 347) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-β-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 348) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-β-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 349) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-β-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 350) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-β-Ala-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 351) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-β-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 352) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(β-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH 2; (SEQ ID NO: 353) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(β-Ala)2-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 354) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(β-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-NH2; (SEQ ID NO: 356) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-Doc-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 357) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-Doc-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 358) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 359) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(Doc)2-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 360) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(Doc)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 361) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-β-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 362) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-β-Ala-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 363) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-β-Ala-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 364) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(β-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 365) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(β-Ala)2-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 366) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(β-Ala)2-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 367) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2; (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)5-Gln-(Arg)4-NH2; (SEQ ID NO: 370) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 371) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(Doc)2-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 372) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(Doc)2-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 373) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-β-Ala-Lys)-β-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH 2; (SEQ ID NO: 374) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-β-Ala-Lys)-β-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 375) Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Ahx-Cys)-β-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 376) Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Ahx-Cys)-β-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 377) D-Phe-c(Cys-His-D-Phe-Arg-Trp-β-Ala-D-Cys)-Thr-β-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 378) D-Phe-c(Cys-His-D-Phe-Arg-Trp-β-Ala-D-Cys)-Thr-β-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 379) Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-β-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 380) Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-β-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 381) Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-β-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 382) Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-β-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 383) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-β-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 384) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-β-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 38) Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-β-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 386) Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-β-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 387) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-β-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 388) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-β-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 389) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-(β-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 390) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-(β-Ala)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 391) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (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; (SEQ ID NO: 394) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-(Doc)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 395) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-β-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 396) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-β-Ala-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 397) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-(β-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 398) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-(β-Ala)2-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 399) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 400) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-Doc-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 401) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 402) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-(Doc)2-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 403) Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-β-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 404) Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-β-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 405) Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-β-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 406) Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-β-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 407) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Apn-Cys)-β-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)-β-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 409) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Ahx-Cys)-β-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 410) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Ahx-Cys)-β-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 411) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-β-Ala-Cys)-β-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 412) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-β-Ala-Cys)-β-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 413) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-β-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 414) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-β-Ala-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 415) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-β-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 416) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-(β-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 417) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-(β-Ala)2-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 418) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-(β-Ala)2-(Arg)5-Gln-(Arg)3-NH2; (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; (SEQ ID NO: 420) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-Doc-Gly-(Arg)5-Gln-(Arg)3-NH2; (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; (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; (SEQ ID NO: 425) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-β-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 426) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-β-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 427) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-β-Ala-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 428) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-β-Ala-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 429) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-(β-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 430) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-(β-Ala)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 431) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-(β-Ala)2-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 432) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-(β-Ala)2-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 433) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 434) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-Doc-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 435) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-Doc-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 436) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-Doc-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 437) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 438) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-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-β-Ala-D-Cys)-(Doc)2-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 440) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-(Doc)2-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 441) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-β-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 442) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-β-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 443) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-(β-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 444) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-(β-Ala)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 445) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 446) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-Doc-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 447) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 448) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-β-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 449) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-β-Ala-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 450) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-(β-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 451) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-(β-Ala)2-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 452) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 453) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-Doc-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 454) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 455) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-(Doc)2-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 456) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-β-Ala-D-Cys)-Thr-β-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 457) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-β-Ala-D-Cys)-Thr-β-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 458) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-β-Ala-D-Cys)-Thr-β-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 459) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-β-Ala-D-Cys)-Thr-(β-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 460) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-β-Ala-D-Cys)-Thr-(β-Ala)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 461) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-β-Ala-D-Cys)-Thr-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 462) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-β-Ala-D-Cys)-Thr-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 463) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-β-Ala-D-Cys)-Thr-Doc-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 464) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-β-Ala-D-Cys)-Thr-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 465) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-β-Ala-D-Cys)-Thr-(Doc)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 466) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gly-Cys)-β-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 467) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gly-Cys)-β-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 468) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-β-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 469) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-β-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 470) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-(β-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 471) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-(β-Ala)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 472) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-β-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 473) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-β-Ala-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 474) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-(β-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 475) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-(β-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)-Gln-(Arg)-NH; (SEQ ID NO: 477) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-Doc-(Arg)-Gln-(Arg)-NH; (SEQ ID NO: 478) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-(Doc)-Tyr-Gly-(Arg)-Gln-(Arg)-NH; (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)-Gln-(Arg)-NH; (SEQ ID NO: 481) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-Doc-(Arg)-Gln-(Arg)-NH; (SEQ ID NO: 482) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-(Doc)-Tyr-Gly-(Arg)-Gln-(Arg)-NH; (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)-β-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 485) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-β-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 486) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-(β-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 487) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-(β-Ala)2-(Arg)5-Gln-(Arg)3-NH2; (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; (SEQ ID NO: 491) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-(Doc)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 492) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-β-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 493) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-β-Ala-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 494) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-(β-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 495) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-(β-Ala)2-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 496) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2; (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; (SEQ ID NO: 499) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-(Doc)2-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 500) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-β-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 501) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-β-Ala-(Arg)5-Gln-(Arg)3-NH; (SEQ ID NO: 502) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-(β-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 503) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-(β-Ala)2-(Arg)5-Gln-(Arg)3-NH2; (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; (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; (SEQ ID NO: 507) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-(Doc)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 508) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-β-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 509) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-β-Ala-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 510) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-(β-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 511) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-(β-Ala)2-(Arg)5-Gln-(Arg)4-NH2; (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; (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; (SEQ ID NO: 515) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-(Doc)2-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 516) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-β-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 517) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-β-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 518) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-(β-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 519) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-(β-Ala)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 520) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-β-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 521) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-β-Ala-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 522) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-(β-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 523) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-(β-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; (SEQ ID NO: 525) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-Doc-(Arg)-Gln-(Arg)-NH; (SEQ ID NO: 526)Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 527) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-(Doc)-(Arg)-Gln-(Arg)-NH; (SEQ ID NO: 528)Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO: 529) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-Doc-(Arg)-Gln-(Arg)-NH; (SEQ ID NO: 530) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-(Doc)-Tyr-Gly-(Arg)-Gln-(Arg)-NH; and (SEQ ID NO: 531) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-(Doc)-(Arg)-Gln-(Arg)-NH, or a pharmaceutically acceptable salt thereof.

[0355] In some embodiments, the compound of formula (V) is disclosed in International Application Publication No. WO2007 / 008684, which is incorporated by reference herein in its entirety.

[0356] In some embodiments, the MC4R agonist is a compound of formula (VI): Ac-c(Cys-Glu-His-A 1 -Arg-A2 -A 3 -Cys)-(Pro)2-Lys-Asp-NH2(VI) or a pharmaceutically acceptable salt thereof, wherein A 1 is the D-isomer of X-Phe or 2-Nal, where X is a halogen; A 2 is Bal, 1-Nal, 2-Nal, or Trp; A 3 is Aib, Ala, β-Ala or Gly.

[0357] In some embodiments, the compound of formula (VI) is selected from: (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; (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-1-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; (SEQ ID NO: 537) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-β-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 a pharmaceutically acceptable salt thereof.

[0358] In an exemplary embodiment, the MC4R agonist is a compound of formula (VII): [ka] or a pharmaceutically acceptable salt thereof [wherein X is -CH2-SS-CH2-, -C(CH3)2-SS-CH2-, -CH2-SSC(CH3)2-, -C(CH3)2-SSC(CH3)] z -, -(CH2)2-SS-CH2-, -CH2-SS-(CH2)2, -(CH2)2-SS-(CH2)2-, -C(CH3)2-SS-(CH2)2-, -(CH2)2-SSC(CH3)2-, -(CH2) t -C(O)-NR 8 -(CH2) r - and -(CH2) r -NR 8 -C(O)-(CH2) t - selected from the group consisting of; R 1 and R 5 Each of the is independently H, (C1 to C 10 ) alkyl, or substituted (C1-C 10 ) alkyl; R 2 and R 3 Each of the is independently H, (C1 to C 10 ) alkyl, (C1-C 10 )heteroalkyl, aryl(C1-C5) alkyl, substituted (C1-C 10 ) Alkyl, substituted (C1-C 10 ) heteroalkyl, or substituted aryl(C1-C5) alkyl, or R 2 and R 3 may be condensed with each other to form a ring; R 4 is OH or NH; R 6 and R 7 Each of the is independently H, (C1 to C 10 ) alkyl, or substituted (C1-C 10 ) alkyl; A 1 is an L-amino acid or a D-amino acid, or is missing; A 2 are His, 2-Pal, 3-Pal, 4-Pal, (X 1 , X 2 , X 3, X 4 , X 5 ) Phe, Taz, 2-Thi, or 3-Thi; A 3 is D-Bal, D-1-Nal, D-2-Nal, D-Phe, or D-(X 1 , X 2 , X 3 , X 4 , X 5 ) Phe; A 4 is Arg, hArg, Dab, Dap, Lys, or Orn; A 5 are Bal, 1-Nal, 2-Nal, (X 1 , X 2 , X 3 , X 4 , X 5 ) Phe, or Trp; r is, independently for each occurrence, 1, 2, 3, 4, or 5; and t is, independently for each occurrence, 1 or 2; or a pharmaceutically acceptable salt thereof.

[0359] In some embodiments of the compound of Formula (VII), A 1 is Ala, D-Ala, Asn, Asp, Gln, Glu, or Gly.

[0360] Exemplary compounds according to formula (VII) include: (SEQ ID NO: 539) c[hydantoin(C(O)-(Nle-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH2; (SEQ ID NO: 540) c[hydantoin (C(O)-(Ala-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH2; (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; (SEQ ID NO: 543) c[hydantoin (C(O)-(Val-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH2; (SEQ ID NO: 544) c[hydantoin (C(O)-(Abu-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH2; (SEQ ID NO: 545) c[hydantoin (C(O)-(Leu-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH2; (SEQ ID NO: 546) c[hydantoin (C(O)-(Ile-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH2; (SEQ ID NO: 547) c[hydantoin (C(O)-(Cha-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH2; (SEQ ID NO: 548) c[hydantoin (C(O)-(A6c-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH2; (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]-NH; and (SEQ ID NO: 551) c[hydantoin (C(O)-(Gly-Cys))-Glu-His-D-Phe-Arg-Trp-Cys]-NH or a pharmaceutically acceptable salt thereof.

[0361] In some embodiments, the compound of formula (VII) is disclosed in International Application Publication No. WO2008 / 147556, which is incorporated by reference herein in its entirety.

[0362] In some embodiments, the MC4R agonist is a compound of formula (VIII): (R 2 R 3 )-A 0 -A1 -c(A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 )-A 10 -R 1 (VIII) or a pharmaceutically acceptable salt thereof, wherein A 0 is an aromatic amino acid; A 1 Acc, HN-(CH2) m -C(O), an L-amino acid or a D-amino acid; A 2 is Asp, Cys, D-Cys, hCys, D-hCys, Glu, Pen, or D-Pen; A 3 is Aib, Ala, β-Ala, Gaba, Gly, or a D-amino acid; A 4 are His, 2-Pal, 3-Pal, 4-Pal, (X 1 , X 2 , X 3 , X 4 , X 5 ) Phe, Taz, 2-Thi, or 3-Thi; A 5 are D-Bal, D-1-Nal, D-2-Nal, D-Phe, L-Phe, D-(X 1 , X 2 , X 3 , X 4 , X 5 )Phe, L-Phe, D-Trp, or D-(Et)Tyr; A 6 is Arg, hArg, Dab, Dap, Lys, Orn, or HN-CH((CH2) n -N(R 4 R 5 ))-C(O);A 7 is Bal, D-Bal, Bip, D-Bip, 1-Nal, D-1-Nal, 2-Nal, D-2-Nal, or D-Trp; A 8 are Acc, Aha, Ahx, Ala, D-Ala, β-Ala, Apn, Gaba, Gly, HN-(CH2) s -C(O) or deleted; A9 is Cys, D-Cys, hCys, D-hCys, Dab, Dap, Lys, Orn, Pen, or D-Pen; A 10 Acc, HN-(CH2) t -C(O), L-amino acids or D-amino acids, or deleted; R 1 is OH, or NH; R 2 and R 3 Each of H, (C1 to C 30 ) alkyl, (C1-C 30 ) heteroalkyl, (C1-C 30 ) Acyl, (C2-C 30 ) alkenyl, (C2-C 30 ) alkynyl, aryl (C1-C 30 ) Alkyl, aryl (C1-C 30 ) Acyl, Substituted (C1-C 30 ) Alkyl, substituted (C1-C 30 ) Heteroalkyl, substituted (C1-C 30 ) Acyl, Substituted (C2-C 30 ) Alkenyl, substituted (C2-C 30 ) alkynyl, substituted aryl (C1-C 30 ) alkyl and substituted aryl (C1-C 30 ) acyl; R 4 and R 5 Each of H, (C1 to C 40 ) alkyl, (C1-C 40 ) heteroalkyl, (C1-C 40 ) Acyl, (C2-C 40 ) alkenyl, (C2-C 40 ) alkynyl, aryl (C1-C 40 ) Alkyl, aryl (C1-C 40 ) Acyl, Substituted (C1-C 40 ) Alkyl, substituted (C1-C 40 ) Heteroalkyl, substituted (C1-C 40 ) Acyl, Substituted (C2-C 40 ) Alkenyl, substituted (C2-C 40 ) alkynyl, substituted aryl (C1-C 40) Aryl, substituted aryl (C1-C 40 ) Acyl, (C1-C 40 m, for each occurrence, is independently 1, 2, 3, 4, 5, 6, or 7; n, for each occurrence, is independently 1, 2, 3, 4, 5, 6, or 7; s, for each occurrence, is independently 1, 2, 3, 4, 5, 6, or 7; t, for each occurrence, is independently 1, 2, 3, 4, 5, 6, or 7; X 1 , X 2 , X 3 , X 4 , and X 5 are, independently for each occurrence, H, F, Cl, Br, I, (C1 to C 10 ) Alkyl, substituted (C1-C 10 ) Alkyl, (C2-C 10 ) Alkenyl, substituted (C2-C 10 ) alkenyl, (C2-C 10 ) alkynyl, substituted (C2-C 10 ) alkynyl, aryl, substituted aryl, OH, NH2, NO2, or CN.

[0363] In one embodiment of Formula (VIII), R 4 (C1~C 40 ) Acyl, aryl (C1-C 40 ) Acyl, Substituted (C1-C 40 ) acyl, substituted aryl (C1-C 40 ) Acyl, (C1-C 40 ) alkylsulfonyl, or -C(NH)-NH, when R 5 is H or (C1~C 40 ) alkyl, (C1-C 40 ) heteroalkyl, (C2-C 40 ) alkenyl, (C2-C 40 ) alkynyl, aryl (C1-C 40 ) Alkyl, substituted (C1-C 40 ) Alkyl, substituted (C1-C 40 ) Heteroalkyl, substituted (C2-C 40 ) Alkenyl, substituted (C2-C 40) alkynyl, or substituted aryl (C1-C 40 ) alkyl.

[0364] In one embodiment of Formula (VIII), R 2 (C1~C 30 ) Acyl, aryl (C1-C 30 ) Acyl, Substituted (C1-C 30 ) acyl, or substituted aryl (C1-C 30 ) acyl, R 3 is H, (C1~C 30 ) alkyl, (C1-C 30 ) heteroalkyl, (C2-C 30 ) alkenyl, (C2-C 30 ) alkynyl, aryl (C1-C 30 ) Alkyl, substituted (C1-C 30 ) Alkyl, substituted (C1-C 30 ) Heteroalkyl, substituted (C2-C 30 ) Alkenyl, substituted (C2-C 30 ) alkynyl, or substituted aryl (C1-C 30 ) alkyl.

[0365] In one embodiment of Formula (VIII), A 2 If is Cys, D-Cys, hCys, D-hCys, Pen, or D-Pen, then A 9 is Cys, D-Cys, hCys, D-hCys, Pen, or D-Pen.

[0366] In one embodiment of Formula (VIII), A 2 If is Asp or Glu, A 9 is Dab, Dap, Orn, or Lys.

[0367] In one embodiment of Formula (VIII), A 8 is Ala or Gly, A 1 is not Nle; or a pharmaceutically acceptable salt thereof.

[0368] In some embodiments of Formula (VIII), A0 is 1-Nal, 2-Nal, His, Pff, Phe, Trp, or Tyr; A 1 is Arg;A 2 is Cys; A 3 is D-Ala;A 4 is H;A 5 is D-Phe; A 6 is Arg;A 7 is Trp;A 8 is deleted;A 9 is Cys; A 10 is missing; or a pharmaceutically acceptable salt thereof.

[0369] Particular compounds in the immediately preceding group of compounds of formula (VIII) include: (SEQ ID NO: 552)Ac-Tyr-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 553) Ac-2-Nal-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 554) Ac-l-Nal-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 555)Ac-Phe-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 556) Ac-Trp-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 557)Ac-Pff-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 558) H-His-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH; and (SEQ ID NO: 559)Ac-His-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2, or a pharmaceutically acceptable salt thereof.

[0370] In some embodiments, the MC4R agonist is an agonist described in WO2014 / 144260A1, which is incorporated herein by reference.

[0371] In an exemplary embodiment, the MC4R agonist is a compound represented by formula (IX): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is H or (C1-C6) acyl; R 2 is -NR 3 R 4 , or -OR 5 (where R 3 , R 4 , and R 5 are each independently H or (C1-C6) alkyl; A 1 is an amino acid residue selected from Arg, Lys, Orn, His, Nle, Phe, Val, Leu, Trp, Tyr, Ala, Ser, Thr, Gln, Asn, Asp, Glu, or TzAla; or A 1 is optionally substituted -(C1-C 12 )-alkyl or optionally substituted -(C6-C 18 )-aryl or optionally substituted -(C5-C 18 )-heteroaryl or aryl moiety is optionally substituted (C6-C 18 ) aryl, wherein the alkyl portion is optionally substituted (C1-C 12 ) alkyl, aralkyl, or heteroaryl moieties are optionally substituted (C5-C 18 ) heteroaryl, wherein the alkyl portion is optionally substituted (C1-C 12 ) alkyl, heteroaralkyl, or a moiety selected from the group consisting of: A 2 and A 8are each independently an amino acid residue selected from Cys, hCys, Pen, Asp, Glu, Lys, Orn, Dbu, or Dpr; A 2 and A 8 are selected in pairs to be able to form a covalent bond between their respective side chains; A 3 is absent or an amino acid residue selected from Ala, Tle, Val, Leu, Ile, Cha, Pro, Ser, Thr, Lys, Arg, His, Phe, Gln, Sar, Gly, Asn, Aib, or residue Y, wherein Y is a residue of the following structural formula: [ka] where R is an amino acid selected from the group consisting of 11 and R 12 are each independently H, —CH3, phenyl, or benzyl; R 21 , R 22 , R 23 , and R 24 are each independently H, -CH3, -CF3, phenyl, benzyl, F, Cl, Br, I, -OCH3, or -OH; R 31 , R 32 , R 33 , R 34 , R 41 , R 42 , and R 43 are each independently H, -CH3, -CF3, phenyl, benzyl, F, Cl, Br, I, -OCH3, or -OH; A 4 is absent or an amino acid residue selected from Atc, Ala, QAla, Aib, Sar, Ser, Thr, Pro, Hyp, Asn, Gln, optionally substituted His, Trp, Tyr, Lys, Arg, sChop, or residue X, where X is of the following formula: [ka] where R is an amino acid selected from the group consisting of 51 and R 52are each independently H, —CH3, phenyl, or benzyl; R 61 , R 62 , R 63 , and R 64 are each independently H, -CH3, -CF3, phenyl, benzyl, F, Cl, Br, I, -OCH3, or -OH; R 71 , R 72 , R 73 , R 74 , R 81 , R 82 , and R 83 are each independently H, -CH3, -CF3, phenyl, benzyl, F, Cl, Br, I, -OCH3, or -OH; A 5 is optionally substituted Phe, optionally substituted 1-Nal, or optionally substituted 2-Nal; A 6 is Arg;A 7 is Trp, and all amino acid residues are in either the L- or D-configuration.

[0372] Exemplary compounds of formula (IX) include: (SEQ ID NO: 560)Ac-Arg-c(Cys-D-Ala-His-D-Phe(pF)-Arg-Trp-Cys)-NH2; (SEQ ID NO: 561) Ac-Arg-c(Cys-D-Ala-Pro-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 562)Ac-Arg-c(Cys-D-Ala-Pro-D-Phe(pF)-Arg-Trp-Cys)-NH2; (SEQ ID NO: 563)Ac-Arg-c(Cys-D-Ala-Pro-D-Phe(pF)-Arg-Trp-Cys)-NH2; (SEQ ID NO: 564)Ac-Arg-c(Cys-D-Ala-Ser-D-Phe(pF)-Arg-Trp-Cys)-NH2; (SEQ ID NO: 565) Ac-Arg-c(Cys-D-Ala-Thr-D-Phe(p-CN)-Arg-Trp-Cys)-NH2; (SEQ ID NO: 566) Ac-Arg-c(Cys-D-Ala-Asn-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 567) Ac-Arg-c(Cys-D-Ala-Gln-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 568) Ac-Arg-c(Cys-D-Ala-Trp-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 569)Ac-Arg-c(Cys-D-Val-His-D-Phe-Arg-Trp-Cys)-NH2; (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)-NH; and (SEQ ID NO: 572) Ac-Arg-c(Cys-D-Ser-Pro-D-Phe-Arg-Trp-Cys)-NH2, or a pharmaceutically acceptable salt thereof.

[0373] In yet another embodiment, a polypeptide of the invention includes any one of the following structural formulas: (SEQ ID NO: 573)Ac-Arg-c(hCys-D-Ala-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 574)Ac-Arg-c(hCys-Ala-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 575)Ac-Arg-c(hCys-Ala-D-Phe-Arg-Trp-Cys)-OH; (SEQ ID NO: 576)Ac-Arg-c(Cys-D-Ala-D-Phe-Arg-Trp-hCys)-NH2; (SEQ ID NO: 577) Ac-Arg-c(Pen-D-Ala-D-Phe-Arg-Trp-hCys)-NH2; (SEQ ID NO: 578)Ac-Arg-c(hCys-D-Ala-D-Phe(pF)-Arg-Trp-Cys)-NH2; (SEQ ID NO: 579) Ac-Arg-c(hCys-Pro-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 580) Ac-Nle-c(hCys-Pro-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 581) Arg-c(hCys-Pro-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 582) CH3-(CH2)4-CO-c(hCys-Pro-D-Phe-Arg-Trp-Cys)-NH2; and (SEQ ID NO: 583) benzylCO-c(hCys-Pro-D-Phe-Arg-Trp-Cys)-NH2, or a pharmaceutically acceptable salt thereof.

[0374] In further embodiments, polypeptides of the invention include polypeptides represented by any one of the following structural formulas: (SEQ ID NO: 584) Ac-Arg-c(Asp-D-Ala-D-Phe-Arg-Trp-Dbu)-NH2; (SEQ ID NO: 585) Ac-Arg-c(Glu-D-Ala-D-Phe-Arg-Trp-Dpr)-NH2; (SEQ ID NO: 586) Ac-Arg-c(Glu-Ala-D-Phe-Arg-Trp-Dpr)-NH2; (SEQ ID NO: 587) Ac-Arg-c(Dpr-D-Ala-D-Phe-Arg-Trp-Glu)-NH2; (SEQ ID NO: 588) Ac-Arg-c(Dpr-D-Ala-D-Phe(4-F)-Arg-Trp-Glu)-NH2; (SEQ ID NO: 589) Ac-Arg-c(Dpr-Ala-D-Phe-Arg-Trp-Glu)-NH2; (SEQ ID NO: 590) Ac-Arg-c(Dpr-Ala-D-Phe-Arg-Trp-Glu)-OH; (SEQ ID NO: 591) Ac-Nle-c(Dpr-Ala-D-Phe-Arg-Trp-Glu)-NH2; (SEQ ID NO: 592) Arg-c(Dpr-Ala-D-Phe-Arg-Trp-Glu)-NH2; (SEQ ID NO: 593) CH3-(CH2)4-CO-c(Dpr-Ala-D-Phe-Arg-Trp-Glu)-NH2; or (SEQ ID NO: 594) benzyl-CO-c(Dpr-Ala-D-Phe-Arg-Trp-Glu)-NH or a pharmaceutically acceptable salt thereof.

[0375] In yet another embodiment, the polypeptides of the present invention include polypeptides represented by formula (IX), wherein A 4 is an amino acid residue selected from Atc, Ala, QAla, Aib, Sar, Ser, Thr, Pro, Hyp, Asn, Gln, substituted His, Trp, Tyr, Lys, Arg, sChop, or residue X. Examples of such peptides include peptides represented by any one of the following structural formulas: (SEQ ID NO: 595) Ac-Arg-c(Cys-D-Ala-His(3-Me)-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 596) Ac-Arg-c(Cys-D-Ala-His(1-Me)-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 568) Ac-Arg-c(Cys-D-Ala-Trp-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 567) Ac-Arg-c(Cys-D-Ala-Gln-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 566) Ac-Arg-c(Cys-D-Ala-Asn-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 597)Ac-Arg-c(Cys-D-Ala-Arg-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 598)Ac-Arg-c(Cys-D-Ala-Tyr-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 599) Ac-Arg-c(Cys-D-Ala-D-Pro-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 561) Ac-Arg-c(Cys-D-Ala-Pro-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 563)Ac-Arg-c(Cys-D-Ala-Pro-D-Phe(pF)-Arg-Trp-Cys)-NH2; (SEQ ID NO: 600) Ac-Arg-c(Cys-D-Ala-Atc-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 601) Ac-Arg-c(Cys-D-Ala-QAla-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 602) Ac-Arg-c(Cys-D-Ala-sChp-D-Phe-Arg-Trp-Cys)-NH; or (SEQ ID NO: 603) Ac-Arg-c(Cys-D-Ala-XD-Phe-Arg-Trp-Cys)-NH2, or a pharmaceutically acceptable salt thereof.

[0376] In exemplary embodiments, the polypeptides of the invention include polypeptides represented by any one of the following structural formulas: (SEQ ID NO: 574)Ac-Arg-c(hCys-Ala-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 573)Ac-Arg-c(hCys-D-Ala-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 604) Ac-Arg-c(hCys-D-Ala-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 585) Ac-Arg-c(Glu-D-Ala-D-Phe-Arg-Trp-Dpr)-NH2; (SEQ ID NO: 586) Ac-Arg-c(Glu-Ala-D-Phe-Arg-Trp-Dpr)-NH2; (SEQ ID NO: 605) Ac-Arg-c(hCys-Aib-D-Phe-Arg-Trp-Cys)-NH2; (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; (SEQ ID NO: 608)Ac-Arg-c(hCys-D-Val-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 609) Ac-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 610) Ac-Arg-c(hCys-D-Gln-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 611) Ac-Arg-c(hCys-Ala-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 612) Ac-Arg-c(D-Pen-D-Ala-D-Phe-Arg-Trp-hCys)-NH2; (SEQ ID NO: 576)Ac-Arg-c(Cys-D-Ala-D-Phe-Arg-Trp-hCys)-NH2; (SEQ ID NO: 613) Ac-Arg-c(Pen-D-Ala-D-Phe-Arg-Trp-hCys)-NH2; (SEQ ID NO: 614)Ac-Arg-c(D-hCys-D-Ala-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 579) Ac-Arg-c(hCys-Pro-D-Phe-Arg-Trp-Cys)-NH; or (SEQ ID NO: 615) Ac-Arg-c(hCys-D-Pro-D-Phe-Arg-Trp-Cys)-NH2, or a pharmaceutically acceptable salt thereof.

[0377] In another embodiment, the polypeptides of the present invention include polypeptides represented by formula (IX), wherein A 3 is an amino acid residue selected from Tle, Val, Leu, Ile, Cha, Pro, Ser, Thr, Lys, Arg, His, Phe, Gln, Sar, Gly, Asn, or Aib; A 4is an amino acid residue selected from Atc, Ala, QAla, Aib, Sar, Ser, Thr, Pro, Hyp, Asn, Gln, substituted His, Trp, Tyr, Lys, Arg, sChop, or residue X. An example of such a polypeptide is a polypeptide represented by any one of the following structural formulas: (SEQ ID NO: 616) Ac-Arg-c(Cys-Val-Gln-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 570) Ac-Arg-c(Cys-D-Val-Gln-D-Phe-Arg-Trp-Cys)-NH; or (SEQ ID NO: 617)Ac-Arg-c(Cys-D-Val-His(1-Me)-D-Phe-Arg-Trp-Cys)-NH2, or a pharmaceutically acceptable salt thereof.

[0378] In further embodiments, the polypeptides of the invention include polypeptides represented by any one of the following structural formulas: (SEQ ID NO: 618) Ac-TzAla-c(Cys-Ala-Gln-D-Phe-Arg-Trp-Cys)-NH; or (SEQ ID NO: 619)Ac-Glu-c(Cys-Ala-His-D-Phe-Arg-Trp-Cys)-NH2, or a pharmaceutically acceptable salt thereof.

[0379] In yet another embodiment, the polypeptides of the invention include polypeptides represented by any one of the following structural formulas: (SEQ ID NO: 596) Ac-Arg-c(Cys-D-Ala-His(1-Me)-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 567) Ac-Arg-c(Cys-D-Ala-Gln-D-Phe-Arg-Trp-Cys)-NH; or (SEQ ID NO: 566) Ac-Arg-c(Cys-D-Ala-Asn-D-Phe-Arg-Trp-Cys)-NH2, or a pharmaceutically acceptable salt thereof.

[0380] In further embodiments, the polypeptides of the invention include polypeptides represented by any one of the following structural formulas: (SEQ ID NO: 620)Ac-Arg-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 621) Ac-Arg-c(Cys-D-Ile-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO: 622) Ac-Arg-c(Cys-D-Tle-His-D-Phe-Arg-Trp-Cys)-NH; or (SEQ ID NO: 569)Ac-Arg-c(Cys-D-Val-His-D-Phe-Arg-Trp-Cys)-NH2, or a pharmaceutically acceptable salt thereof.

[0381] In further embodiments, the polypeptides of the invention include polypeptides represented by any one of the following structural formulas: (SEQ ID NO: 623) Ac-Arg-c(Cys-D-Ala-His(1-Me)-D-2-Nal-Arg-Trp-Cys)-NH2; (SEQ ID NO: 624) Ac-Arg-c(Cys-D-Ala-Gln-D-2-Nal-Arg-Trp-Cys)-NH; or (SEQ ID NO: 625) Ac-Arg-c(Cys-D-Ala-Asn-D-2-Nal-Arg-Trp-Cys)-NH2, or a pharmaceutically acceptable salt thereof.

[0382] In further embodiments, the polypeptides of the invention include polypeptides represented by any one of the following structural formulas: (SEQ ID NO: 626)Ac-Arg-c(Cys-D-Ala-His(1-Me)-D-Phe-Arg-Trp-Cys)-OH; (SEQ ID NO: 627) Ac-Arg-c(Cys-D-Ala-Gln-D-Phe-Arg-Trp-Cys)-OH; or (SEQ ID NO: 628) Ac-Arg-c(Cys-D-Ala-Asn-D-Phe-Arg-Trp-Cys)-OH, or a pharmaceutically acceptable salt thereof.

[0383] In an exemplary embodiment, the MC4R agonist is a compound represented by formula (X): [ka] or a pharmaceutically acceptable salt thereof, wherein R1 is -NH-C(O)- or -C(O)-NH-; R2 is -H, -CH2-, or R2 combined with R3 forms a pyrrolidine ring optionally substituted with -OH; R3 is -(CH2)2- if R2 is -CH2-, otherwise R3 is [ka] Selected from;R 4a , R 4b , and R 4c are each independently hydrogen, halo, (C1-C 10 ) Alkyl-halo, (C1-C 10 ) alkyl-dihalo, (C1-C 10 ) alkyl-trihalo, (C1-C 10 ) alkyl, (C1-C 10 ) alkoxy, (C1-C 10 ) selected from alkylthio, aryl, aryloxy, nitro, nitrile, sulfonamido, amino, hydroxyl, carboxy, and alkoxy-carbonyl; R 5 is -OH or -N(R 6a )(R 6b ) and R 6a and R 6b are each independently H or a C1-C4 linear, branched, or cyclic alkyl chain; R 7 is —H or —C(O)—NH 2 ; w is independently in each instance 0 to 5; x is 1 to 5; y is 1 to 5; and z is independently in each instance 1 to 5.

[0384] In one exemplary embodiment, R 4a , R 4b , and R 4c is not hydrogen.

[0385] An example of a compound of formula (X) is a cyclic peptide defined by formula (XI): [ka] or a pharmaceutically acceptable salt thereof.

[0386] In one exemplary 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 exemplary 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.

[0387] In some embodiments, the MC4R agonist is an agonist described in WO2014 / 144260A1, which is incorporated herein by reference.

[0388] In an exemplary embodiment, the MC4 agonist is a compound represented by formula (XII): A1-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, which are capable of forming disulfide bridges, or Glu, Asp, Lys, Orn, Dpr, Dbu, which are capable of forming lactam bridges; Xxx is Asn, Gln, Ser, Thr; Yyy is Lys, Arg, D-Lys, D-Arg; A1 is H, Ac; and A2 is OH, NH2.

[0389] In embodiments, the MC4R agonist is selected from one or more of the following compounds (or a pharmaceutically acceptable salt thereof): (SEQ ID NO: 629) Ac-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 630) Ac-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 631) Ac-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2; (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; (SEQ ID NO: 634) Ac-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH; (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) HD-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) HD-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) HD-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) HD-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) HD-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) HD-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) HD-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) HD-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; (SEQ ID NO: 668) HD-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 669) Ac-D-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 670) HD-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 671) Ac-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 672) Ac-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 673) H-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 674) H-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 675) Ac-D-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 676) HD-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) HD-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 679) Ac-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 680) H-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 681) H-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 682) Ac-D-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 683) HD-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 684) Ac-D-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 685) HD-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 686) Ac-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 687) Ac-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 688) H-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 689) H-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 690) Ac-D-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 691) HD-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, or (SEQ ID NO: 693) HD-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2.

[0390] In some embodiments, the MC4R agonist is a compound of formula (XII-a): H-Yyy-c(Aaa-Xxx-D-Phe-Arg-Trp-Bbb)-NH2(XII-a) or a pharmaceutically acceptable salt thereof, wherein Aaa and Bbb are selected from Cys, hCys, Pen, which are capable of forming disulfide bridges, or Glu, Asp, Lys, Orn, Dpr, Dbu, which are capable of forming lactam bridges; Xxx is Asn, Gln, Ser, Thr; and Yyy is Lys, Arg, D-Lys, D-Arg.

[0391] In some embodiments, the compound of formula (XII-a) is selected from: (SEQ ID NO: 635) H-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 643) H-Lys-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 646) HD-Lys-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 650) H-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 653) HD-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 658) H-Lys-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 661) HD-Lys-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 665) H-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 668) HD-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 673) H-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 676) HD-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 680) H-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 683) HD-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 688) H-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 691) HD-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH; and (SEQ ID NO: 693) HD-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2.

[0392] In some embodiments, the MC4R agonist is a compound of formula (XII-b): Ac-Yyy-c(Aaa-Xxx-D-Phe-Arg-Trp-Bbb)-NH2(XII-b) or a pharmaceutically acceptable salt thereof, wherein Aaa and Bbb are selected from Cys, hCys, Pen, which are capable of forming disulfide bridges, or Glu, Asp, Lys, Orn, Dpr, Dbu, which are capable of forming lactam bridges; Xxx is Asn, Gln, Ser, Thr; and Yyy is Lys, Arg, D-Lys, D-Arg.

[0393] In some embodiments, the compound of formula (XII-b) is selected from: (SEQ ID NO: 629) Ac-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 630) Ac-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 631) Ac-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2; (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; (SEQ ID NO: 637) Ac-D-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 641) Ac-Lys-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 645) Ac-D-Lys-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 652) Ac-D-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 656) Ac-Lys-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 660) Ac-D-Lys-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 667) Ac-D-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 671) Ac-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 675) Ac-D-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 682) Ac-D-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 686) Ac-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 690) Ac-D-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH; and (SEQ ID NO: 692) Ac-D-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2.

[0394] In some embodiments, the MC4R agonist is a compound of formula (XII-c): A1-Yyy-c(Aaa-Xxx-D-Phe-Arg-Trp-Bbb)-A2(XII-c) or a pharmaceutically acceptable salt thereof, wherein A1 is H or Ac; A2 is OH or NH2; Yyy is L-Arg or D-Arg; Aaa and Bbb are selected from Cys, hCys, and Pen, which can form disulfide bridges, or Glu, Asp, Lys, Orn, Dpr, and Dbu, which can form lactam bridges; and Xxx is Asn, Gln, Ser, or Thr.

[0395] In some embodiments, the compound of formula (XII-c) is selected from: (SEQ ID NO: 629) Ac-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 630) Ac-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 631) Ac-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2; (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; (SEQ ID NO: 634) Ac-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH; (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) HD-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) HD-Arg-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) HD-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) HD-Arg-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; (SEQ ID NO: 668) HD-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 669) Ac-D-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 670) HD-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 679) Ac-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 680) H-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 681) H-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 682) Ac-D-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 683) HD-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO: 684) Ac-D-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH; and (SEQ ID NO: 685) HD-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH.

[0396] In some embodiments, the MC4R agonist is a compound of formula (XII-d): A1-Yyy-c(Aaa-Xxx-D-Phe-Arg-Trp-Bbb)-A2(XII-d) or a pharmaceutically acceptable salt thereof, wherein A1 is H or Ac; A2 is OH or NH2; Yyy is L-Lys or D-Lys; Aaa and Bbb are selected from Cys, hCys, and Pen, which can form disulfide bridges, or Glu, Asp, Lys, Orn, Dpr, and Dbu, which can form lactam bridges; and Xxx is Asn, Gln, Ser, or Thr.

[0397] In some embodiments, the compound of formula (XII-d) is selected from: (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) HD-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) HD-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; (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) HD-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) HD-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; (SEQ ID NO: 672) Ac-Lys-c(hCys-Se...

Claims

1. 1. A method of treating a disease, disorder, or condition in a subject, comprising administering to the subject a melanocortin-4 receptor (MC4R) agonist, wherein the subject: (i) has or is identified as having non-genetic obesity; (ii) has or perceives to have brain tissue damage; and / or (iii) has or has been identified as having a proliferative brain disease; The method.

2. The method of claim 1 comprising (i).

3. The method of claim 1, comprising (ii).

4. The method of claim 1 , comprising (iii).

5. 2. The method of claim 1, wherein the non-genetic obesity comprises obesity caused by a neurodevelopmental abnormality or brain malformation.

6. 10. The method of claim 1, wherein the brain tissue damage is in the hypothalamus.

7. 7. The method of claim 6, wherein the brain tissue damage is in the hypothalamic paraventricular nucleus, the hypothalamic ventromedial nucleus, or the hypothalamic arcuate nucleus.

8. 8. The method of claim 7, wherein the brain injury or trauma occurs in the ventromedial nucleus.

9. 10. The method of claim 1, wherein the disease, disorder, or condition comprises hypothalamic obesity.

10. 10. The method of claim 1, wherein the proliferative brain disease comprises a benign tumor, a benign lesion, or a malignant tumor (e.g., cancer).

11. 11. The method of claim 10, wherein the proliferative brain disease is in the hypothalamus.

12. 12. The method of any one of claims 10 or 11, wherein the proliferative brain disease is present in the hypothalamic paraventricular nucleus, the hypothalamic ventromedial nucleus, or the hypothalamic arcuate nucleus.

13. 11. The method of claim 10, wherein the proliferative brain disease comprises craniopharyngioma or astrocytoma.

14. 10. The method of claim 1, wherein the subject has undergone surgery (e.g., tumor removal or bariatric surgery) or has undergone radiation.

15. The method of claim 1 , wherein the subject is obese, for example severely obese.

16. The method of claim 1 , wherein the subject has bulimia.

17. The subject has a blood pressure of 35 kg / m or less prior to administration of the MC4R agonist, e.g., when the MC4R agonist is prescribed or at the time of the first administration. ２ greater than (e.g., ≥ 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 kg / m ２ 2. The method of claim 1, wherein the subject has a body mass index (BMI) of 100 or greater.

18. The method of claim 1, wherein the subject has failed one or more previous therapies, e.g., exercise, diet, or behavioral therapies, prior to administration of the MC4R agonist, e.g., when the MC4R agonist is prescribed or at the time of first administration.

19. 2. 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), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXIV), (XXV), (XXVII), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXXII), (XXXIII), (XXXIV), (XXXV), or (XXXVI) (e.g., those described herein).

20. The method of claim 1 , wherein the MC4R agonist is a peptide or small molecule, or a pharmaceutically acceptable salt thereof.

21. The method of claim 1, wherein the MC4R agonist is, for example, a peptide selected from any one of SEQ ID NOs: 1-915.

22. The MC4R agonist is Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH ２ The method of claim 1, wherein the sequence is not (SEQ ID NO: 140).

23. The method of claim 1 , wherein the MC4R agonist is a small molecule, or a pharmaceutically acceptable salt thereof.

24. 21. The method of claim 20, wherein the MC4R agonist is selected from any one of Compound Nos. 100-825, or a pharmaceutically acceptable salt thereof.

25. 21. The method of claim 20, wherein the MC4R agonist is a compound of any one of formulas (XIV) to (XXXVI), or a pharmaceutically acceptable salt thereof.

26. 21. The method of claim 20, wherein the MC4R agonist is a compound of formula (XIV), or a pharmaceutically acceptable salt thereof.

28. 21. The method of claim 20, wherein the MC4R agonist is selected from any one of compounds 100-221, or a pharmaceutically acceptable salt thereof.

29. 21. The method of claim 20, wherein the MC4R agonist is a compound of formula (XV), or a pharmaceutically acceptable salt thereof.

30. 30. The method of claim 29, wherein the MC4R agonist is selected from any one of compounds 300-383, or a pharmaceutically acceptable salt thereof.

31. 21. The method of claim 20, wherein the MC4R agonist is a compound of formula (XVI), or a pharmaceutically acceptable salt thereof.

32. 32. The method of claim 31, wherein the MC4R agonist is selected from any one of compounds 390-394, or a pharmaceutically acceptable salt thereof.

33. 21. The method of claim 20, wherein the MC4R agonist is a compound of formula (XVII), or a pharmaceutically acceptable salt thereof:

34. 34. The method of claim 33, wherein the MC4R agonist is selected from any one of compounds 400-403, or a pharmaceutically acceptable salt thereof.

35. 21. The method of claim 20, wherein the MC4R agonist is a compound of formula (XX), or a pharmaceutically acceptable salt thereof.

36. 37. The method of claim 36, wherein the MC4R agonist is selected from any one of compounds 410-449, or a pharmaceutically acceptable salt thereof.

37. 21. The method of claim 20, wherein the MC4R agonist is a compound of formula (XXI), or a pharmaceutically acceptable salt thereof.

38. 38. The method of claim 37, wherein the MC4R agonist is selected from any one of compounds 460-481, or a pharmaceutically acceptable salt thereof.

39. 21. The method of claim 20, wherein the MC4R agonist is a compound of formula (XXIV), or a pharmaceutically acceptable salt thereof.

40. 40. The method of claim 39, wherein the MC4R agonist is selected from any one of compounds 550-576, or a pharmaceutically acceptable salt thereof.

41. 21. The method of claim 20, wherein the MC4R agonist is compound 580, or a pharmaceutically acceptable salt thereof.

42. 21. The method of claim 20, wherein the MC4R agonist is selected from any one of compounds 600-626, or a pharmaceutically acceptable salt thereof.

43. 21. The method of claim 20, wherein the MC4R agonist is a compound of any of formulas (XXVIII), (XXVIIIa), (XXVIIIb), (XXVIIIc), and (XXVIIId) or a pharmaceutically acceptable salt thereof.

44. 44. The method of claim 43, wherein the MC4R agonist is selected from any one of compounds 650-682, or a pharmaceutically acceptable salt thereof.

45. 21. The method of claim 20, wherein the MC4R agonist is a compound of any of formulas (XXVIII), (XXVIIIa), (XXVIIIb), (XXVIIIc), (XXVIIId), (XXVIIIe), and (XXVIIIf) or a pharmaceutically acceptable salt thereof.

46. 46. ​​The method of claim 45, wherein the MC4R agonist is selected from any one of compounds 690-693, or a pharmaceutically acceptable salt thereof.

47. 21. The method of claim 20, wherein the MC4R agonist is a compound of any of formulas (XXIX), (XXIXa), (XXIXb), (XXIXc), (XXIXd), (XXIXe), and (XXIXf) or a pharmaceutically acceptable salt thereof.

48. 48. The method of claim 47, wherein the MC4R agonist is selected from any one of compounds 700-737, or a pharmaceutically acceptable salt thereof.

49. 21. The method of claim 20, wherein the MC4R agonist is a compound of formula (XXX) or a pharmaceutically acceptable salt thereof.

50. 50. The method of claim 49, wherein the MC4R agonist is selected from any one of compounds 740-741, or a pharmaceutically acceptable salt thereof.

51. 21. The method of claim 20, wherein the MC4R agonist is selected from any one of compounds 742-751, or a pharmaceutically acceptable salt thereof.

52. 21. The method of claim 20, wherein the MC4R agonist is selected from any one of compounds 760-762, or a pharmaceutically acceptable salt thereof.

53. 21. The method of claim 20, wherein the MC4R agonist is a compound of any one of formulas (XXXIV) to (XXXVI) or a pharmaceutically acceptable salt thereof.

54. 54. The method of claim 53, wherein the MC4R agonist is selected from any one of compounds 1000-1013, or a pharmaceutically acceptable salt thereof.

55. 21. The method of claim 20, wherein the MC4R agonist is selected from any one of compounds 800-825, or a pharmaceutically acceptable salt thereof.

56. The method of claim 1 , wherein the MC4R agonist is formulated as a pharmaceutical composition.

57. 57. The method of claim 56, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

58. 58. The method of claim 57, wherein the pharmaceutical composition comprises polyethylene glycol (e.g., a modified polyethylene glycol, e.g., mPEG-DSPE, e.g., mPEG-2,000-DSPE).

59. 10. The method of claim 1, comprising administering the MC4R agonist to the subject in a unit dose suitable for injection, e.g., subcutaneous injection.

60. 60. The method of claim 59, wherein the unit dosage form is disposed in a delivery device, such as a syringe (e.g., a prefilled syringe), an implantable device, a needleless hypodermic injection device, an infusion pump (e.g., an implantable infusion pump), or an osmotic delivery system.

61. The method of claim 1 , wherein the MC4R agonist is administered subcutaneously, for example, by subcutaneous injection.

62. 10. The method of claim 1, comprising administering the MC4R agonist to the subject in a unit dose suitable for oral delivery.

63. The method of claim 1 , wherein the subject is a human.

64. The method of claim 1, wherein the subject is an adult (e.g., 18 years of age or older).

65. 10. The method of claim 1, wherein the subject is a pediatric subject, e.g., a child (e.g., under 18, 16, 14, 12, 10, 8, 6, or 4 years of age).

66. 10. The method of claim 1, wherein the subject has previously been treated for obesity, e.g., non-genetic obesity, e.g., hypothalamic obesity, prior to administration of the MC4R agonist.

67. The method of claim 1, wherein the subject exhibits a decrease in BMI after the first administration of the MC4R agonist (e.g., at least 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 4 months, 5 months, 6 months, 8 months, 10 months, 1 year, or more).

68. The method of claim 67, wherein the reduction in the subject's BMI is 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20% or more, for example, compared to a reference standard (e.g., BMI before administration of the MC4R agonist).

69. The method of claim 1 , wherein an additional agent (e.g., an additional therapeutic agent) is administered to the subject.

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