Cyclic peptides as proprotein convertase subtilisin / kexin type 9 (PCSK9) inhibitors for the treatment of metabolic disorders

Abstract

The present disclosure provides inhibitors of PCSK9 useful in the treatment of lipid metabolism and other diseases in which PCSK9 plays a role, having formula (I): [Case 1] TIFF2022509184000055.tif32170 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, wherein R 1 , X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 and X 13 is described herein).

Description

[Technical Field]

[0001] Related Applications This application claims the benefit of and priority to U.S. Provisional Patent Application No. 62 / 772,033, filed November 27, 2018, the entire contents of which are incorporated herein by reference in their entirety.

[0002] The present disclosure is directed to modulators of proprotein convertase subtilisin / kexin type 9 (PCSK9) that are useful in treating diseases or disorders associated with the PCSK9 protease. Specifically, the disclosure relates to peptides and compositions that inhibit PCSK9, methods of treating diseases or disorders associated with PCSK9, and methods of synthesizing these peptides. [Background technology]

[0003] Proprotein convertase subtilisin / kexin type 9 (PCSK9) is a member of the secreted subtilase, subtilisin serine protease family and is expressed in many tissues and cell types. The PCSK9 protein contains a signal sequence, a prodomain, a catalytic domain containing a triad of conserved residues (D186, H226, and S386), and a C-terminal domain. It is synthesized as a soluble 74-kDa precursor that undergoes autocatalytic cleavage in the endoplasmic reticulum. Autocatalytic activity has been shown to be required for secretion.

[0004] PCSK9 has a significant effect on plasma low-density lipoprotein cholesterol (LDL-C) levels through its regulation of the hepatic low-density lipoprotein receptor (LDLR), the primary pathway by which cholesterol is removed from the circulation. PCSK9 binds to the LDLR and targets it for lysosomal degradation, thereby increasing plasma LDL-C levels and ultimately increasing the risk of coronary heart disease (CHD) (Maxwell KN, Proc. Natl. Acad. Sci., 101, 2004, 7100-7105; Park, SW, J. Biol. Chem. 279, 2004, 50630-50638; Lagace TA, et al. J. Clin. Invest. 2006, 116(11):2995-3005). Overexpression of mouse or human PCSK9 in mice has been shown to increase total and LDL-C levels and dramatically reduce hepatic LDLR protein levels, without any observed effects on mRNA, SREBP, or the nuclear-cytoplasmic ratio of SREBP protein (Maxwell KN, Proc. Natl. Acad. Sci. 101 (2004): 7100-7105). Furthermore, mutations in PCSK9 that cause loss of PCSK9 function in mouse models have also been shown to reduce total and LDL-C levels (Cohen, JC, et al., N. Engl. J. Med., 354, 2006, 1264-1272). Thus, the results indicate that modulation of PCSK9 results in reduced LDLR protein levels.

[0005] Genetic deletion of PCSK9 has also been performed in mice. PCSK9 knockout mice exhibit approximately 50% reduction in plasma cholesterol levels and increased sensitivity to statins in lowering plasma cholesterol (Rashid, S., et al., Proc. Natl. Acad. Sci., 2005, 102:5374-5379). Human genetic data strongly support the role of PCSK9 in LDL homeostasis. The association between PCSK9 and plasma LDL-C levels was first demonstrated by the discovery of a PCSK9 missense mutation in patients with an autosomal dominant form of familial hypercholesterolemia (Abifadel, M., et al. Nature, 2003, 34:154-6). Patients carrying PCSK9 gain-of-function alleles have elevated plasma LDL-C levels and increased risk of premature CHD, whereas those carrying PCSK9 loss-of-function alleles have significantly reduced plasma LDL-C and are protected from CHD.

[0006] PCSK9 also contributes to lipoprotein(a) (Lp(a)) metabolism. Lp(a) is a proatherogenic lipoprotein composed of LDL particles covalently bound to apoLp(a). Human genetic studies indicate that Lp(a) is significantly associated with CHD risk. PCSK9 therapeutic antibodies have been shown to significantly reduce Lp(a) levels in patients with hypercholesterolemia. (Desai, NR, et. al., Circulation. 2013, 128(9):962-969; Lambert, G., et. al., Clin. Sci. 2017, 7, 131, 261-268). Patients receiving statin therapy treated with monoclonal antibodies against PCSK9 showed up to a 32% reduction in Lp(a) levels compared to placebo. (Desai NR,et.al.,Circulation.2013,128(9):962-969).

[0007] In addition to its effects on the cardiovascular system, PCSK9 plays an important role in sepsis, a life-threatening condition caused by the body's response to infection. Overexpression of PCSK9 in septic mice has been shown to exacerbate sepsis by increasing inflammation, whereas inhibition of PCSK9 has been shown to reduce mortality. (Dwivedi, DJ, et al., Shock, 2016, 46(6), 672-680) Furthermore, flow cytometry studies in human HepG2 cells have shown that PCSK9 negatively regulates gram-negative glycolipid (LPS) uptake by hepatocytes through modulation of LDLR-mediated bacterial lipid uptake of lipoteichoic acid (LTA) and LPS via an LDL-dependent mechanism. (Grin, PM, et al., Nature, 2018, 8(1):10496) Therefore, inhibiting PCSK9 may treat sepsis by reducing the body's immune response to infection.

[0008] Currently, there are no known small molecule inhibitors of PCSK9. The only known commercially available inhibitor of PCSK9 is an anti-PCSK9 antibody. Therefore, inhibiting PCSK9 with a small molecule inhibitor could be a treatment for a range of diseases, including hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, peripheral arterial disease, vascular inflammation, elevated Lp(a), elevated LDL, triglyceride-rich lipoprotein (TRL), elevated triglycerides, sepsis, xanthomas, and other disorders. For these reasons, there remains a need for novel and potent small molecule inhibitors of PCSK9. Summary of the Invention [Means for solving the problem]

[0009] A first aspect of the present disclosure provides a cyclic polypeptide of formula (I) (SEQ ID NO: 39): [ka] (In the formula, R 1 is H or (C1-C4) alkyl; X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 Shows the connection point to; X 2 is L-Pro or D-Pro; X 3 is L-Arg, D-Arg, L-Ser, D-Ser, L-His, D-His, L-Ala or D-Ala; X 4 are L-Asp, D-Asp, L-Asn, D-Asn, L-Glu, D-Glu, L-Lys, D-Lys, L-Gln, D-Gln, L-Pro, D-Pro, L-Ala, D-Ala, L-(N-Me)Glu or D-(N-Me)Glu; X 5 is L-(N-Me)Ala, D-(N-Me)Ala, L-(N-Me)Glu or D-(N-Me)Glu; X 6 are L-Bip, D-Bip, L-(4-CF3)Phe, D-(4-CF3)Phe, L-(3,4-diCl)Phe, D-(3,4-diCl)Phe, L-(3-F)Phe, D-(3-F)Phe, L-(4-Cl)Phe or D-(4-Cl)Phe; X 7 is L-(N-Me)Ala, D-(N-Me)Ala, L-(N-Me)Phe or D-(N-Me)Phe; X 8 are L-Bip, D-Bip, L-Ser, D-Ser, L-Tyr, D-Tyr, L-(4-CF3)Phe, D-(4-CF3)Phe, L-Ala, D-Ala, L-Phe, D-Phe, L-Val or D-Val; X 9 is L-Thr or D-Thr; X 10 is L-Thr, D-Thr, L-Ser or D-Ser; X 11 is L-Ser, D-Ser, L-Asp, D-Asp, L-Asn, D-Asn, L-Pro, D-Pro, L-Ala, D-Ala, L-Hse or D-Hse; X 12 is L-Val, D-Val, L-Glu or D-Glu; X 13 is L-Phe or D-Phe; where Bip is 4-phenyl-phenylalanine; Hse is homoserine; (4-CF3)Phe is 4-trifluoromethyl-phenylalanine; (3,4-diCl)Phe is 3,4-dichloro-phenylalanine; (3-F)Phe is 3-fluoro-phenylalanine; (4-Cl)Phe is 4-chloro-phenylalanine) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof.

[0010] In one embodiment, the present disclosure provides a polypeptide of formula (I) (SEQ ID NO: 40), wherein: R 1 is H or (C1-C4) alkyl; X 1 is absent or is Gly; X 2 is L-Pro or D-Pro; X 3 is L-Arg, D-Arg, L-Ser, D-Ser, L-His, D-His, L-Ala or D-Ala; X 4 are L-Asp, D-Asp, L-Asn, D-Asn, L-Glu, D-Glu, L-Lys, D-Lys, L-Gln, D-Gln, L-Pro, D-Pro, L-Ala, D-Ala, L-(N-Me)Glu or D-(N-Me)Glu; X 5is L-(N-Me)Ala, D-(N-Me)Ala, L-(N-Me)Glu or D-(N-Me)Glu; X 6 are L-Bip, D-Bip, L-(4-CF3)Phe, D-(4-CF3)Phe, L-(3,4-diCl)Phe, D-(3,4-diCl)Phe, L-(3-F)Phe, D-(3-F)Phe, L-(4-Cl)Phe or D-(4-Cl)Phe; X 7 is L-(N-Me)Ala, D-(N-Me)Ala, L-(N-Me)Phe or D-(N-Me)Phe; X 8 are L-Bip, D-Bip, L-Ser, D-Ser, L-Tyr, D-Tyr, L-(4-CF3)Phe, D-(4-CF3)Phe, L-Ala, D-Ala, L-Phe, D-Phe, L-Val or D-Val; X 9 is L-Thr or D-Thr; X 10 is L-Thr, D-Thr, L-Ser or D-Ser; X 11 is L-Ser, D-Ser, L-Asp, D-Asp, L-Asn, D-Asn, L-Pro, D-Pro, L-Ala, D-Ala, L-Hse or D-Hse; X 12 is L-Val, D-Val, L-Glu or D-Glu; X 13 is L-Phe or D-Phe; where Bip is 4-phenyl-phenylalanine; Hse is homoserine; (4-CF3)Phe is 4-trifluoromethyl-phenylalanine; (3,4-diCl)Phe is 3,4-dichloro-phenylalanine; (3-F)Phe is 3-fluoro-phenylalanine; (4-Cl)Phe is 4-chloro-phenylalanine); or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof.

[0011] Another aspect of the present disclosure relates to a cyclic polypeptide of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment, prevention, amelioration or delay of progression of a PCSK9-mediated disease or disorder, or for use in the treatment, prevention, amelioration or delay of progression of a disease or disorder requiring inhibition of PCSK9 or PCSK9 activity.

[0012] In another aspect, the disclosure relates to the use of a cyclic polypeptide of formula (I) or a pharmaceutically acceptable salt thereof for the treatment, prevention, amelioration, or delay of progression of a PCSK9-mediated disease or disorder, or for the treatment, prevention, amelioration, or delay of progression of a disease or disorder requiring inhibition of PCSK9 or PCSK9 activity.

[0013] Another aspect of the present disclosure relates to the use of a cyclic polypeptide of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment, prevention, amelioration or delay of progression of a PCSK9-mediated disease or disorder, or for the treatment, prevention, amelioration or delay of progression of a disease or disorder requiring inhibition of PCSK9 or PCSK9 activity.

[0014] In another aspect, the present disclosure relates to a method for treating, preventing, ameliorating, or delaying the progression of a PCSK9-mediated disease or disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a cyclic polypeptide of formula (I) according to the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

[0015] Another aspect of the present disclosure relates to a method for treating, preventing, ameliorating, or delaying the progression of a PCSK9-mediated disease or disorder, or a disease or disorder requiring inhibition of PCSK9 or PCSK9 activity, comprising administering to a patient in need thereof a therapeutically effective amount of a cyclic polypeptide of Formula (I) according to the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

[0016] In another aspect, the present disclosure relates to a method of treating, preventing, inhibiting, or eliminating hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, vascular inflammation, xanthomas, peripheral arterial disease, sepsis, elevated Lp(a), elevated LDL, elevated TRL, or elevated triglycerides, comprising administering a therapeutically effective amount of a cyclic polypeptide of Formula (I) or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0017] Another aspect of the present disclosure is a method for (i) lowering Lp(a), (ii) lowering Lp(a) plasma levels, (iii) lowering Lp(a) serum levels, (iv) lowering serum TRL or LDL levels, (v) lowering serum triglyceride levels, (vi) lowering LDL-C, (vii) lowering total plasma apoB concentrations, (viii) lowering LDL apoB, (ix) lowering TRL The present invention relates to a method of (i) lowering Lp(a), (ii) lowering Lp(a) plasma levels, (iii) lowering Lp(a) serum levels, (iv) lowering serum TRL or LDL levels, (v) lowering serum triglyceride levels, (vi) lowering LDL-C, (vii) lowering total plasma apoB concentrations, (viii) lowering LDL apoB, (ix) lowering TRL apoB, or (x) lowering non-HDL-C, comprising administering to a patient in need thereof a therapeutically effective amount of a cyclic polypeptide of formula (I) or a pharmaceutically acceptable salt thereof.

[0018] In another aspect, the present disclosure also relates to a method for (i) lowering LDL-C, (ii) lowering total apolipoprotein B (apoB) levels, (iii) lowering LDL apoB, (iv) lowering TRL apoB, or (v) lowering non-HDL-C, and combinations thereof, in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a cyclic polypeptide of Formula (I) or a pharmaceutically acceptable salt thereof.

[0019] Another aspect of the present disclosure relates to a method for reducing the total plasma concentration of a marker selected from (i) LDL-C, (ii) apoB, (iii) LDL apoB, (iv) TRL apoB, and (v) non-HDL-C, and combinations thereof, in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a cyclic polypeptide of formula (I) or a pharmaceutically acceptable salt thereof.

[0020] In another aspect, the present disclosure relates to a pharmaceutical composition comprising (e.g., a therapeutically effective amount of) a cyclic polypeptide of formula (I) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0021] Another aspect of the present disclosure relates to a pharmaceutical composition comprising (e.g., a therapeutically effective amount of) a cyclic polypeptide of Formula (I) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients, for use in treating a PCSK9-mediated disease or disorder.

[0022] In another aspect, the disclosure relates to a method of modulating PCSK9, comprising administering to a patient in need thereof a cyclic polypeptide of formula (I) or a pharmaceutically acceptable salt thereof.

[0023] Another aspect of the present disclosure relates to a method of inhibiting PCSK9 activity comprising administering to a patient in need thereof a cyclic polypeptide of formula (I) or a pharmaceutically acceptable salt thereof. In another aspect, the present disclosure relates to a method of inhibiting PCSK9 activity comprising administering to a patient in need thereof a cyclic polypeptide of formula (I) or a pharmaceutically acceptable salt thereof.

[0024] In another aspect, the present disclosure relates to a method for treating a PCSK9-mediated disease or disorder, comprising administering to a patient in need of such treatment a therapeutically effective amount of a cyclic polypeptide of formula (I) or a pharmaceutically acceptable salt thereof.

[0025] Another aspect of the present disclosure relates to a method of lowering LDL-C in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a cyclic polypeptide of formula (I) or a pharmaceutically acceptable salt thereof, thereby lowering LDL-C in the patient.

[0026] In another aspect, the present disclosure relates to a cyclic polypeptide of Formula (I), or a pharmaceutically acceptable salt thereof, for use in treating a PCSK9-mediated disease or disorder.

[0027] Another aspect of the present disclosure relates to a cyclic polypeptide of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of a PCSK9-mediated disease or disorder selected from hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, peripheral arterial disease, vascular inflammation, elevated Lp(a), elevated LDL, elevated TRL, elevated triglycerides, sepsis, and xanthomas.

[0028] In another aspect, the disclosure relates to the use of a cyclic polypeptide of Formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a PCSK9-mediated disease or disorder.

[0029] Another aspect of the present disclosure relates to a cyclic polypeptide of Formula (I) or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for treating a disease associated with inhibited PCSK9 activity.

[0030] In another aspect, the present disclosure relates to the use of a cyclic polypeptide of formula (I) or a pharmaceutically acceptable salt thereof in the treatment of a disease associated with inhibited PCSK9 activity.

[0031] In certain aspects, the PCSK9 modulating or inhibiting cyclic polypeptides of the present disclosure can be administered alone or in combination with other compounds, including other PCSK9 modulators or inhibitors or other therapeutic agents.

[0032] Thus, in another aspect, the present disclosure relates to a combination comprising (eg, a therapeutically effective amount of) a cyclic polypeptide of formula (I) or a pharmaceutically acceptable salt thereof and one or more therapeutically active agents.

[0033] 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 disclosure belongs. As used herein, the singular forms also include the plural unless clearly indicated otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice and testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and references mentioned herein are incorporated by reference. References cited herein are not admitted to be prior art to the claimed disclosure. In case of conflict, the present disclosure, including definitions, will control. Furthermore, the materials, methods, and examples are illustrative only and not limiting.

[0034] Other features and advantages of the present disclosure will become apparent from the following detailed description and claims. DETAILED DESCRIPTION OF THE INVENTION

[0035] The present disclosure relates to peptides and compositions capable of modulating the activity of PCSK9. The present disclosure features methods for treating, preventing, or ameliorating a disease or disorder involving PCSK9 by administering a therapeutically effective amount of a cyclic polypeptide of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof to a patient in need of such treatment, prevention, or amelioration. The disclosed methods can be used to treat various PCSK9-dependent diseases and disorders by modulating or inhibiting PCSK9. Inhibition or modulation of PCSK9 provides a novel approach to the treatment, prevention, or amelioration of diseases including, but not limited to, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease (including aortic disease and cerebrovascular disease), peripheral arterial disease, vascular inflammation, elevated Lp(a), elevated LDL, elevated TRL, elevated triglycerides, sepsis, and xanthomas.

[0036] By inhibiting PCSK9, the cyclic polypeptides of the present disclosure are useful for treating hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, peripheral arterial disease, vascular inflammation, elevated Lp(a), elevated LDL, elevated TRL (e.g., elevated VLDL and / or chylomicrons), elevated triglycerides, sepsis, and xanthomas.

[0037] For example, because PCSK9 can no longer bind to the low-density lipoprotein receptor (LDLR) or any other target receptor, the cyclic polypeptide of formula (I) of the present disclosure binds to PCSK9, thereby inhibiting PCSK9 and / or PCSK9 activity. For example, when PCSK9 is blocked, more LDLR is recycled and present on the cell surface to remove LDL-particles from the extracellular fluid. Therefore, blocking PCSK9 can reduce blood LDL-particle concentrations.

[0038] Thus, it is possible that polypeptides of the present disclosure may be useful in the treatment, prevention, amelioration, or delay of progression of PCSK9-mediated diseases or disorders or diseases or disorders in which PCSK9 plays a role, as well as conditions, diseases, and disorders in which modulation of PCSK9 or PCSK9 activity is beneficial.

[0039] Accordingly, it is further possible that cyclic polypeptides of the present disclosure may be useful in the treatment, prevention, amelioration, or delay of progression of diseases or disorders requiring inhibition of PCSK9 or PCSK9 activity.

[0040] Such diseases and disorders include those selected from hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, peripheral arterial disease, vascular inflammation, elevated Lp(a), elevated LDL, elevated TRL (e.g., elevated VLDL and / or chylomicrons), elevated triglycerides, sepsis, and xanthomas.

[0041] Various embodiments of the present disclosure are described herein, and it will be recognized that features specified in each embodiment may be combined with other specified features of other embodiments to provide further embodiments.

[0042] In a first aspect of the present disclosure, the cyclic polypeptide of formula (I) is [ka] and pharmaceutically acceptable salts, hydrates, solvates, stereoisomers and tautomers thereof, wherein R 1 , X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 and X 13 is as described herein above).

[0043] Details of the present disclosure are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, exemplary methods and materials are described here. Other features, objects, and advantages of the present disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms include the plural unless expressly indicated otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited herein are incorporated by reference in their entirety.

[0044] Definitions of terms and conventions used Terms not specifically defined herein shall be given the meaning that would be given to them by one of ordinary skill in the art in light of this disclosure and content. However, as used in this specification and the appended claims, unless otherwise specified, the following terms have the meanings indicated and the following conventions are to be adhered to.

[0045] Chemical Nomenclature, Terminology and Conventions Unless otherwise specified, conventional definitions of terms and conventional stable atom valences are presumed and achieved in all formulas and groups.

[0046] The articles "a" and "an" are used in this disclosure to refer to one or to more than one (e.g., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0047] The term "and / or" is used in this disclosure to mean either "and" or "or," unless otherwise specified.

[0048] "Alkyl" means a straight or branched chain saturated hydrocarbon containing from 1 to 12 carbon atoms. Examples of (C1-C6) alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.

[0049] As used herein, the terms "polypeptide" and "peptide" are used interchangeably to refer to two or more amino acids linked together. Except for the abbreviations for rare or unnatural amino acids set forth in Table 1 below, art-recognized three-letter or one-letter abbreviations are used to designate the amino acid residues that make up the peptides and polypeptides of the present disclosure. If preceded by a "D", the amino acid is a D-amino acid. If preceded by an "L", the amino acid is an L-amino acid. If the one-letter abbreviation is capitalized, it refers to an L-amino acid. If the one-letter abbreviation is lowercase, it refers to a D-amino acid. Groups or strings of amino acid abbreviations are used to designate peptides. Peptides are designated with the N-terminus on the left, and sequences are written from N- to C-terminus.

[0050] Any of the amino acid residues of formula (I) listed above or its related formulas described herein, such as formulas (I), (II), (III), (IV), (V) and (VI), may be conservatively substituted, provided that the peptides or polypeptides of the disclosure still retain their functional activity and structural properties (e.g., extended half-life, protection from degradation, structural constraints). Principles and examples of acceptable conservative amino acid substitutions are further described herein.

[0051] The peptides of the present disclosure contain unnatural amino acids (ie, compounds that do not occur in nature) and other amino acid analogs as known in the art, which may alternatively be used.

[0052] Those skilled in the art will recognize that various amino acid substitutions, e.g., conservative amino acid substitutions, do not necessarily reduce the activity and can be made in any order in the cyclic polypeptides described herein. As used herein, "an amino acid commonly used as a substitute therefor" includes conservative substitutions (i.e., substitution with an amino acid of equivalent chemical characteristics). For conservative substitutions, nonpolar (hydrophobic) amino acids include alanine, leucine, isoleucine, valine, glycine, proline, phenylalanine, tryptophan, and methionine. Polar (hydrophilic), neutral amino acids include serine, threonine, cysteine, tyrosine, asparagine, and glutamine. Positively charged (basic) amino acids include arginine, lysine, and histidine. Negatively charged (acidic) amino acids include aspartic acid and glutamic acid. Examples of amino acid substitutions include substituting an L-amino acid with its corresponding D-amino acid, substituting cysteine ​​with homocysteine ​​or other unnatural amino acids with thiol-containing side chains, substituting lysine with homolysine, diaminobutyric acid, diaminopropionic acid, ornithine or other unnatural amino acids with amino-containing side chains, or substituting alanine with norvaline.

[0053] The term "amino acid," as used herein, refers to all natural amino acids, unnatural amino acids, amino acid analogs and amino acid mimetics that function similarly to the natural amino acids, and their D and L stereoisomers, provided that their structure allows for such stereoisomeric forms. Amino acids are referred to herein by their name, by any of their commonly known three letter symbols, or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission.

[0054] The term "natural" refers to a material that is found in nature and has not been manipulated by man. Similarly, "non-naturally occurring," "non-natural," and the like, as used herein, refer to a material that is not found in nature or that has been structurally modified or synthesized by man. The term "naturally occurring" when used in conjunction with an amino acid refers to the 20 conventional amino acids (i.e., alanine (A or Ala), cysteine ​​(C or Cys), aspartic acid (D or Asp), glutamic acid (E or Glu), phenylalanine (F or Phe), glycine (G or Gly), histidine (H or His), isoleucine (I or Ile), lysine (K or Lys), leucine (L or Leu), methionine (M or Met), asparagine (N or Asn), proline (P or Pro), glutamine (Q or Gln), arginine (R or Arg), serine (S or Ser), threonine (T or Thr), valine (V or Val), tryptophan (W or Trp), and tyrosine (Y or Tyr)).

[0055] The terms "non-naturally occurring amino acid" and "unnatural amino acid," as used herein, are intended interchangeably to refer to amino acid structures, whether the same or different, that cannot be produced biosynthetically in any organism using unmodified or modified genes from any organism. These include, but are not limited to, modified amino acids and / or amino acid analogs that are not one of the 20 naturally occurring amino acids, selenocysteine, pyrrolysine (Pyl), or pyrroline-carboxy-lysine (e.g., Pcl as described in WO 2010 / 48582).

[0056] Modified encoded amino acids include hydroxyproline, gamma-carboxyglutamate, O-phosphoserine, azetidinecarboxylic acid, 2-aminodipic acid, 3-aminodipic acid, beta-alanine, aminopropionic acid, 2-aminobutyric acid, 4-aminobutyric acid, 6-aminocaproic acid, 2-aminoheptanoic acid, 2-aminoisobutyric acid, 3-aminoisobutyric acid, 2-aminopimelic acid, tertiary butylglycine, 2,4-diaminoisobutyric acid, desmosine, 2,2'-diaminopimelic acid, and 2,3-diaminoproline. Examples of amino acids include, but are not limited to, pionic acid, N-ethylglycine, N-methylglycine, N-ethylasparagine, homoproline, hydroxylysine, allo-hydroxylysine, 3-hydroxyproline, 4-hydroxyproline, isodesmosine, allo-isoleucine, N-methylalanine, N-methylglycine, N-methylisoleucine, N-methylpentylglycine, N-methylvaline, naphthalanine, norvaline, norleucine, ornithine, pentylglycine, pipecolic acid, and thioproline. The term "amino acid" also includes naturally occurring amino acids that are metabolic products in certain organisms but are not encoded by the genetic code for incorporation into proteins. Such amino acids include, but are not limited to, ornithine, D-ornithine, and D-arginine.

[0057] A peptide is defined herein as an organic compound containing two or more amino acids covalently linked by peptide bonds. Peptides may be referred to in terms of the number of constituent amino acids, i.e., dipeptides, or dimers contain two amino acid residues, tripeptides or trimers contain three, etc. Peptides containing 10 or fewer amino acids may be called oligopeptides, while those with more than 10 amino acid residues are polypeptides.

[0058] The term "peptide," as used herein, means two or more amino acids linked together via a peptide bond.

[0059] [Table 1]

[0060] [Table 2]

[0061] Salts, Prodrugs, Derivatives and Solvates Terminology and Conventions "Prodrug" or "prodrug derivative" refers to a covalently bonded derivative or carrier of a parent polypeptide or active drug substance that undergoes at least some biotransformation before exhibiting its pharmacological effect(s). Generally, such prodrugs have metabolically cleavable groups that are rapidly converted in vivo to yield the parent polypeptide, e.g., by hydrolysis in blood, and generally include ester and amide analogs of the parent polypeptide. The prodrugs are formulated for improved chemical stability, improved patient acceptance and compliance, improved bioavailability, extended duration of action, improved organ selectivity, improved formulation (e.g., improved water solubility), and / or reduced side effects (e.g., toxicity). Generally, the prodrug itself has reduced or no biological activity and is stable under normal conditions.Prodrugs can be readily prepared from the parent polypeptide using methods known in the art, such as those described in: A Textbook of Drug Design and Development, Krogsgaard-Larsen and H. Bundgaard (eds.), Gordon & Breach, 1991, especially Chapter 5: "Design and Applications of Prodrugs"; Design of Prodrugs, H. Bundgaard (ed.), Elsevier, 1985; Prodrugs: Topical and Ocular Drug Delivery, KB Sloan (ed.), Marcel Dekker, 1998; Methods in Enzymology, K. Widder et al. (eds.), Vol. 42, Academic Press, 1985, especially pp. 309-396; Burger's Medicinal Chemistry and Drug Discovery, 5th Ed., M. Wolff (ed.), John Wiley & Sons, 1985. Sons, 1995, especially Vol. 1 and pp. 172-178 and pp. 949-982; Pro-Drugs as Novel Delivery Systems, T. Higuchi and V. Stella (eds.), Am. Chem. Soc., 1975; Bioreversible Carriers in Drug Design, EB Roche (ed.), Elsevier, 1987 (each of which is incorporated herein by reference in its entirety).

[0062] As used herein, "pharmaceutically acceptable prodrugs" means prodrugs of the polypeptides of the present disclosure that are suitable, within the scope of sound medical judgment, for use in contact with the tissues of humans and lower animals, and that are effective for their intended use without excessive toxicity, irritation, allergic response, or the like, at a reasonable benefit / risk ratio, and preferably in zwitterionic form.

[0063] "Salt" refers to the ionic form of the parent polypeptide or the reaction product of the parent compound with a suitable acid or base to make an acid or base salt. Salts of the polypeptides of the present disclosure can be synthesized from a parent polypeptide containing a basic or acidic moiety by conventional chemical methods. Generally, salts are prepared by reacting the free base or free acidic parent polypeptide with a stoichiometric or excess amount of the desired salt-forming inorganic or organic acid or base in a suitable solvent or various combinations of solvents.

[0064] "Pharmaceutically acceptable salt" refers to a salt of a polypeptide of the present disclosure that is suitable, within the scope of sound medical judgment, for use in contact with the tissues of humans and lower animals, without undue toxicity, irritation, allergic response, or the like, commensurate with a reasonable benefit / risk ratio, generally soluble or dispersible in water or oil, and effective for its intended use. The term includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. Since the polypeptides of the present disclosure are useful in both free base and salt form, in practice, use of the salt form amounts to use of the base form. Lists of suitable salts are provided, for example, in S. M. Birge et al., J. Pharm. Sci., 1977, 66, pp. 1-19, which is hereby incorporated by reference in its entirety.

[0065] Pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, nitric acid, phosphoric acid, and the like, and organic acids such as acetic acid, trichloroacetic acid, trifluoroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 2-acetoxybenzoic acid, butyric acid, camphoric acid, camphorsulfonic acid, cinnamic acid, citric acid, digluconic acid, ethanesulfonic acid, glutamic acid, glycolic acid, glycerophosphate, hemisulfonic acid, "Acetone" refers to salts formed with acids such as 2-hydroxyethanesulfonic acid (isethionic acid), lactic acid, maleic acid, hydroxymaleic acid, malic acid, malonic acid, mandelic acid, mesitylenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, nicotinic acid, 2-naphthalenesulfonic acid, oxalic acid, pamoic acid, pectinic acid, phenylacetic acid, 3-phenylpropionic acid, picric acid, pivalic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, tartaric acid, p-toluenesulfonic acid, undecanoic acid, and the like, which retain the biological effectiveness and properties of the free base and which are not biologically or otherwise undesirable.

[0066] "Pharmaceutically acceptable base addition salts" refers to salts formed with inorganic bases, such as hydroxides, carbonates, or bicarbonates of ammonia or ammonium or metal cations, such as sodium, potassium, lithium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum, which retain the biological effectiveness and properties of the free acids and are not biologically or otherwise undesirable. Particularly preferred are the ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable non-toxic organic bases include salts derived from primary, secondary, and tertiary amines, quaternary amine compounds, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, isopropylamine, tripropylamine, tributylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, and the like. , histidine, caffeine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, tetramethylammonium compounds, tetraethylammonium compounds, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, N,N'-dibenzylethylenediamine, polyamine resins, etc. Particularly preferred non-toxic organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0067] "Solvate" refers to a complex of variable stoichiometry formed by a solute, such as a polypeptide of Formula (I), and a solvent, such as water, ethanol, or acetic acid. This physical association may involve varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances, a solvate is capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Generally, such solvents selected for the purposes of this disclosure do not interfere with the biological activity of the solute. Solvates encompass both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, methanolates, and the like.

[0068] "Hydrate" means a solvate where the solvent molecule is water.

[0069] Although specifically pharmaceutically acceptable forms thereof are not explicitly stated or indicated, the polypeptides of the present disclosure, as discussed below, include the free base or acid, their salts, solvates, and prodrugs, and may contain oxidized sulfur atoms or quaternary nitrogen atoms in their structure. Such forms, particularly pharmaceutically acceptable forms, are intended to be encompassed by the appended claims.

[0070] Isomers Terminology and Conventions "Isomers" means compounds or polypeptides having the same number and kind of atoms, and hence the same molecular weight, but differing with regard to the arrangement or configuration of the atoms in space. The term includes stereoisomers and geometric isomers.

[0071] "Stereoisomer" or "optical isomer" refers to a stable isomer that has at least one chiral atom or restricted rotation resulting in a perpendicular plane of asymmetry (e.g., certain biphenyl, allene, and spiro compounds) and is capable of rotating plane-polarized light. Because asymmetric centers and other chemical structures exist in the polypeptides of the present disclosure that can give rise to stereoisomerism, the present disclosure contemplates stereoisomers and mixtures thereof. The polypeptides of the present disclosure and their salts contain asymmetric carbon atoms and therefore can exist as single stereoisomers, racemates, and as mixtures of enantiomers and diastereomers. Typically, such compounds or polypeptides are prepared as racemic mixtures. However, if desired, such compounds or polypeptides can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. As discussed in more detail below, individual stereoisomers of a compound or polypeptide are prepared by synthesis from optically active starting materials containing the desired chiral center, or by preparing a mixture of enantiomeric products followed by separation or resolution, e.g., by conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, use of chiral resolving agents, or direct separation of enantiomers on a chiral chromatographic column. Starting compounds or amino acids of particular stereochemistry are either commercially available or are made by the methods described below and resolved by techniques well known in the art.

[0072] "Enantiomers" means a pair of stereoisomers that are non-superimposable mirror images of each other.

[0073] "Diastereoisomers" or "diastereomers" mean optical isomers that are not mirror images of one another.

[0074] A "racemic mixture" or "racemate" means a mixture containing equal amounts of individual enantiomers.

[0075] "Non-racemic mixture" means a mixture containing unequal portions of individual enantiomers.

[0076] Some of the polypeptides of the present disclosure can exist in multiple tautomeric forms, and as noted above, the polypeptides of the present disclosure include all such tautomeric forms.

[0077] It is well known in the art that the biological and pharmacological activity of a compound or polypeptide is sensitive to the stereochemistry of the compound or polypeptide. Thus, for example, enantiomers often exhibit significantly different biological activities, including differences in pharmacokinetic properties, including metabolism, protein binding, etc., and pharmacological properties, including the type and degree of activity exhibited, toxicity, etc. Thus, one skilled in the art will recognize that one enantiomer may be more active or exhibit beneficial effects when enriched relative to or separated from other enantiomers. Furthermore, one skilled in the art will know, from this disclosure and knowledge of the prior art, how to separate, enrich, or selectively prepare enantiomers of the polypeptides of the present disclosure.

[0078] Thus, while a racemic form of a drug may be used, it is often less effective than administering an equal amount of enantiomerically pure drug; in fact, one enantiomer may be pharmacologically inactive and merely serve as a simple diluent. For example, ibuprofen was previously administered as a racemate, but only the S-isomer of ibuprofen has been shown to be effective as an anti-inflammatory agent (however, in the case of ibuprofen, the R-isomer is inactive but is converted to the S-isomer in vivo, and therefore the drug's racemic form acts less rapidly than the pure S-isomer). Furthermore, the pharmacological activity of enantiomers may have different biological activities. For example, S-penicillamine is a treatment for chronic arthritis, while R-penicillamine is toxic. In fact, some purified enantiomers have advantages over racemates, as the purified individual isomers have been reported to have faster transdermal penetration rates compared to the racemic mixture. See U.S. Patent Nos. 5,114,946 and 4,818,541.

[0079] Therefore, if one enantiomer is more pharmacologically active, less toxic, or exhibits more favorable disposition in the body than the other enantiomer, it may be therapeutically beneficial to administer that enantiomer preferentially. In this way, the patient undergoing treatment will be exposed to a lower total dose of the drug and also to lower doses of potentially harmful enantiomers or inhibitors of the other enantiomers.

[0080] The preparation of pure enantiomers, or mixtures of a desired enantiomeric excess (ee) or enantiomeric purity, is accomplished by one or more of many methods: (a) separation or resolution of enantiomers, or (b) enantioselective synthesis, or a combination thereof, known to those skilled in the art. These resolution methods generally rely on chiral recognition and include, for example, chromatography using chiral stationary phases, enantioselective host-guest complexation, resolution or synthesis using chiral auxiliaries, enantioselective synthesis, enzymatic and non-enzymatic kinetic resolution, or spontaneous enantioselective crystallization. Such methods are generally disclosed in Chiral Separation Techniques: A Practical Approach (2nd Ed.), G. Subramanian (ed.), Wiley-VCH, 2000; T.E. Beesley and R.P.W. Scott, Chiral Chromatography, John Wiley & Sons, 1999; and Satinder Ahuja, Chiral Separations by Chromatography, Am. Chem. Soc., 2000. Furthermore, there are similarly well-known methods for quantifying enantiomeric excess or purity, such as GC, HPLC, CE or NMR, and methods for determining absolute configuration and conformation, such as CD ORD, X-ray crystallography or NMR.

[0081] In general, unless a specific stereochemistry or isomeric form is specifically indicated in the compound name or structure, all tautomeric and isomeric forms and mixtures of a chemical structure or compound are intended, whether as individual geometric or stereoisomers or racemic or non-racemic mixtures.

[0082] Medication Administration and Treatment Terms and Conventions A "patient" or "subject" is a mammal, such as a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon, or rhesus monkey. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

[0083] The terms "pharmaceutically effective amount" or "therapeutically effective amount" or "effective amount" refer to an amount of a polypeptide according to the present disclosure that, when administered to a patient in need thereof, is sufficient to effect treatment for a disease state, condition, or disorder for which the polypeptide is useful. Such an amount is sufficient to elicit the biological or medical response in a tissue, system, or patient that is sought by the researcher or clinician. The amount of a polypeptide according to the present disclosure that constitutes a therapeutically effective amount will vary depending on factors such as the polypeptide and its biological activity, the composition used for administration, the time of administration, the route of administration, the rate of excretion of the polypeptide, the duration of treatment, the type and severity of the disease state or disorder being treated, drugs used in combination or concomitantly with the polypeptide of the present disclosure, and the patient's age, weight, general health, sex, and diet. Such a therapeutically effective amount can be routinely determined by one of ordinary skill in the art having regard to their own knowledge, the prior art, and this disclosure.

[0084] As used herein, the term "pharmaceutical composition" refers to a polypeptide of the present disclosure or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, together with at least one pharmaceutically acceptable carrier, in a form suitable for oral or parenteral administration.

[0085] "Carrier" encompasses carriers, excipients, and diluents that are involved in transporting or carrying a pharmaceutical agent from one organ or part of the body of a subject to another organ or part of the body, and refers to a substance, composition, or vehicle, such as a liquid or solid injectable, diluent, excipient, solvent, or encapsulating material.

[0086] "Combination" refers to either a fixed combination in one unit dosage form or a combined administration, wherein a cyclic polypeptide of the present disclosure and at least one combination partner (e.g., another drug, as described below, also referred to as a "therapeutic agent" or "co-administered agent") can be administered independently at the same time or separately within a time interval, particularly one that allows the combination partners to exhibit a beneficial effect from the simultaneous action of the therapeutic agents. This beneficial effect of the combination includes, but is not limited to, a cooperative, e.g., synergistic, effect and / or pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents, or any combination thereof. In one embodiment, the administration of the therapeutic agents in the combination occurs over a defined period of time (e.g., minutes, hours, days, or weeks, depending on the combination selected).

[0087] The single components may be packaged together in a kit or individually packaged. One or both of the components (e.g., powder or liquid) may be reconstituted or diluted to the desired dosage before administration. The terms "co-administration" or "administration in combination," etc., as used herein, are meant to encompass the administration of selected combination partners to a single subject (e.g., patient) in need thereof, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.

[0088] As used herein, the term "pharmaceutical combination" refers to a product resulting from the mixing or combining of multiple therapeutic agents, and includes both fixed and non-fixed combinations of therapeutic agents. The term "fixed combination" means that the therapeutic agents, e.g., a cyclic polypeptide of the present disclosure and a combination partner, are both administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the therapeutic agents, e.g., a cyclic polypeptide of the present disclosure and a combination partner, are both administered to a patient as separate entities, either simultaneously, at the same time, or sequentially, without specific time restrictions, such that such administration provides therapeutically effective levels of the two compounds in the patient's body. The latter also applies to cocktail therapy, e.g., the administration of three or more therapeutic agents.

[0089] A subject (preferably a human) is "in need" of treatment if such subject would benefit biologically, medically, or in quality of life from such treatment.

[0090] The terms "PCSK9" or "proprotein convertase subtilisin / kexin type 9" refer interchangeably to a naturally occurring human proprotein convertase belonging to the proteinase K subfamily of the secreted subtilase family. PCSK9 is synthesized as a soluble proenzyme that undergoes autocatalytic intermolecular processing in the endoplasmic reticulum and is thought to function as a proprotein convertase. PCSK9 contributes to cholesterol homeostasis and may contribute to the differentiation of cortical neurons. Mutations in the PCSK9 gene are a cause of autosomal dominant familial hypercholesterolemia. (Burnett and Hooper, Clin. Biochem. Rev. (2008) 29(1):11-26).

[0091] As used herein, the terms "inhibit," "inhibition," or "inhibiting" refer to the alleviation or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0092] As used herein, the terms "treat," "treating," or "treatment" of any disease or disorder refers to alleviating or ameliorating the disease or disorder (i.e., slowing or halting the progression of the disease or at least one of its clinical symptoms); or alleviating or ameliorating at least one physical parameter or biomarker (including those that may not be discernible to the patient) associated with the disease or disorder.

[0093] As used herein, the terms "prevent," "preventing," or "prevention" in reference to any disease or disorder refers to the prophylactic treatment of the disease or disorder; or the delay in the onset or progression of the disease or disorder.

[0094] "Pharmaceutically acceptable" means that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients comprising the formulation and / or the mammal being treated therewith.

[0095] "Disorder" means, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.

[0096] "Administer," "administering," or "administration" means either administering the disclosed polypeptides or pharmaceutically acceptable salts or compositions of the disclosed polypeptides directly to a subject, or administering to a subject a prodrug derivative or analog of the polypeptides or a pharmaceutically acceptable salt or composition of the polypeptides, which can form an equivalent amount of active polypeptide in the subject's body.

[0097] "Prodrug" means a polypeptide that is convertible in vivo by metabolic means (eg, by hydrolysis) to the disclosed polypeptide.

[0098]

[0023] (Unless specifically stated otherwise) "polypeptides of the disclosure," "polypeptides of Formula (I)," "polypeptides of the disclosure," "cyclic polypeptides of the disclosure," "cyclic polypeptides of Formula (I)," "cyclic polypeptides of the disclosure," and equivalent expressions refer to polypeptides of Formulas (I), (II), (III), (IV), (V), and (VI) as set forth herein, including their tautomers, prodrugs, salts, particularly pharmaceutically acceptable salts thereof, and solvates and hydrates (where the context so permits), as well as all stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers, and radiolabeled polypeptides (including deuterium substitutions), and inherently formed moieties (e.g., solvates and / or hydrates). For purposes of the present disclosure, solvates and hydrates are generally considered compositions. Generally, and preferably, polypeptides of the disclosure and formulas depicting polypeptides of the disclosure are understood to include only stable compounds thereof and to exclude unstable polypeptides, even though unstable polypeptides may be considered literally encompassed by the polypeptide formula. Similarly, reference to intermediates, whether or not they themselves are claimed, is intended to encompass their salts and solvates, so far as the context so permits. For clarity, specific examples, where the context so permits, may be given in the text, but these examples are purely illustrative and are not intended to exclude other examples, where the context so permits.

[0099] By "stable polypeptide" or "stable structure" is meant a polypeptide that is robust enough to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an effective therapeutic or diagnostic agent. For example, polypeptides that have "dangling valences" or are carbanions are not polypeptides contemplated by the present disclosure.

[0100] In certain embodiments, the term "about" or "approximately" means within 20%, preferably within 10%, and more preferably within 5% of a given value or range.

[0101] As used herein, a "modulator of PCSK9" refers to a peptide or polypeptide that is capable of modulating the biological activity or function of PCSK9 and / or downstream pathways mediated by PCSK9 activity.

[0102] As used herein, an "inhibitor of PCSK9" refers to a peptide or polypeptide capable of inhibiting PCSK9 biological activity or function and / or downstream pathways mediated by PCSK9 signaling. Inhibitors of PCSK9 activity include polypeptides that block, attenuate, suppress, or reduce (to any extent, including significantly) PCSK9 biological activity, including downstream pathways mediated by PCSK9 activity.

[0103] As used herein, the terms "disorders or diseases responsive to the inhibition of PCSK9," "disorders and conditions responsive to the inhibition of PCSK9," "disorders and conditions responsive to the inhibition of PCSK9 activity," "disorders responsive to the inhibition of PCSK9," "disorders responsive to the inhibition of PCSK9 activity," "disorders contributed to by PCSK9," and the like include hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease (including aortic disease and cerebrovascular disease), peripheral arterial disease, vascular inflammation, elevated Lp(a), elevated LDL, elevated TRL, elevated triglycerides, sepsis, and xanthomas.

[0104] As used herein, "inhibition of PCSK9 activity" or "inhibition of PCSK9" refers to a decrease in PCSK9 activity, for example, by administration of the peptides and polypeptides of the present disclosure.

[0105] The term "hypercholesterolemia" or "dyslipidemia" includes, for example, familial and non-familial hypercholesterolemia. Familial hypercholesterolemia (FH) is an autosomal dominant disorder characterized by elevated serum cholesterol bound to low-density lipoprotein (LDL). Familial hypercholesterolemia includes both heterozygous FH and homozygous FH. Hypercholesterolemia (or dyslipidemia) is the presence of elevated levels of cholesterol in the blood. This is in the form of hyperlipidemia (elevated levels of lipids in the blood) and hyperlipoproteinemia (elevated levels of lipoproteins in the blood).

[0106] Hyperlipidemia is an elevation of lipids in the bloodstream. These lipids include cholesterol, cholesterol esters, phospholipids, and triglycerides. Hyperlipidemia includes, for example, types I, IIa, IIb, III, IV, and V.

[0107] Hypertriglyceridemia refers to high blood levels of triglycerides. Elevated triglyceride levels, even in the absence of hypercholesterolemia, are associated with atherosclerosis and predispose to cardiovascular disease.

[0108] "Sitosterolemia" or "phytosterolemia" is a rare, autosomal recessively inherited disorder of lipid metabolism characterized by excessive absorption of sitosterol from the gastrointestinal tract and reduced biliary excretion of dietary sterols (i.e., leading to hypercholesterolemia, tendon and tuberous xanthomas, and premature onset of atherosclerosis) and altered cholesterol synthesis.

[0109] "Atherosclerosis" includes hardening of the arteries associated with the accumulation of fatty substances, cholesterol, cellular waste products, calcium, and fibrin in the inner lining of the arteries. The resulting buildup is called plaque.

[0110] "Atherosclerosis" or "arteriosclerotic vascular disease (ASVD)" is a specific form of arteriosclerosis involving thickening, hardening, and loss of elasticity of the arterial wall as a result of the invasion and accumulation of white blood cells, which contain both live, activated white blood cells (inflammatory products) and remnants of dead cells, including cholesterol and triglycerides. Thus, atherosclerosis is a syndrome that affects arterial blood vessels due to a chronic inflammatory response of white blood cells in the arterial wall.

[0111] "Coronary heart disease," also known as atherosclerotic cardiovascular disease, coronary heart disease, or ischemic heart disease, is the most common type of heart disease and causes heart attacks. This disease is caused by plaque that builds up along the inner walls of the heart's arteries, narrowing the artery's lumen and reducing blood flow to the heart.

[0112] "Xanthomas" are a skin manifestation of lipidosis in which lipids accumulate in large foam cells within the skin. Xanthomas are associated with hyperlipidemia.

[0113] The term "elevated Lp(a) concentration" as used herein refers to a serum Lp(a) concentration greater than 30 mg / dL (75 nmol / L). "Elevated serum Lp(a)" means a serum Lp(a) level greater than about 14 mg / dL. In certain embodiments, a patient is considered to have elevated serum Lp(a) if the serum Lp(a) level measured in the patient is greater than about 15 mg / dL, about 20 mg / dL, about 25 mg / dL, about 30 mg / dL, about 35 mg / dL, about 40 mg / dL, about 45 mg / dL, about 50 mg / dL, about 60 mg / dL, about 70 mg / dL, about 80 mg / dL, about 90 mg / dL, about 100 mg / dL, about 20 mg / dL, about 140 mg / dL, about 150 mg / dL, about 180 mg / dL, or about 200 mg / dL. Serum Lp(a) levels can be measured in a patient after a meal. In some embodiments, Lp(a) levels are measured after a period of fasting (e.g., after 8 hours, 10 hours, 12 hours, or more of fasting). Although any clinically acceptable diagnostic method may be used in the context of the present disclosure, representative methods for measuring serum Lp(a) in patients include, but are not limited to, immunoturbidimetry, ELISA, nephelometry, immunoturbidimetry, and dissociation-enhanced lanthanide fluorescent immunoassay.

[0114] "Elevated triglyceride levels" or "ETL" means any degree of triglyceride level that is determined to be undesirable or targeted for regulation.

[0115] "Sepsis" is a systemic response characterized by arterial hypotension, metabolic acidosis, decreased systemic vascular resistance, tachypnea, and organ dysfunction. Sepsis can result from septicemia (i.e., organisms, their metabolic end products, or toxins in the bloodstream), including bacteremia (i.e., bacteria in the blood) and toxemia (i.e., toxins in the blood), including endotoxemia (i.e., endotoxins in the blood). The term "sepsis" also encompasses fungemia (i.e., fungi in the blood), viremia (i.e., viruses or virus particles in the blood), and parasitemia (i.e., parasitic or protozoan parasites in the blood). Thus, sepsis and septic shock (acute circulatory failure due to sepsis, often associated with multiple organ failure and high mortality) can be caused by many organisms.

[0116] Specific embodiments of the polypeptides of formula (I) The present disclosure relates to polypeptides or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof capable of modulating PCSK9, which are useful for treating diseases and disorders associated with modulation of the PCSK9 protein or enzyme. In another embodiment, the present disclosure relates to polypeptides or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof capable of inhibiting PCSK9, which are useful for treating diseases and disorders associated with inhibition of the PCSK9 protein or enzyme. The present disclosure further relates to polypeptides or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof useful for inhibiting PCSK9.

[0117] In one embodiment, the compound of formula (I) has formula (II): Formula (II) (SEQ ID NO: 44): [ka] and the structures of its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers and tautomers.

[0118] In another embodiment, the polypeptide of formula (I) has formula (III) (SEQ ID NO: 45): [ka] and the structures of its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers and tautomers.

[0119] In another embodiment, the polypeptide of formula (I) has formula (IV) (SEQ ID NO: 46): [ka] and the structures of its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers and tautomers.

[0120] In another embodiment, the polypeptide of formula (I) has formula (V) (SEQ ID NO: 47): [ka] and the structures of its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers and tautomers.

[0121] In another embodiment, the polypeptide of formula (I) has formula (VI) (SEQ ID NO: 48): [ka] and the structures of its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers and tautomers.

[0122] In some embodiments of the above formulas (i.e., Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), and / or Formula (VI)), R 1 is H or (C1-C3) alkyl. In another embodiment, R 1 is methyl or ethyl. In another embodiment, R 1 is H. In another embodiment, R 1 is H, methyl or ethyl.

[0123] In some embodiments of the above formula, X 1 is absent or is Gly. 1 is absent, Gly-L-Lys* or Gly-D-Lys*. 1 is absent, Gly or Gly-L-Lys*. 1 is absent, Gly or Gly-D-Lys*. 1 is Gly-L-Lys* or Gly-D-Lys*. 1 is Gly. In another embodiment, X 1 does not exist.

[0124] In some embodiments of the above formula, X 2 is D-Pro. In another embodiment, X 2 is L-Pro.

[0125] In some embodiments of the above formula, X 3 is D-Arg, D-Ser, D-His, or D-Ala. 3 is L-Arg, L-Ser, L-His, or L-Ala. 3 is L-Arg, L-Ser, or L-His. 3 is L-Arg, L-His, or L-Ala. 3 is L-Ser, L-His, or L-Ala. 3 is L-His or L-Ala. 3 is L-Arg or L-Ser. 3 is L-Ser or L-Ala. 3 is L-Arg or L-Ala. 3 is L-Arg, L-Ser or L-Ala.

[0126] In some embodiments of the above formula, X 4 is D-Asp, D-Asn, D-Glu, D-Lys, D-Gln, D-Pro, D-Ala, or D-(N-Me)Glu. 4 is L-Asp, L-Asn, D-Asn, L-Glu, D-Glu, L-Lys, D-Lys, L-Gln, D-Gln, L-Pro, D-Pro, L-Ala, D-Ala, L-(N-Me)Glu, or D-(N-Me)Glu. 4 is L-Asp, D-Asp, L-Asn, L-Glu, D-Glu, L-Lys, D-Lys, L-Gln, D-Gln, L-Pro, D-Pro, L-Ala, D-Ala, L-(N-Me)Glu, or D-(N-Me)Glu. 4 is L-Asp, D-Asp, L-Asn, D-Asn, L-Glu, L-Lys, D-Lys, L-Gln, D-Gln, L-Pro, D-Pro, L-Ala, D-Ala, L-(N-Me)Glu, or D-(N-Me)Glu. 4 is L-Asp, D-Asp, L-Asn, D-Asn, L-Glu, D-Glu, L-Lys, L-Gln, D-Gln, L-Pro, D-Pro, L-Ala, D-Ala, L-(N-Me)Glu, or D-(N-Me)Glu. 4 is L-Asp, D-Asp, L-Asn, D-Asn, L-Glu, D-Glu, L-Lys, D-Lys, L-Gln, L-Pro, D-Pro, L-Ala, D-Ala, L-(N-Me)Glu, or D-(N-Me)Glu. 4 is L-Asp, D-Asp, L-Asn, D-Asn, L-Glu, D-Glu, L-Lys, D-Lys, L-Gln, D-Gln, L-Pro, L-Ala, D-Ala, L-(N-Me)Glu or D-(N-Me)Glu.

[0127] In another embodiment, X 4is L-Asp, D-Asp, L-Asn, D-Asn, L-Glu, D-Glu, L-Lys, D-Lys, L-Gln, D-Gln, L-Pro, D-Pro, L-Ala, L-(N-Me)Glu, or D-(N-Me)Glu. 4 is L-Asp, D-Asp, L-Asn, D-Asn, L-Glu, D-Glu, L-Lys, D-Lys, L-Gln, D-Gln, L-Pro, D-Pro, L-Ala, D-Ala, or L-(N-Me)Glu. 4 is L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu. 4 is L-Asp, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu. 4 is L-Asp, L-Asn, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu. 4 is L-Asp, L-Asn, L-Glu, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu. 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Pro, L-Ala, or L-(N-Me)Glu. 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Ala, or L-(N-Me)Glu. 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, or L-(N-Me)Glu. 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, or L-Ala. 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu.

[0128] In some embodiments of the above formula, X5 is D-(N-Me)Ala, L-(N-Me)Glu, or D-(N-Me)Glu. 5 is L-(N-Me)Ala, L-(N-Me)Glu, or D-(N-Me)Glu. 5 is L-(N-Me)Ala, D-(N-Me)Ala, or D-(N-Me)Glu. 5 is L-(N-Me)Ala, D-(N-Me)Ala, or L-(N-Me)Glu. 5 is D-(N-Me)Ala or D-(N-Me)Glu. 5 is L-(N-Me)Ala or L-(N-Me)Glu.

[0129] In some embodiments of the above formula, X 6 is D-Bip, L-(4-CF3)Phe, D-(4-CF3)Phe, L-(3,4-diCl)Phe, D-(3,4-diCl)Phe, L-(3-F)Phe, D-(3-F)Phe, L-(4-Cl)Phe or D-(4-Cl)Phe. 6 is L-Bip, L-(4-CF3)Phe, D-(4-CF3)Phe, L-(3,4-diCl)Phe, D-(3,4-diCl)Phe, L-(3-F)Phe, D-(3-F)Phe, L-(4-Cl)Phe, or D-(4-Cl)Phe. 6 is L-Bip, D-Bip, D-(4-CF3)Phe, L-(3,4-diCl)Phe, D-(3,4-diCl)Phe, L-(3-F)Phe, D-(3-F)Phe, L-(4-Cl)Phe or D-(4-Cl)Phe. 6 is L-Bip, D-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, D-(3,4-diCl)Phe, L-(3-F)Phe, D-(3-F)Phe, L-(4-Cl)Phe or D-(4-Cl)Phe. 6is L-Bip, D-Bip, L-(4-CF3)Phe, D-(4-CF3)Phe, D-(3,4-diCl)Phe, L-(3-F)Phe, D-(3-F)Phe, L-(4-Cl)Phe, or D-(4-Cl)Phe. 6 is L-Bip, D-Bip, L-(4-CF3)Phe, D-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, D-(3-F)Phe, L-(4-Cl)Phe or D-(4-Cl)Phe.

[0130] In another embodiment, X 6 is L-Bip, D-Bip, L-(4-CF3)Phe, D-(4-CF3)Phe, L-(3,4-diCl)Phe, D-(3,4-diCl)Phe, D-(3-F)Phe, L-(4-Cl)Phe or D-(4-Cl)Phe. 6 is L-Bip, D-Bip, L-(4-CF3)Phe, D-(4-CF3)Phe, L-(3,4-diCl)Phe, D-(3,4-diCl)Phe, L-(3-F)Phe, L-(4-Cl)Phe, or D-(4-Cl)Phe. 6 is L-Bip, D-Bip, L-(4-CF3)Phe, D-(4-CF3)Phe, L-(3,4-diCl)Phe, D-(3,4-diCl)Phe, L-(3-F)Phe, D-(3-F)Phe or D-(4-Cl)Phe. 6 is L-Bip, D-Bip, L-(4-CF3)Phe, D-(4-CF3)Phe, L-(3,4-diCl)Phe, D-(3,4-diCl)Phe, L-(3-F)Phe, D-(3-F)Phe, or L-(4-Cl)Phe. 6 is D-Bip, D-(4-CF3)Phe, D-(3,4-diCl)Phe, D-(3-F)Phe, or D-(4-Cl)Phe. 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe.

[0131] In some embodiments of the above formula, X 7 is D-(N-Me)Ala, L-(N-Me)Phe or D-(N-Me)Phe. 7 is L-(N-Me)Ala, L-(N-Me)Phe, or D-(N-Me)Phe. 7 is L-(N-Me)Ala, D-(N-Me)Ala, or D-(N-Me)Phe. 7 is L-(N-Me)Ala, D-(N-Me)Ala, or L-(N-Me)Phe. 7 is D-(N-Me)Ala or D-(N-Me)Phe. 7 is L-(N-Me)Ala or L-(N-Me)Phe.

[0132] In some embodiments of the above formula, X 8 is D-Bip, L-Ser, D-Ser, L-Tyr, D-Tyr, L-(4-CF3)Phe, D-(4-CF3)Phe, L-Ala, D-Ala, L-Phe, D-Phe, L-Val, or D-Val. 8 is L-Bip, L-Ser, D-Ser, L-Tyr, D-Tyr, L-(4-CF3)Phe, D-(4-CF3)Phe, L-Ala, D-Ala, L-Phe, D-Phe, L-Val, or D-Val. 8 is L-Bip, D-Bip, D-Ser, L-Tyr, D-Tyr, L-(4-CF3)Phe, D-(4-CF3)Phe, L-Ala, D-Ala, L-Phe, D-Phe, L-Val, or D-Val. 8 is L-Bip, D-Bip, L-Ser, L-Tyr, D-Tyr, L-(4-CF3)Phe, D-(4-CF3)Phe, L-Ala, D-Ala, L-Phe, D-Phe, L-Val, or D-Val. 8is L-Bip, D-Bip, L-Ser, D-Ser, D-Tyr, L-(4-CF3)Phe, D-(4-CF3)Phe, L-Ala, D-Ala, L-Phe, D-Phe, L-Val, or D-Val. 8 is L-Bip, D-Bip, L-Ser, D-Ser, L-Tyr, L-(4-CF3)Phe, D-(4-CF3)Phe, L-Ala, D-Ala, L-Phe, D-Phe, L-Val, or D-Val. 8 is L-Bip, D-Bip, L-Ser, D-Ser, L-Tyr, D-Tyr, D-(4-CF3)Phe, L-Ala, D-Ala, L-Phe, D-Phe, L-Val, or D-Val. 8 is L-Bip, D-Bip, L-Ser, D-Ser, L-Tyr, D-Tyr, L-(4-CF3)Phe, L-Ala, D-Ala, L-Phe, D-Phe, L-Val, or D-Val. 8 is L-Bip, D-Bip, L-Ser, D-Ser, L-Tyr, D-Tyr, L-(4-CF3)Phe, D-(4-CF3)Phe, D-Ala, L-Phe, D-Phe, L-Val or D-Val.

[0133] In another embodiment, X 8 is L-Bip, D-Bip, L-Ser, D-Ser, L-Tyr, D-Tyr, L-(4-CF3)Phe, D-(4-CF3)Phe, L-Ala, L-Phe, D-Phe, L-Val, or D-Val. 8 is L-Bip, D-Bip, L-Ser, D-Ser, L-Tyr, D-Tyr, L-(4-CF3)Phe, D-(4-CF3)Phe, L-Ala, D-Ala, D-Phe, L-Val, or D-Val. 8 is L-Bip, D-Bip, L-Ser, D-Ser, L-Tyr, D-Tyr, L-(4-CF3)Phe, D-(4-CF3)Phe, L-Ala, D-Ala, L-Phe, L-Val, or D-Val. 8is L-Bip, D-Bip, L-Ser, D-Ser, L-Tyr, D-Tyr, L-(4-CF3)Phe, D-(4-CF3)Phe, L-Ala, D-Ala, L-Phe, D-Phe, or D-Val. 8 is L-Bip, D-Bip, L-Ser, D-Ser, L-Tyr, D-Tyr, L-(4-CF3)Phe, D-(4-CF3)Phe, L-Ala, D-Ala, L-Phe, D-Phe, or L-Val. 8 is D-Bip, D-Ser, D-Tyr, D-(4-CF3)Phe, D-Ala, D-Phe, or D-Val. 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val.

[0134] In some embodiments of the above formula, X 9 is D-Thr. In another embodiment, X 9 is L-Thr.

[0135] In some embodiments of the above formula, X 10 is D-Thr, L-Ser, or D-Ser. 10 is L-Thr, L-Ser, or D-Ser. 10 is L-Thr, D-Thr or D-Ser. 10 is L-Thr, D-Thr or L-Ser. 10 is D-Thr or D-Ser. 10 is L-Thr or L-Ser.

[0136] In some embodiments of the above formula, X 11 is D-Ser, L-Asp, D-Asp, L-Asn, D-Asn, L-Pro, D-Pro, L-Ala, D-Ala, L-Hse, or D-Hse. 11is L-Ser, L-Asp, D-Asp, L-Asn, D-Asn, L-Pro, D-Pro, L-Ala, D-Ala, L-Hse, or D-Hse. 11 is L-Ser, D-Ser, D-Asp, L-Asn, D-Asn, L-Pro, D-Pro, L-Ala, D-Ala, L-Hse, or D-Hse. 11 is L-Ser, D-Ser, L-Asp, L-Asn, D-Asn, L-Pro, D-Pro, L-Ala, D-Ala, L-Hse, or D-Hse. 11 is L-Ser, D-Ser, L-Asp, D-Asp, D-Asn, L-Pro, D-Pro, L-Ala, D-Ala, L-Hse, or D-Hse. 11 is L-Ser, D-Ser, L-Asp, D-Asp, L-Asn, L-Pro, D-Pro, L-Ala, D-Ala, L-Hse, or D-Hse. 11 is L-Ser, D-Ser, L-Asp, D-Asp, L-Asn, D-Asn, D-Pro, L-Ala, D-Ala, L-Hse, or D-Hse. 11 is L-Ser, D-Ser, L-Asp, D-Asp, L-Asn, D-Asn, L-Pro, L-Ala, D-Ala, L-Hse or D-Hse.

[0137] In another embodiment, X 11 is L-Ser, D-Ser, L-Asp, D-Asp, L-Asn, D-Asn, L-Pro, D-Pro, D-Ala, L-Hse, or D-Hse. 11 is L-Ser, D-Ser, L-Asp, D-Asp, L-Asn, D-Asn, L-Pro, D-Pro, L-Ala, L-Hse, or D-Hse. 11 is L-Ser, D-Ser, L-Asp, D-Asp, L-Asn, D-Asn, L-Pro, D-Pro, L-Ala, D-Ala, or D-Hse. 11is L-Ser, D-Ser, L-Asp, D-Asp, L-Asn, D-Asn, L-Pro, D-Pro, L-Ala, D-Ala, or L-Hse. 11 is D-Ser, D-Asp, D-Asn, D-Pro, D-Ala, or D-Hse. 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala or L-Hse.

[0138] In some embodiments of the above formula, X 12 is L-Val, D-Val, L-Glu, or D-Glu. 12 is L-Val, D-Val, L-Glu, or D-Glu. 12 is D-Val, L-Glu, or D-Glu. 12 is L-Val, L-Glu, or D-Glu. 12 is L-Val, D-Val, or D-Glu. 12 is L-Val, D-Val, or L-Glu. 12 is L-Val or D-Glu. 12 is D-Val or D-Glu. 12 is D-Val or D-Glu. 12 is L-Val or L-Glu.

[0139] In some embodiments of the above formula, X 13 is D-Phe. In another embodiment, X 13 is L-Phe.

[0140] In some embodiments of the above formula, X 13 is L-Phe, and X 2 is L-Pro. In another embodiment, X 13 is L-Phe, and X 9 is L-Thr. In another embodiment, X13 is L-Phe, and X 12 is L-Val or L-Glu. 13 is L-Phe, and X 12 In another embodiment, X is L-Val. 13 is L-Phe, and X 1 In another embodiment, X is absent or is Gly. 13 is L-Phe, and X 10 is L-Thr or L-Ser. 13 is L-Phe, and R 1 is H or (C1-C3) alkyl. In another embodiment, X 13 is L-Phe, and R 1 is H.

[0141] In some embodiments of the above formula, X 2 is L-Pro, X 9 is L-Thr. 2 is L-Pro, X 12 is L-Val or L-Glu. 2 is L-Pro, X 12 In another embodiment, X is L-Val. 2 is L-Pro, X 1 is absent or is Gly. 2 is L-Pro, X 10 is L-Thr or L-Ser. 2 is L-Pro and R 1 is H or (C1-C3) alkyl. In another embodiment, X 2 is L-Pro and R 1 is H.

[0142] In some embodiments of the above formula, X 9 is L-Thr and X 12 is L-Val or L-Glu. 9 is L-Thr and X12 In another embodiment, X is L-Val. 9 is L-Thr and X 1 is absent or is Gly. 9 is L-Thr and X 10 is L-Thr or L-Ser. 9 is L-Thr and R 1 is H or (C1-C3) alkyl. In another embodiment, X 9 is L-Thr and R 1 is H.

[0143] In some embodiments of the above formula, X 12 is L-Val or L-Glu, and X 1 is absent or is Gly. 12 is L-Val or L-Glu, and X 10 is L-Thr or L-Ser. 12 is L-Val or L-Glu, and R 1 is H or (C1-C3) alkyl. In another embodiment, X 12 is L-Val or L-Glu, and R 1 is H. In another embodiment, X 12 is L-Val and X 1 is absent or is Gly. 12 is L-Val and X 10 is L-Thr or L-Ser. 12 is L-Val and R 1 is H or (C1-C3) alkyl. In another embodiment, X 12 is L-Val and R 1 is H.

[0144] In some embodiments of the above formula, X 1 is absent or is Gly, and X 10 is L-Thr or L-Ser. 1is absent or is Gly, and R 1 is H or (C1-C3) alkyl. In another embodiment, X 1 is absent or is Gly, and R 1 is H. In another embodiment, X 10 is L-Thr or L-Ser, and R 1 is H or (C1-C3) alkyl. In another embodiment, X 10 is L-Thr or L-Ser, and R 1 is H.

[0145] In some embodiments of the above formula, X 13 is L-Phe, and X 2 is L-Pro, X 9 is L-Thr. 13 is L-Phe, and X 2 is L-Pro, X 12 is L-Val or L-Glu. 13 is L-Phe, and X 2 is L-Pro, X 12 In another embodiment, X is L-Val. 13 is L-Phe, and X 2 is L-Pro, X 1 is absent or is Gly. 13 is L-Phe, and X 2 is L-Pro, X 10 is L-Thr or L-Ser. 13 is L-Phe, and X 2 is L-Pro and R 1 is H or (C1-C3) alkyl. In another embodiment, X 13 is L-Phe, and X 2 is L-Pro and R 1 is H.

[0146] In some embodiments of the above formula, X 13 is L-Phe, and X 9 is L-Thr and X12 is L-Val or L-Glu. 13 is L-Phe, and X 9 is L-Thr and X 12 In another embodiment, X is L-Val. 13 is L-Phe, and X 9 is L-Thr and X 1 is absent or is Gly. 13 is L-Phe, and X 9 is L-Thr and X 10 is L-Thr or L-Ser. 13 is L-Phe, and X 9 is L-Thr and R 1 is H or (C1-C3) alkyl. In another embodiment, X 13 is L-Phe, and X 9 is L-Thr and R 1 is H.

[0147] In some embodiments of the above formula, X 9 is L-Thr and X 12 is L-Val or L-Glu, and X 1 is absent or is Gly. 9 is L-Thr and X 12 is L-Val or L-Glu, and X 10 is L-Thr or L-Ser. 9 is L-Thr and X 12 is L-Val or L-Glu, and R 1 is H or (C1-C3) alkyl. In another embodiment, X 9 is L-Thr and X 12 is L-Val or L-Glu, and R 1 is H.

[0148] In some embodiments of the above formula, X 9 is L-Thr and X 12 is L-Val, and X 1is absent or is Gly. 9 is L-Thr and X 12 is L-Val and X 10 is L-Thr or L-Ser. 9 is L-Thr and X 12 is L-Val and R 1 is H or (C1-C3) alkyl. In another embodiment, X 9 is L-Thr and X 12 is L-Val and R 1 is H. In another embodiment, X 12 is L-Val or L-Glu, and X 1 is absent or is Gly, and X 10 is L-Thr or L-Ser. 12 is L-Val or L-Glu, and X 1 is absent or is Gly, and R 1 is H or (C1-C3) alkyl. In another embodiment, X 12 is L-Val or L-Glu, and X 1 is absent or is Gly, and R 1 is H. In another embodiment, X 1 is absent or is Gly, and X 10 is L-Thr or L-Ser, and R 1 is H or (C1-C3) alkyl. In another embodiment, X 1 is absent or is Gly, and X 10 is L-Thr or L-Ser, and R 1 is H.

[0149] In some embodiments of the above formula, X 13 is L-Phe, and X 2 is L-Pro, X 9 is L-Thr and X 12 is L-Val or L-Glu. 13 is L-Phe, and X 2 is L-Pro, X9 is L-Thr and X 12 In another embodiment, X is L-Val. 13 is L-Phe, and X 2 is L-Pro, X 9 is L-Thr and X 1 is absent or is Gly. 13 is L-Phe, and X 2 is L-Pro, X 9 is L-Thr and X 10 is L-Thr or L-Ser. 13 is L-Phe, and X 2 is L-Pro, X 9 is L-Thr and R 1 is H or (C1-C3) alkyl. In another embodiment, X 13 is L-Phe, and X 2 is L-Pro, X 9 is L-Thr and R 1 is H. In another embodiment, X 13 is L-Phe, and X 2 is L-Pro, X 9 is L-Thr and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 Indicates the connection point to

[0150] In some embodiments of the above formula, X 13 is L-Phe, and X 2 is L-Pro, X 12 is L-Val or L-Glu, and X 1 is absent or is Gly. 13 is L-Phe, and X 2 is L-Pro, X 12 is L-Val or L-Glu, and X 10 is L-Thr or L-Ser. 13 is L-Phe, and X 2 is L-Pro, X12 is L-Val or L-Glu, and R 1 is H or (C1-C3) alkyl. In another embodiment, X 13 is L-Phe, and X 2 is L-Pro, X 12 is L-Val or L-Glu, and R 1 is H. In another embodiment, X 13 is L-Phe, and X 2 is L-Pro, X 12 is L-Val and X 1 is absent or is Gly. 13 is L-Phe, and X 2 is L-Pro, X 12 is L-Val and X 10 is L-Thr or L-Ser. 13 is L-Phe, and X 2 is L-Pro, X 12 is L-Val and R 1 is H or (C1-C3) alkyl. In another embodiment, X 13 is L-Phe, and X 2 is L-Pro, X 12 is L-Val and R 1 is H. In another embodiment, X 13 is L-Phe, and X 2 is L-Pro, X 1 is absent or is Gly, and X 10 is L-Thr or L-Ser. 13 is L-Phe, and X 2 is L-Pro, X 1 is absent or is Gly, and R 1 is H or (C1-C3) alkyl. In another embodiment, X 13 is L-Phe, and X 2 is L-Pro, X 1 is absent or is Gly, and R 1 is H.

[0151] In some embodiments of the above formula, X 13 is L-Phe, and X 2 is L-Pro, X 12 is L-Val or L-Glu, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 In another embodiment, X 13 is L-Phe, and X 2 is L-Pro, X 12 is L-Val and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 In another embodiment, X 13 is L-Phe, and X 2 is L-Pro, X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 10 is L-Thr or L-Ser. 13 is L-Phe, and X 2 is L-Pro, X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to R 1 is H or (C1-C3) alkyl. In another embodiment, X 13 is L-Phe, and X 2 is L-Pro, X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to R 1 is H.

[0152] In some embodiments of the above formula, X 13 is L-Phe, and X 9 is L-Thr and X 12 is L-Val or L-Glu, and X1 is absent or is Gly. 13 is L-Phe, and X 9 is L-Thr and X 12 is L-Val or L-Glu, and X 10 is L-Thr or L-Ser. 13 is L-Phe, and X 9 is L-Thr and X 12 is L-Val or L-Glu, and R 1 is H or (C1-C3) alkyl. In another embodiment, X 13 is L-Phe, and X 9 is L-Thr and X 12 is L-Val or L-Glu, and R 1 is H. In another embodiment, X 13 is L-Phe, and X 9 is L-Thr and X 12 is L-Val and X 1 is absent or is Gly. 13 is L-Phe, and X 9 is L-Thr and X 12 is L-Val and X 10 is L-Thr or L-Ser. 13 is L-Phe, and X 9 is L-Thr and X 12 is L-Val and R 1 is H or (C1-C3) alkyl. In another embodiment, X 13 is L-Phe, and X 9 is L-Thr and X 12 is L-Val and R 1 is H.

[0153] In some embodiments of the above formula, X 13 is L-Phe, and X 9 is L-Thr and X 12 is L-Val or L-Glu, and X 1is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 In another embodiment, X 13 is L-Phe, and X 9 is L-Thr and X 12 is L-Val and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 Indicates the connection point to

[0154] In some embodiments of the above formula, X 13 is L-Phe, and X 12 is L-Val or L-Glu, and X 1 is absent or is Gly, and X 10 is L-Thr or L-Ser. 13 is L-Phe, and X 12 is L-Val or L-Glu, and X 1 is absent or is Gly, and R 1 is H or (C1-C3) alkyl. In another embodiment, X 13 is L-Phe, and X 12 is L-Val or L-Glu, and X 1 is absent or is Gly, and R 1 is H. In another embodiment, X 13 is L-Phe, and X 12 is L-Val and X 1 is absent or is Gly, and X 10 is L-Thr or L-Ser. 13 is L-Phe, and X 12 is L-Val and X 1 is absent or is Gly, and R 1 is H or (C1-C3) alkyl. In another embodiment, X 13 is L-Phe, and X 12 is L-Val and X 1 is absent or is Gly, and R 1is H.

[0155] In some embodiments of the above formula, X 13 is L-Phe, and X 1 is absent or is Gly, and X 10 is L-Thr or L-Ser, and R 1 is H or (C1-C3) alkyl. In another embodiment, X 13 is L-Phe, and X 1 is absent or is Gly, and X 10 is L-Thr or L-Ser, and R 1 is H.

[0156] In some embodiments of the above formula, X 13 is L-Phe, and X 12 is L-Val or L-Glu, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 10 is L-Thr or L-Ser. 13 is L-Phe, and X 12 is L-Val or L-Glu, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to R 1 is H or (C1-C3) alkyl. In another embodiment, X 13 is L-Phe, and X 12 is L-Val or L-Glu, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to R 1 is H. In another embodiment, X 13 is L-Phe, and X 12 is L-Val and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR1 indicates the connection point to X 10 is L-Thr or L-Ser. 13 is L-Phe, and X 12 is L-Val and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to R 1 is H or (C1-C3) alkyl. In another embodiment, X 13 is L-Phe, and X 12 is L-Val and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to R 1 is H.

[0157] In some embodiments of the above formula, X 13 is L-Phe, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys, where * is NHR 1 indicates the connection point to X 10 is L-Thr or L-Ser, and R 1 is H or (C1-C3) alkyl. In another embodiment, X 13 is L-Phe, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 10 is L-Thr or L-Ser, and R 1 is H.

[0158] In some embodiments of the above formula, X 13 is L-Phe, and X 2 is L-Pro, X 9 is L-Thr and X 12 is L-Val or L-Glu, and X 1 is absent or is Gly. 13is L-Phe, and X 2 is L-Pro, X 9 is L-Thr and X 12 is L-Val or L-Glu, and X 10 is L-Thr or L-Ser. 13 is L-Phe, and X 2 is L-Pro, X 9 is L-Thr and X 12 is L-Val or L-Glu, and R 1 is H or (C1-C3) alkyl. In another embodiment, X 13 is L-Phe, and X 2 is L-Pro, X 9 is L-Thr and X 12 is L-Val or L-Glu, and R 1 is H. In another embodiment, X 13 is L-Phe, and X 2 is L-Pro, X 9 is L-Thr and X 12 is L-Val and X 1 is absent or is Gly. 13 is L-Phe, and X 2 is L-Pro, X 9 is L-Thr and X 12 is L-Val and X 10 is L-Thr or L-Ser. 13 is L-Phe, and X 2 is L-Pro, X 9 is L-Thr and X 12 is L-Val and R 1 is H or (C1-C3) alkyl. In another embodiment, X 13 is L-Phe, and X 2 is L-Pro, X 9 is L-Thr and X 12 is L-Val and R 1 is H.

[0159] In some embodiments of the above formula, X13 is L-Phe, and X 2 is L-Pro, X 9 is L-Thr and X 12 is L-Val or L-Glu, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 In another embodiment, X 13 is L-Phe, and X 2 is L-Pro, X 9 is L-Thr and X 12 is L-Val and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 Indicates the connection point to

[0160] In some embodiments of the above formula, X 13 is L-Phe, and X 2 is L-Pro, X 9 is L-Thr and X 12 is L-Val or L-Glu, and X 1 is absent or is Gly, and X 10 is L-Thr or L-Ser. 13 is L-Phe, and X 2 is L-Pro, X 9 is L-Thr and X 12 is L-Val or L-Glu, and X 1 is absent or is Gly, and R 1 is H or (C1-C3) alkyl. In another embodiment, X 13 is L-Phe, and X 2 is L-Pro, X 9 is L-Thr and X 12 is L-Val or L-Glu, and X 1 is absent or is Gly, and R 1 is H. In another embodiment, X 13 is L-Phe, and X 9 is L-Thr and X12 is L-Val or L-Glu, and X 1 is absent or is Gly, and X 10 is L-Thr or L-Ser, and R 1 is H or (C1-C3) alkyl. In another embodiment, X 13 is L-Phe, and X 9 is L-Thr and X 12 is L-Val or L-Glu, and X 1 is absent or is Gly, and X 10 is L-Thr or L-Ser, and R 1 is H. In another embodiment, X 13 is L-Phe, and X 2 is L-Pro, X 9 is L-Thr and X 12 is L-Val and X 1 is absent or is Gly, and X 10 is L-Thr or L-Ser. 13 is L-Phe, and X 2 is L-Pro, X 9 is L-Thr and X 12 is L-Val and X 1 is absent or is Gly, and R 1 is H or (C1-C3) alkyl. In another embodiment, X 13 is L-Phe, and X 2 is L-Pro, X 9 is L-Thr and X 12 is L-Val and X 1 is absent or is Gly, and R 1 is H. In another embodiment, X 13 is L-Phe, and X 9 is L-Thr and X 12 is L-Val and X 1 is absent or is Gly, and X 10 is L-Thr or L-Ser, and R 1 is H or (C1-C3) alkyl. In another embodiment, X 13is L-Phe, and X 9 is L-Thr and X 12 is L-Val or L-Glu, and X 1 is absent or is Gly, and X 10 is L-Thr or L-Ser, and R 1 is H.

[0161] In some embodiments of the above formula, X 13 is L-Phe, and X 2 is L-Pro, X 9 is L-Thr and X 12 is L-Val or L-Glu, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 10 is L-Thr or L-Ser. 13 is L-Phe, and X 2 is L-Pro, X 9 is L-Thr and X 12 is L-Val or L-Glu, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to R 1 is H or (C1-C3) alkyl. In another embodiment, X 13 is L-Phe, and X 2 is L-Pro, X 9 is L-Thr and X 12 is L-Val or L-Glu, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to R 1 is H. In another embodiment, X 13 is L-Phe, and X 9 is L-Thr and X 12 is L-Val or L-Glu, and X 1is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 10 is L-Thr or L-Ser, and R 1 is H or (C1-C3) alkyl. In another embodiment, X 13 is L-Phe, and X 9 is L-Thr and X 12 is L-Val or L-Glu, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 10 is L-Thr or L-Ser, and R 1 is H. In another embodiment, X 13 is L-Phe, and X 2 is L-Pro, X 9 is L-Thr and X 12 is L-Val and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 10 is L-Thr or L-Ser. 13 is L-Phe, and X 2 is L-Pro, X 9 is L-Thr and X 12 is L-Val and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to R 1 is H or (C1-C3) alkyl. In another embodiment, X 13 is L-Phe, and X 2 is L-Pro, X 9 is L-Thr and X 12 is L-Val and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to R1 is H. In another embodiment, X 13 is L-Phe, and X 9 is L-Thr and X 12 is L-Val and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 10 is L-Thr or L-Ser, and R 1 is H or (C1-C3) alkyl. In another embodiment, X 13 is L-Phe, and X 9 is L-Thr and X 12 is L-Val or L-Glu, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 10 is L-Thr or L-Ser, and R 1 is H.

[0162] In some embodiments of the above formula, X 13 is L-Phe, and X 9 is L-Thr and X 12 is L-Val or L-Glu, and X 1 is absent or is Gly, and X 10 is L-Thr or L-Ser, and R 1 is H or (C1-C3) alkyl. In another embodiment, X 13 is L-Phe, and X 9 is L-Thr and X 12 is L-Val or L-Glu, and X 1 is absent or is Gly, and X 10 is L-Thr or L-Ser, and R 1 is H. In another embodiment, X 13 is L-Phe, and X 9 is L-Thr and X 12 is L-Val and X 1 is absent or is Gly, and X 10is L-Thr or L-Ser, and R 1 is H or (C1-C3) alkyl. In another embodiment, X 13 is L-Phe, and X 9 is L-Thr and X 12 is L-Val and X 1 is absent or is Gly, and X 10 is L-Thr or L-Ser, and R 1 is H.

[0163] In some embodiments of the above formula, X 13 is L-Phe, and X 9 is L-Thr and X 12 is L-Val or L-Glu, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 10 is L-Thr or L-Ser, and R 1 is H or (C1-C3) alkyl. In another embodiment, X 13 is L-Phe, and X 9 is L-Thr and X 12 is L-Val or L-Glu, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 10 is L-Thr or L-Ser, and R 1 is H. In another embodiment, X 13 is L-Phe, and X 9 is L-Thr and X 12 is L-Val and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 10 is L-Thr or L-Ser, and R 1 is H or (C1-C3) alkyl. In another embodiment, X 13 is L-Phe, and X 9is L-Thr and X 12 is L-Val and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 10 is L-Thr or L-Ser, and R 1 is H.

[0164] In some embodiments of the above formula, X 13 is L-Phe, and X 2 is L-Pro, X 9 is L-Thr and X 12 is L-Val or L-Glu, and X 1 is absent or is Gly, and X 10 is L-Thr or L-Ser, and R 1 is H or (C1-C3) alkyl. In another embodiment, X 13 is L-Phe, and X 2 is L-Pro, X 9 is L-Thr and X 12 is L-Val or L-Glu, and X 1 is absent or is Gly, and X 10 is L-Thr or L-Ser, and R 1 is H. In another embodiment, X 13 is L-Phe, and X 2 is L-Pro, X 9 is L-Thr and X 12 is L-Val and X 1 is absent or is Gly, and X 10 is L-Thr or L-Ser, and R 1 is H or (C1-C3) alkyl. In another embodiment, X 13 is L-Phe, and X 2 is L-Pro, X 9 is L-Thr and X 12 is L-Val and X 1 is absent or is Gly, and X 10 is L-Thr or L-Ser, and R 1is H.

[0165] In some embodiments of the above formula, X 13 is L-Phe, and X 2 is L-Pro, X 9 is L-Thr and X 12 is L-Val or L-Glu, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 10 is L-Thr or L-Ser, and R 1 is H or (C1-C3) alkyl. In another embodiment, X 13 is L-Phe, and X 2 is L-Pro, X 9 is L-Thr and X 12 is L-Val or L-Glu, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 10 is L-Thr or L-Ser, and R 1 is H. In another embodiment, X 13 is L-Phe, and X 2 is L-Pro, X 9 is L-Thr and X 12 is L-Val and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 10 is L-Thr or L-Ser, and R 1 is H or (C1-C3) alkyl. In another embodiment, X 13 is L-Phe, and X 2 is L-Pro, X 9 is L-Thr and X 12 is L-Val and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1indicates the connection point to X 10 is L-Thr or L-Ser, and R 1 is H.

[0166] In some embodiments of the above formula, R 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala. 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu. 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu. 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe.

[0167] In some embodiments of the above formula, R 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala. 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu. 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu. 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1indicates the connection point to X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe.

[0168] In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe.

[0169] In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val.

[0170] In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr.

[0171] In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 10 is L-Thr or L-Ser.

[0172] In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 10 is L-Thr or L-Ser, and X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala or L-Hse.

[0173] In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 3is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 10 is L-Thr or L-Ser, and X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala or L-Hse, and X 12 is L-Val or L-Glu.

[0174] In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X10 is L-Thr or L-Ser, and X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala or L-Hse, and X 12 is L-Val or L-Glu, and X 13 is L-Phe.

[0175] In some embodiments of the above formula, R 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 3 is L-Arg, L-Ser, L-His, or L-Ala. 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu. 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu. 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe.

[0176] In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe. 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val.

[0177] In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr. In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 10 is L-Thr or L-Ser.

[0178] In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 3is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 10 is L-Thr or L-Ser, and X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala, or L-Hse. 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 10 is L-Thr or L-Ser, and X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala or L-Hse, and X 12is L-Val or L-Glu.

[0179] In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 10 is L-Thr or L-Ser, and X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala or L-Hse, and X 12 is L-Val or L-Glu, and X 13 is L-Phe.

[0180] In some embodiments of the above formula, R 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu. 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 4is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu. 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe.

[0181] In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe.

[0182] In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val. 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr.

[0183] In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 10 is L-Thr or L-Ser. 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 10 is L-Thr or L-Ser, and X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala or L-Hse.

[0184] In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 10 is L-Thr or L-Ser, and X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala or L-Hse, and X 12 is L-Val or L-Glu. 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 10 is L-Thr or L-Ser, and X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala or L-Hse, and X 12 is L-Val or L-Glu, and X 13 is L-Phe.

[0185] In some embodiments of the above formula, R 1 is H or (C1-C4) alkyl, and X 1is absent or is Gly, and X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu. 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe. 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe.

[0186] In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val. 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr.

[0187] In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 10 is L-Thr or L-Ser.1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 10 is L-Thr or L-Ser, and X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala or L-Hse.

[0188] In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 10 is L-Thr or L-Ser, and X 11is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala or L-Hse, and X 12 is L-Val or L-Glu. 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 10 is L-Thr or L-Ser, and X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala or L-Hse, and X 12 is L-Val or L-Glu, and X 13 is L-Phe.

[0189] In some embodiments of the above formula, R 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe. 1 is H or (C1-C4) alkyl, and X1 is absent or is Gly, and X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe.

[0190] In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val. 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 6is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr.

[0191] In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 10 is L-Thr or L-Ser. 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 10 is L-Thr or L-Ser, and X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala or L-Hse.

[0192] In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 10 is L-Thr or L-Ser, and X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala or L-Hse, and X 12 is L-Val or L-Glu. 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 10 is L-Thr or L-Ser, and X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala or L-Hse, and X 12 is L-Val or L-Glu, and X 13 is L-Phe.

[0193] In some embodiments of the above formula, R 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 7 is L-(N-Me)Ala or L-(N-Me)Phe. 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5is L-(N-Me)Ala or L-(N-Me)Glu, and X 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val.

[0194] In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr. In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 10is L-Thr or L-Ser.

[0195] In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 10 is L-Thr or L-Ser, and X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala, or L-Hse. 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 10 is L-Thr or L-Ser, and X 11is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala or L-Hse, and X 12 is L-Val or L-Glu.

[0196] In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 10 is L-Thr or L-Ser, and X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala or L-Hse, and X 12 is L-Val or L-Glu, and X 13 is L-Phe.

[0197] In some embodiments of the above formula, R 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val. 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr.

[0198] In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 8is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 10 is L-Thr or L-Ser. 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 10 is L-Thr or L-Ser, and X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala or L-Hse.

[0199] In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 10 is L-Thr or L-Ser, and X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala or L-Hse, and X 12 is L-Val or L-Glu. 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 10 is L-Thr or L-Ser, and X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala or L-Hse, and X 12 is L-Val or L-Glu, and X 13 is L-Phe.

[0200] In some embodiments of the above formula, R 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 9 is L-Thr. In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 9 is L-Thr and X 10 is L-Thr or L-Ser.

[0201] In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 9 is L-Thr and X 10 is L-Thr or L-Ser, and X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala, or L-Hse. 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 9 is L-Thr and X 10 is L-Thr or L-Ser, and X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala or L-Hse, and X 12 is L-Val or L-Glu.

[0202] In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 9 is L-Thr and X 10 is L-Thr or L-Ser, and X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala or L-Hse, and X 12 is L-Val or L-Glu, and X 13 is L-Phe.

[0203] In some embodiments of the above formula, R 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 10 is L-Thr or L-Ser. 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 10 is L-Thr or L-Ser, and X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala or L-Hse.

[0204] In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 10 is L-Thr or L-Ser, and X 11is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala or L-Hse, and X 12 is L-Val or L-Glu. 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 10 is L-Thr or L-Ser, and X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala or L-Hse, and X 12 is L-Val or L-Glu, and X 13 is L-Phe.

[0205] In some embodiments of the above formula, R 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala, or L-Hse. 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala or L-Hse, and X 12 is L-Val or L-Glu.

[0206] In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala or L-Hse, and X 12 is L-Val or L-Glu, and X 13 is L-Phe.

[0207] In some embodiments of the above formula, R 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 10 is L-Thr or L-Ser, and X12 is L-Val or L-Glu, and X 13 is L-Phe.

[0208] In some embodiments of the above formula, R 1 is H or (C1-C4) alkyl, and X 1 is absent or is Gly, and X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 10 is L-Thr or L-Ser, and X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala or L-Hse, and X 13 is L-Phe.

[0209] In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe.

[0210] In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val.

[0211] In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr.

[0212] In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 10 is L-Thr or L-Ser.

[0213] In another embodiment, R 1 is H or (C1-C4) alkyl, and X1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 10 is L-Thr or L-Ser, and X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala or L-Hse.

[0214] In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 10 is L-Thr or L-Ser, and X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala or L-Hse, and X 12 is L-Val or L-Glu.

[0215] In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 10 is L-Thr or L-Ser, and X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala or L-Hse, and X 12 is L-Val or L-Glu, and X 13 is L-Phe.

[0216] In some embodiments of the above formula, R 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 3 is L-Arg, L-Ser, L-His, or L-Ala. 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu. 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu. 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe.

[0217] In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe. 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val.

[0218] In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr. In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 10 is L-Thr or L-Ser.

[0219] In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 10 is L-Thr or L-Ser, and X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala, or L-Hse. 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 10 is L-Thr or L-Ser, and X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala or L-Hse, and X 12 is L-Val or L-Glu.

[0220] In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 10is L-Thr or L-Ser, and X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala or L-Hse, and X 12 is L-Val or L-Glu, and X 13 is L-Phe. In some embodiments of the above formula, R 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu. 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu. 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe.

[0221] In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe.

[0222] In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val. 1 is H or (C1-C4) alkyl, and X 1is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr.

[0223] In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 10 is L-Thr or L-Ser. 1is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 10 is L-Thr or L-Ser, and X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala or L-Hse.

[0224] In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 10 is L-Thr or L-Ser, and X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala or L-Hse, and X 12 is L-Val or L-Glu. 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 10 is L-Thr or L-Ser, and X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala or L-Hse, and X 12 is L-Val or L-Glu, and X 13 is L-Phe.

[0225] In some embodiments of the above formula, R 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu. 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe. 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe.

[0226] In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 3is L-Arg, L-Ser, L-His or L-Ala, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val. 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr.

[0227] In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 10 is L-Thr or L-Ser. 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 10 is L-Thr or L-Ser, and X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala or L-Hse.

[0228] In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 3is L-Arg, L-Ser, L-His or L-Ala, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 10 is L-Thr or L-Ser, and X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala or L-Hse, and X 12 is L-Val or L-Glu. 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 10 is L-Thr or L-Ser, and X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala or L-Hse, and X 12 is L-Val or L-Glu, and X 13is L-Phe.

[0229] In some embodiments of the above formula, R 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe. 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe.

[0230] In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 3is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val. 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr.

[0231] In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 3is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 10 is L-Thr or L-Ser. 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 10 is L-Thr or L-Ser, and X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala or L-Hse.

[0232] In another embodiment, R 1is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 10 is L-Thr or L-Ser, and X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala or L-Hse, and X 12 is L-Val or L-Glu. 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 10 is L-Thr or L-Ser, and X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala or L-Hse, and X 12 is L-Val or L-Glu, and X 13 is L-Phe.

[0233] In some embodiments of the above formula, R 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 7 is L-(N-Me)Ala or L-(N-Me)Phe. 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val.

[0234] In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr. In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X10 is L-Thr or L-Ser.

[0235] In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 10 is L-Thr or L-Ser, and X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala, or L-Hse. 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 10 is L-Thr or L-Ser, and X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala or L-Hse, and X 12 is L-Val or L-Glu.

[0236] In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 10 is L-Thr or L-Ser, and X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala or L-Hse, and X 12 is L-Val or L-Glu, and X 13 is L-Phe.

[0237] In some embodiments of the above formula, R 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1indicates the connection point to X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val. 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr.

[0238] In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 10 is L-Thr or L-Ser. 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 10 is L-Thr or L-Ser, and X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala or L-Hse.

[0239] In another embodiment, R1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 10 is L-Thr or L-Ser, and X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala or L-Hse, and X 12 is L-Val or L-Glu. 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 8is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 10 is L-Thr or L-Ser, and X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala or L-Hse, and X 12 is L-Val or L-Glu, and X 13 is L-Phe.

[0240] In some embodiments of the above formula, R 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 9 is L-Thr. In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 9 is L-Thr and X 10 is L-Thr or L-Ser.

[0241] In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 9 is L-Thr and X 10 is L-Thr or L-Ser, and X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala, or L-Hse. 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 9 is L-Thr and X 10 is L-Thr or L-Ser, and X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala or L-Hse, and X 12 is L-Val or L-Glu.

[0242] In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 9 is L-Thr and X 10 is L-Thr or L-Ser, and X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala or L-Hse, and X 12 is L-Val or L-Glu, and X13 is L-Phe.

[0243] In some embodiments of the above formula, R 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 10 is L-Thr or L-Ser. 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 10 is L-Thr or L-Ser, and X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala or L-Hse.

[0244] In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 10 is L-Thr or L-Ser, and X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala or L-Hse, and X 12 is L-Val or L-Glu. 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 10 is L-Thr or L-Ser, and X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala or L-Hse, and X 12 is L-Val or L-Glu, and X 13 is L-Phe.

[0245] In some embodiments of the above formula, R 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala, or L-Hse. 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala or L-Hse, and X 12 is L-Val or L-Glu.

[0246] In another embodiment, R 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala or L-Hse, and X 12 is L-Val or L-Glu, and X 13 is L-Phe.

[0247] In some embodiments of the above formula, R 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9is L-Thr and X 10 is L-Thr or L-Ser, and X 12 is L-Val or L-Glu, and X 13 is L-Phe.

[0248] In some embodiments of the above formula, R 1 is H or (C1-C4) alkyl, and X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 indicates the connection point to X 2 is L-Pro, X 3 is L-Arg, L-Ser, L-His or L-Ala, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, and X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe or L-(4-Cl)Phe, and 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe or L-Val; 9 is L-Thr and X 10 is L-Thr or L-Ser, and X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala or L-Hse, and X 13 is L-Phe.

[0249] Embodiment 1. Polypeptides according to formula (I) (In the formula, R 1 is H or (C1-C4) alkyl; X 1 is absent or is Gly; X 2 is L-Pro or D-Pro; X 3 is L-Arg, D-Arg, L-Ser, D-Ser, L-His, D-His, L-Ala or D-Ala; X 4 is L-Asp, D-Asp, L-Asn, D-Asn, L-Glu, D-Glu, L-Lys, D-Lys, L-Gln, D-Gln, L-Pro, D-Pro, L-Ala, D-Ala, L-(N-Me)Glu or D-(N-Me)Glu; X 5 is L-(N-Me)Ala, D-(N-Me)Ala, L-(N-Me)Glu or D-(N-Me)Glu; X 6 is L-Bip, D-Bip, L-(4-CF3)Phe, D-(4-CF3)Phe, L-(3,4-diCl)Phe, D-(3,4-diCl)Phe, L-(3-F)Phe, D-(3-F)Phe, L-(4-Cl)Phe or D-(4-Cl)Phe; X 7 is L-(N-Me)Ala, D-(N-Me)Ala, L-(N-Me)Phe or D-(N-Me)Phe; X 8 is L-Bip, D-Bip, L-Ser, D-Ser, L-Tyr, D-Tyr, L-(4-CF3)Phe, D-(4-CF3)Phe, L-Ala, D-Ala, L-Phe, D-Phe, L-Val or D-Val; X 9 [[ID=3××××××]]is L-Thr or D-Thr; X 10 is L-Thr, D-Thr, L-Ser or D-Ser; X 11 is L-Ser, D-Ser, L-Asp, D-Asp, L-Asn, D-Asn, L-Pro, D-Pro, L-Ala, D-Ala, L-Hse or D-Hse; X 12 is L-Val, D-Val, L-Glu or D-Glu; X 13 It should be noted that there seems to be an error in the tag "ID=3××××××" in the original text. It should probably be a correct 7-digit tag like other tags. If this is a real error in the original, it may need to be corrected before accurate translation and further processing.is L-Phe or D-Phe; where: Bip is 4-phenyl-phenylalanine; Hse is homoserine; (4-CF3)Phe is 4-trifluoromethyl-phenylalanine; (3,4-diCl)Phe is 3,4-dichloro-phenylalanine; (3-F)Phe is 3-fluoro-phenylalanine; (4-Cl)Phe is 4-chloro-phenylalanine) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof.

[0250] Embodiment 2. X 13 is L-Phe.

[0251] Embodiment 3. X 2 3. The polypeptide of embodiment 1 or 2, wherein is L-Pro.

[0252] Embodiment 4. X 9 The polypeptide according to any one of embodiments 1 to 3, wherein is L-Thr.

[0253] Embodiment 5. The polypeptide of embodiment 1, having formula (II), formula (III), formula (IV), formula (V), or formula (VI).

[0254] Embodiment 6. X 12 The polypeptide according to any one of embodiments 1 to 5, wherein is L-Val or L-Glu.

[0255] Embodiment 7. X 12 7. The polypeptide according to any one of embodiments 1 to 6, wherein is L-Val or L-Glu.

[0256] Embodiment 8. X 12 The polypeptide according to any one of embodiments 1 to 7, wherein is L-Val.

[0257] Embodiment 9. X 1 9. The polypeptide according to any one of embodiments 1 to 8, wherein:

[0258] Embodiment 10. X 1 The polypeptide according to any one of embodiments 1 to 9, wherein is Gly.

[0259] Embodiment 11. X 10 11. The polypeptide according to any one of embodiments 1 to 10, wherein is L-Thr or L-Ser.

[0260] Embodiment 12. R 1 12. The polypeptide of any one of embodiments 1 to 11, wherein is H or (C1-C3) alkyl.

[0261] Embodiment 13. R 1 13. The polypeptide of any one of embodiments 1 to 12, wherein

[0262] Non-limiting exemplary compounds of the present disclosure include:

[0263] [Table 3]

[0264] [Table 4]

[0265] [Table 5]

[0266] [Table 6]

[0267] [Table 7]

[0268] [Table 8]

[0269] [Table 9]

[0270] [Table 10]

[0271] [Table 11]

[0272] [Table 12]

[0273] In the formula, Ac is acetyl, and the acetyl marked with "*" and the amino acid marked with "*" are linked via a sulfide bond formed via their side chains or termini.

[0274] Embodiment 51. A pharmaceutical composition comprising a therapeutically effective amount of a cyclic polypeptide according to any one of embodiments 1 to 50, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0275] Embodiment 52. A combination comprising a polypeptide according to any one of embodiments 1 to 50 or a pharmaceutically acceptable salt thereof, and one or more further therapeutically active agents.

[0276] Embodiment 53. The combination of embodiment 52, wherein the further therapeutically active agent is a statin.

[0277] Embodiment 54. A pharmaceutical composition according to embodiment 51 or a combination according to any one of embodiments 52 or 53 for use in treating, preventing, ameliorating or delaying progression of a PCSK9-mediated disease or disorder.

[0278] Embodiment 55. The pharmaceutical composition or combination of embodiment 54, wherein the PCSK9-mediated disease or disorder, or disease or disorder requiring inhibition of PCSK9 activity, is selected from hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, peripheral arterial disease, vascular inflammation, elevated Lp(a), elevated LDL, elevated TRL, elevated triglycerides, sepsis, and xanthomas.

[0279] Embodiment 56 A method of modulating PCSK9, comprising administering to a patient in need thereof a cyclic polypeptide of any one of Embodiments 1 to 50, or a pharmaceutically acceptable salt thereof.

[0280] Embodiment 57. A method of inhibiting PCSK9, comprising administering to a patient in need thereof a cyclic polypeptide of any one of Embodiments 1 to 50, or a pharmaceutically acceptable salt thereof.

[0281] Embodiment 58. A method for treating, preventing, ameliorating, or delaying the progression of a PCSK9-mediated disease or disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a cyclic polypeptide of any one of embodiments 1 to 50, or a pharmaceutically acceptable salt thereof.

[0282] Embodiment 59. The method of embodiment 58, wherein the PCSK9-mediated disease or disorder is selected from hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, peripheral arterial disease, vascular inflammation, elevated Lp(a), elevated LDL, elevated TRL, elevated triglycerides, sepsis, and xanthomas.

[0283] Embodiment 60. A method for (i) lowering Lp(a), (ii) lowering Lp(a) plasma levels, (iii) lowering Lp(a) serum levels, (iv) lowering serum TRL or LDL levels, (v) lowering serum triglyceride levels, (vi) lowering LDL-C, (vii) lowering total plasma apoB concentration, (viii) lowering LDL apoB, (ix) lowering TRL apoB, or (x) lowering non-HDL-C, comprising administering to a patient in need thereof a therapeutically effective amount of a cyclic polypeptide or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 50, thereby lowering LDL-C in the patient.

[0284] Embodiment 61. The method of any one of embodiments 56-60, wherein the administration is orally, parenterally, subcutaneously, by injection, or by infusion.

[0285] Embodiment 62. A cyclic polypeptide or a pharmaceutically acceptable salt thereof of any one of embodiments 1 to 50 for use in treating a PCSK9-mediated disease or disorder.

[0286] Embodiment 63. The cyclic polypeptide of any one of embodiments 1 to 50, or a pharmaceutically acceptable salt thereof, for use in the treatment, prevention, amelioration, or delay of progression of, or a disease or disorder requiring inhibition of PCSK9.

[0287] Embodiment 64 Use of the polypeptide of any one of Embodiments 1 to 50, or a pharmaceutically acceptable salt thereof, for the treatment, prevention, amelioration, or delay of progression of a PCSK9-mediated disease or disorder, or for the treatment, prevention, amelioration, or delay of progression of a disease or disorder requiring inhibition of PCSK9.

[0288] Embodiment 65 Use of the polypeptide of any one of Embodiments 1 to 50, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating, preventing, ameliorating, or delaying progression of a PCSK9-mediated disease or disorder, or for treating, preventing, ameliorating, or delaying progression of a disease or disorder requiring inhibition of PCSK9.

[0289] Embodiment 66. A method for treating, preventing, ameliorating, or delaying progression of a PCSK9-mediated disease or disorder, or a disease or disorder requiring inhibition of PCSK9 or PCSK9 activity, comprising administering to a patient in need thereof a therapeutically effective amount of a polypeptide of any one of Embodiments 1 to 50, or a pharmaceutically acceptable salt thereof.

[0290] Embodiment 67. The polypeptide for use according to embodiment 63, the use of the polypeptide according to embodiment 64 or 65, or the method according to embodiment 66, wherein the PCSK9-mediated disease or disorder or the disease or disorder requiring inhibition of PCSK9 is selected from hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, peripheral arterial disease, vascular inflammation, elevated Lp(a), elevated LDL, elevated TRL, elevated triglycerides, sepsis, and xanthomas.

[0291] Embodiment 68. A polypeptide according to formula (I) (In the formula, R 1 is H or (C1-C4) alkyl; X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 Shows the connection point to; X 2 is L-Pro or D-Pro; X 3 is L-Arg, D-Arg, L-Ser, D-Ser, L-His, D-His, L-Ala or D-Ala; X 4are L-Asp, D-Asp, L-Asn, D-Asn, L-Glu, D-Glu, L-Lys, D-Lys, L-Gln, D-Gln, L-Pro, D-Pro, L-Ala, D-Ala, L-(N-Me)Glu or D-(N-Me)Glu; X 5 is L-(N-Me)Ala, D-(N-Me)Ala, L-(N-Me)Glu or D-(N-Me)Glu; X 6 are L-Bip, D-Bip, L-(4-CF3)Phe, D-(4-CF3)Phe, L-(3,4-diCl)Phe, D-(3,4-diCl)Phe, L-(3-F)Phe, D-(3-F)Phe, L-(4-Cl)Phe or D-(4-Cl)Phe; X 7 is L-(N-Me)Ala, D-(N-Me)Ala, L-(N-Me)Phe or D-(N-Me)Phe; X 8 are L-Bip, D-Bip, L-Ser, D-Ser, L-Tyr, D-Tyr, L-(4-CF3)Phe, D-(4-CF3)Phe, L-Ala, D-Ala, L-Phe, D-Phe, L-Val or D-Val; X 9 is L-Thr or D-Thr; X 10 is L-Thr, D-Thr, L-Ser or D-Ser; X 11 is L-Ser, D-Ser, L-Asp, D-Asp, L-Asn, D-Asn, L-Pro, D-Pro, L-Ala, D-Ala, L-Hse or D-Hse; X 12 is L-Val, D-Val, L-Glu or D-Glu; X 13 is L-Phe or D-Phe; where: Bip is 4-phenyl-phenylalanine; Hse is homoserine; (4-CF3)Phe is 4-trifluoromethyl-phenylalanine; (3,4-diCl)Phe is 3,4-dichloro-phenylalanine; (3-F)Phe is 3-fluoro-phenylalanine; (4-Cl)Phe is 4-chloro-phenylalanine) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof.

[0292] Embodiment 69. A polypeptide according to embodiment 68, wherein: R 1 is H or (C1-C4) alkyl; X 1 is absent or is Gly; X 2 is L-Pro or D-Pro; X 3 is L-Arg, D-Arg, L-Ser, D-Ser, L-His, D-His, L-Ala or D-Ala; X 4 are L-Asp, D-Asp, L-Asn, D-Asn, L-Glu, D-Glu, L-Lys, D-Lys, L-Gln, D-Gln, L-Pro, D-Pro, L-Ala, D-Ala, L-(N-Me)Glu or D-(N-Me)Glu; X 5 is L-(N-Me)Ala, D-(N-Me)Ala, L-(N-Me)Glu or D-(N-Me)Glu; X 6 are L-Bip, D-Bip, L-(4-CF3)Phe, D-(4-CF3)Phe, L-(3,4-diCl)Phe, D-(3,4-diCl)Phe, L-(3-F)Phe, D-(3-F)Phe, L-(4-Cl)Phe or D-(4-Cl)Phe; X 7 is L-(N-Me)Ala, D-(N-Me)Ala, L-(N-Me)Phe or D-(N-Me)Phe; X8 are L-Bip, D-Bip, L-Ser, D-Ser, L-Tyr, D-Tyr, L-(4-CF3)Phe, D-(4-CF3)Phe, L-Ala, D-Ala, L-Phe, D-Phe, L-Val or D-Val; X 9 is L-Thr or D-Thr; X 10 is L-Thr, D-Thr, L-Ser or D-Ser; X 11 is L-Ser, D-Ser, L-Asp, D-Asp, L-Asn, D-Asn, L-Pro, D-Pro, L-Ala, D-Ala, L-Hse or D-Hse; X 12 is L-Val, D-Val, L-Glu or D-Glu; X 13 is L-Phe or D-Phe; where: Bip is 4-phenyl-phenylalanine; Hse is homoserine; (4-CF3)Phe is 4-trifluoromethyl-phenylalanine; (3,4-diCl)Phe is 3,4-dichloro-phenylalanine; (3-F)Phe is 3-fluoro-phenylalanine; (4-Cl)Phe is 4-chloro-phenylalanine) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof.

[0293] Embodiment 70. X 13 70. The polypeptide of embodiment 68 or 69, wherein is L-Phe.

[0294] Embodiment 71. X 2 The polypeptide according to any one of embodiments 68 to 70, wherein is L-Pro.

[0295] Embodiment 72. X 972. The polypeptide of any one of embodiments 68 to 71, wherein is L-Thr.

[0296] Embodiment 73. The polypeptide of embodiment 68 or 69, having formula (II), formula (III), formula (IV), formula (V), or formula (VI).

[0297] Embodiment 74. X 12 74. The polypeptide of any one of embodiments 68 to 73, wherein is L-Val or L-Glu.

[0298] Embodiment 75. X 12 75. The polypeptide of any one of embodiments 68 to 74, wherein is L-Val or L-Glu.

[0299] Embodiment 76. X 12 76. The polypeptide of any one of embodiments 68 to 75, wherein is L-Val.

[0300] Embodiment 77. X 1 77. The polypeptide of any one of embodiments 68 to 76, wherein:

[0301] Embodiment 78. X 1 The polypeptide of any one of embodiments 68 to 77, wherein is Gly.

[0302] Embodiment 79. X 10 79. The polypeptide of any one of embodiments 68 to 78, wherein is L-Thr or L-Ser.

[0303] Embodiment 80. R 1 80. The polypeptide of any one of embodiments 68-79, wherein is H or (C1-C3) alkyl.

[0304] Embodiment 81. R 1 The polypeptide of any one of embodiments 68 to 80, wherein is H.

[0305] Embodiment 82. A pharmaceutical composition comprising a therapeutically effective amount of a cyclic polypeptide or a pharmaceutically acceptable salt thereof according to any one of embodiments 68 to 81 and 14 to 51, and one or more pharmaceutically acceptable carriers or excipients.

[0306] Embodiment 83. A combination comprising a polypeptide according to any one of claims 68 to 81 and 14 to 51 or a pharmaceutically acceptable salt thereof, and one or more therapeutically active agents.

[0307] Embodiment 84. The combination of embodiment 83, wherein the further therapeutically active agent is a statin.

[0308] Embodiment 85. A pharmaceutical composition according to embodiment 82 or a combination according to any one of embodiments 83 or 84 for use in treating, preventing, ameliorating or delaying progression of a PCSK9-mediated disease or disorder.

[0309] Embodiment 86. The pharmaceutical composition or combination of embodiment 85, wherein the PCSK9-mediated disease or disorder, or disease or disorder requiring inhibition of PCSK9 activity, is selected from hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, peripheral arterial disease, vascular inflammation, elevated Lp(a), elevated LDL, elevated TRL, elevated triglycerides, sepsis, and xanthomas.

[0310] Embodiment 87. A method of modulating PCSK9, comprising administering to a patient in need thereof the cyclic polypeptide of any one of embodiments 68-81 and 14-51, or a pharmaceutically acceptable salt thereof.

[0311] Embodiment 88. A method of inhibiting PCSK9, comprising administering to a patient in need thereof a cyclic polypeptide or a pharmaceutically acceptable salt thereof of any one of embodiments 68-81 and 14-51.

[0312] Embodiment 89. A method for treating, preventing, ameliorating, or delaying the progression of a PCSK9-mediated disease or disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a cyclic polypeptide or a pharmaceutically acceptable salt thereof of any one of embodiments 68-81 and 14-51.

[0313] Embodiment 90. The method of embodiment 89, wherein the PCSK9-mediated disease or disorder is selected from hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, peripheral arterial disease, vascular inflammation, elevated Lp(a), elevated LDL, elevated TRL, elevated triglycerides, sepsis, and xanthomas.

[0314] Embodiment 91. A method for (i) lowering Lp(a), (ii) lowering Lp(a) plasma levels, (iii) lowering Lp(a) serum levels, (iv) lowering serum TRL or LDL levels, (v) lowering serum triglyceride levels, (vi) lowering LDL-C, (vii) lowering total plasma apoB concentration, (viii) lowering LDL apoB, (ix) lowering TRL apoB, or (x) lowering non-HDL-C, comprising administering to a patient in need thereof a therapeutically effective amount of a cyclic polypeptide or a pharmaceutically acceptable salt thereof described in any one of embodiments 68-81 and 14-51, thereby lowering LDL-C in the patient.

[0315] Embodiment 92. The method of any one of embodiments 87-91, wherein the administration is orally, parenterally, subcutaneously, by injection, or by infusion.

[0316] Embodiment 93. The cyclic polypeptide or a pharmaceutically acceptable salt thereof of any one of embodiments 68-81 and 14-51 for use in treating a PCSK9-mediated disease or disorder.

[0317] Embodiment 94. The cyclic polypeptide or pharmaceutically acceptable salt thereof of any one of embodiments 68 to 81 and 14 to 51 for use in the treatment, prevention, amelioration, or delay of progression, or for use in the treatment, prevention, amelioration, or delay of progression of a disease or disorder requiring inhibition of PCSK9.

[0318] Embodiment 95. Use of the polypeptide or pharmaceutically acceptable salt thereof of any one of embodiments 68 to 81 and 14 to 51 for the treatment, prevention, amelioration, or delay of progression of a PCSK9-mediated disease or disorder, or for the treatment, prevention, amelioration, or delay of progression of a disease or disorder requiring inhibition of PCSK9.

[0319] Embodiment 96. Use of a polypeptide or a pharmaceutically acceptable salt thereof according to any one of embodiments 68 to 81 and 14 to 51 in the manufacture of a medicament for treating, preventing, ameliorating, or delaying progression of a PCSK9-mediated disease or disorder, or for treating, preventing, ameliorating, or delaying progression of a disease or disorder requiring inhibition of PCSK9.

[0320] Embodiment 97. A method for treating, preventing, ameliorating, or delaying the progression of a PCSK9-mediated disease or disorder, or a disease or disorder requiring inhibition of PCSK9 or PCSK9 activity, comprising administering to a patient in need thereof a therapeutically effective amount of a polypeptide or a pharmaceutically acceptable salt thereof described in any one of embodiments 68 to 81 and 14 to 51.

[0321] Embodiment 98. The polypeptide for use according to embodiment 94, the use of the polypeptide according to embodiment 95 or 96, or the method according to embodiment 97, wherein the PCSK9-mediated disease or disorder or the disease or disorder requiring inhibition of PCSK9 is selected from hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, peripheral arterial disease, vascular inflammation, elevated Lp(a), elevated LDL, elevated TRL, elevated triglycerides, sepsis, and xanthomas.

[0322] In another embodiment, the polypeptide of Formula (I) is an enantiomer. In some embodiments, the polypeptide is an (S)-enantiomer. In other embodiments, the polypeptide is an (R)-enantiomer. In yet other embodiments, the polypeptide of Formula (I) can be a (+) or (-) enantiomer.

[0323] In another embodiment, the polypeptide of formula (I) is a diastereomer.

[0324] It should be understood that all isomeric forms, including mixtures thereof, are included within the present disclosure. When the polypeptide contains a double bond, the substituent may be in the E or Z configuration. When the polypeptide contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis or trans configuration. All tautomeric forms are also intended to be included.

[0325] The polypeptides of the present disclosure, and their pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, and prodrugs, may exist in their tautomeric form (e.g., as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present disclosure.

[0326] The polypeptides of the present disclosure may contain asymmetric or chiral centers and therefore exist in different stereoisomeric forms. All stereoisomeric forms of the polypeptides of the present disclosure, as well as mixtures thereof, including racemic mixtures, are intended to be part of the present disclosure. Furthermore, the present disclosure encompasses all geometric and positional isomers. For example, if a polypeptide of the present disclosure incorporates a double bond or a fused ring, both cis and trans forms and mixtures are encompassed within the scope of the present disclosure. Each polypeptide disclosed herein includes all enantiomers that conform to the general structure of the polypeptide. The polypeptides may be racemic, enantiomerically pure, or some other form in terms of stereochemistry. Assay results may reflect data collected for racemic, enantiomerically pure, or some other form in terms of stereochemistry.

[0327] Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, chromatography and / or fractional crystallization. Enantiomers can also be separated by converting the enantiomeric mixture to a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., a chiral auxiliary, such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting the individual diastereomers to the corresponding pure enantiomers (e.g., by hydrolysis). Additionally, some of the polypeptides of the present disclosure may be atropisomers (e.g., substituted biaryls) and are considered part of the present disclosure. Enantiomers can also be separated using a chiral HPLC column.

[0328] It is also possible that the polypeptides of the present disclosure may exist in different tautomeric forms, and all such forms are encompassed within the scope of the present disclosure. Also included in the disclosure are, for example, all keto-enol and imine-enamine forms of the present polypeptides.

[0329] All stereoisomers (e.g., geometric isomers, optical isomers, etc.) of the polypeptides (including salts, solvates, esters, and prodrugs of the polypeptides, and salts, solvates, and esters of the prodrugs), such as those that may exist due to asymmetric carbons on various substituents, are contemplated within the scope of the present disclosure, as are positional isomers (e.g., 4-pyridyl and 3-pyridyl), including enantiomeric forms (which may also exist when there are no asymmetric carbons), rotamer forms, atropisomers, and diastereomeric forms. (For example, when a polypeptide of Formula (I) incorporates a double bond or a fused ring, both cis- and trans-forms and mixtures are encompassed within the scope of the present disclosure. Also, for example, all keto-enol and imine-enamine forms of the polypeptides are included in the present disclosure.) Individual stereoisomers of the polypeptides of the present disclosure can be, for example, substantially free of other isomers, or can be mixed, for example, as a racemate or with all other or selected stereoisomers. The chiral centers of the present disclosure can have the S or R configuration as defined by the IUPAC 1974 Recommendations. Use of the terms "salts," "solvates," "esters," "prodrugs," and the like are intended to apply equally to salts, solvates, esters, and prodrugs of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates, or prodrugs of the polypeptides of the present invention.

[0330] Polypeptides of formula (I) can form salts that are also within the scope of this disclosure, and reference herein to a polypeptide of the formula is understood to include reference to salts thereof, unless otherwise indicated.

[0331] The present disclosure relates to polypeptides that are modulators of PCSK9. In one embodiment, the polypeptides of the present disclosure are inhibitors of PCSK9.

[0332] The present disclosure is directed to polypeptides as described herein and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers thereof, and pharmaceutical compositions comprising one or more polypeptides as described herein or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers thereof.

[0333] Polypeptide activity The activity of cyclic polypeptides according to the present disclosure, such as PCSK9, can be assessed using a time-resolved fluorescence resonance energy transfer (TR-FRET) assay, which measures the ability of cyclic polypeptides of the present disclosure to interfere with the binding of human PCSK9 to the human LDLR, providing a measure of both potency (IC50) and efficacy (Amax).

[0334] Solutions of various concentrations are prepared by diluting the cyclic polypeptides of the present disclosure in dimethyl sulfoxide (DMSO), and the resulting solutions are pipetted into the plate. DMSO is used as a negative control. An intermediate plate is prepared by transferring known amounts of each polypeptide solution and control from the compound plate to corresponding wells containing assay buffer and mixing thoroughly. A third plate is then prepared for use in the assay by adding human PCSK9 Alexa Fluor 647, followed by a known amount of each solution from the intermediate plate. Unlabeled human PCSK9 in assay buffer containing DMSO is used as a positive control for the assay. After incubation, human LDLR extracellular domain-europium cryptate is added to each well of the assay plate, and the resulting mixture is incubated for an additional period. The TR-FRET signal is measured, and the FRET ratio (FRET / europium) is used to determine the IC of the cyclic polypeptide. 50 and Amax are calculated.

[0335] Method for synthesizing polypeptides The polypeptides of the present disclosure may be made by a variety of methods, including standard chemistry. Suitable synthetic routes are illustrated in the schemes provided below.

[0336] All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context. The use of any and all examples or exemplary language (e.g., "etc.") provided herein is intended merely to further clarify the disclosure and does not limit the scope of the disclosure unless otherwise stated.

[0337] The peptides and polypeptides of the present disclosure can be produced by known procedures for peptide synthesis. The method for peptide synthesis can be either solid phase synthesis or liquid phase synthesis. Thus, the peptides and polypeptides of interest can be produced by condensing partial peptides or amino acids that can constitute proteins together with their residues, and if the product has a protecting group, the protecting group is removed when the desired peptide can be produced. Known methods for condensation and deprotection include the procedures described in the following references (1) to (5): (1) M. Bodanszky and M.A. Ondetti, Peptide Synthesis, Interscience Publishers, New York, 1966; (2) Schroeder and Luebke, The Peptide, Academic Press, New York, 1965; (3) Nobuo Izumiya et al., Fundamentals and Experiments in Peptide Synthesis, Maruzen, 1975; (4) Haruaki Yajima and Shumpei Sakakibara, Biochemical Experiment Series 1, Protein Chemistry IV, 205, 1977; and (5) Haruaki Yajima (ed.), Development of Drugs - Continued, 14, Peptide Synthesis, Hirokawa Shoten.

[0338] After the reaction, the peptide may be purified and isolated by a combination of conventional purification techniques such as solvent extraction, column chromatography, liquid chromatography, and recrystallization. If the peptide isolated as described above is a free polypeptide, it may be converted into a suitable salt by a known method. Conversely, if the isolated product is a salt, it may be converted into a free peptide by a known method.

[0339] Amides of polypeptides can be obtained by using a peptide synthesis resin suitable for amidation. Examples of such resins include chloromethyl resin, hydroxymethyl resin, benzhydrylamine resin, aminomethyl resin, 4-benzyloxybenzyl alcohol resin, 4-methylbenzhydrylamine resin, PAM resin, 4-hydroxymethylmethylphenylacetamidomethyl resin, polyacrylamide resin, 4-(2',4'-dimethoxyphenyl-hydroxymethyl)phenoxy resin, 4-(2',4'-dimethoxyphenyl-Fmoc-aminomethyl)phenoxy resin, and 2-chlorotrityl chloride resin. Using such resins, amino acids whose side chain α-amino groups and functional groups are appropriately protected are condensed on the resin according to the sequence of the desired peptide using various condensation techniques known per se. At the end of the reaction series, the peptide or protected peptide is removed from the resin, the protecting groups are removed, and, if necessary, disulfide bonds are formed to obtain the desired polypeptide.

[0340] For the condensation of the above-mentioned protected amino acids, various activation reagents for peptide synthesis, such as HATU, HCTU, or carbodiimides, can be used. Carbodiimides include DCC (N,N'-dicyclohexylcarbodiimide), N,N'-diisopropylcarbodiimide, and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide. For activation with such reagents, a racemization inhibitor additive, such as HOBt or Oxyma Pure, can be used. The protected amino acid can be directly added to the resin together with the activating reagent and a racemization inhibitor, or it can be pre-activated as a symmetrical acid anhydride, and then an HOBt (hydroxybenzotriazole) ester or an HOOBt ester can be added to the resin. The solvent for activation of the protected amino acid or condensation with the resin can be appropriately selected from solvents known to be useful for peptide condensation reactions. Examples of suitable solvents include N,N-dimethylformamide, N-methylpyrrolidone, chloroform, trifluoroethanol, dimethyl sulfoxide, DMF, pyridine, dioxane, methylene chloride, tetrahydrofuran, acetonitrile, ethyl acetate, or a suitable mixture thereof. The reaction temperature can be selected from a range known to be useful for peptide bond formation, and is usually selected from the range of about -20°C to about 85°C. The activated amino acid derivative is generally used in an excess of about 1.5 to about 6 times. If the condensation is found to be insufficient by a test using the ninhydrin reaction, the condensation reaction can be repeated to achieve sufficient condensation without removing the protecting group. If repeated condensation still does not provide a sufficient degree of condensation, the unreacted amino group can be acetylated with acetic anhydride or acetylimidazole.

[0341] Protecting groups for the amino group of the starting amino acid include Z, Boc, tertiary amyloxycarbonyl, isobornyloxycarbonyl, 4-methoxybenzyloxycarbonyl, CI-Z, Br-Z, adamantyloxycarbonyl, trifluoroacetyl, phthalyl, formyl, 2-nitrophenylsulfenyl, diphenylphosphinothioyl, or Fmoc. Carboxy protecting groups that can be used include the above-mentioned (C1-C6) alkyl, (C3-C8) cycloalkyl, and (C6-C 10 )aryl-(C1-C2)alkyl and 2-adamantyl, 4-nitrobenzyl, 4-methoxybenzyl, 4-chlorobenzyl, phenacyl, benzyloxycarbonylhydrazide, tert-butoxycarbonylhydrazide, and tritylhydrazide.

[0342] The hydroxyl groups of serine and threonine can be protected by esterification or etherification. Groups suitable for the esterification include carbon-derived groups such as lower alkanoyl groups, e.g., acetyl, aroyl groups, e.g., benzoyl, benzyloxycarbonyl, and ethoxycarbonyl. Groups suitable for the etherification include benzyl, tetrahydropyranyl, and tertiary butyl. Protecting groups for the phenolic hydroxyl group of tyrosine include Bzl or Z (carboxybenzyl), Cl-Bzl, 2-nitrobenzyl, Br-Z, and tertiary butyl.

[0343] Imidazole protecting groups for histidine include Tos or Ts (tosyl), 4-methoxy-2,3,6-triethylbenzenesulfonyl, DNP (2,4-dinitrophenol), benzyloxymethyl, Bum (t-butyloxymethyl), Boc (tert-butyloxycarbonyl), Trt (triphenylmethane), and Fmoc (fluorenylmethyloxycarbonyl).

[0344] The activated carboxyl group of the starting amino acid includes the corresponding acid anhydride, azide, and active ester, for example, an ester with an alcohol, such as pentachlorophenol, 2,4,5-trichlorophenol, 2,4-dinitrophenol, cyanomethyl alcohol, p-nitrophenol, HOBn, N-hydroxysuccinimide, N-hydroxyphthalimide, HOBt (hydroxybenzotriazole), etc. The activated amino group of the starting amino acid includes the corresponding phosphoramide.

[0345] Methods for removing protecting groups include catalytic reduction using hydrogen gas in the presence of a catalyst such as palladium black or palladium on carbon; acid treatment with anhydrous hydrogen fluoride, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, or a mixture of such acids; base treatment with diisopropylethylamine, triethylamine, piperidine, or piperazine; and reduction with sodium metal in liquid ammonia. The removal reaction by acid treatment described above is generally carried out at a temperature of −20° C. to −40° C. and can be advantageously carried out by adding a cation acceptor such as anisole, phenol, thioanisole, m-cresol, p-cresol, dimethyl sulfide, 1,4-butanedithiol, or 1,2-ethanedithiol. The 2,4-dinitrophenyl group used to protect the imidazole group of histidine can be removed by treatment with thiophenol, while the formyl group used to protect the indole group of tryptophan can be removed by alkaline treatment with dilute sodium hydroxide solution or dilute aqueous ammonia, as well as by the above-mentioned acid treatment in the presence of 1,2-ethanedithiol, 1,4-butanedithiol.

[0346] Methods for protecting functional groups that should not participate in the reaction of the starting materials, protecting groups that can be used, methods for removing the protecting groups, and methods for activating functional groups that are to participate in the reaction can all be chosen fairly from among known groups and methods.

[0347] Polypeptides of formula (I) can also be prepared by methods known in the art of organic synthesis, as illustrated in part by the following synthetic schemes. In the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are used as needed, in accordance with general principles or chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T.W. Greene and P.G.M. Buts, "Protective Groups in Organic Synthesis," Third Edition, Wiley, New York 1999). These groups are removed at a convenient stage of polypeptide synthesis, using methods readily apparent to those skilled in the art. The selected steps and reaction conditions and the order of their execution are consistent with the preparation of polypeptides of formula (I).

[0348] Those skilled in the art will recognize whether a stereocenter exists in the polypeptides of formula (I). Accordingly, the present disclosure (unless otherwise specified in the synthesis) encompasses both possible stereoisomers, including not only racemic polypeptides but also individual enantiomers and / or diastereomers as well. When a polypeptide is desired as a single enantiomer or diastereomer, it can be obtained by stereospecific synthesis or by separation of the final product or any convenient intermediate. Resolution of the final product, intermediate, or starting material can be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E.L. Eliel, S.H. Wilen, and L.N. Mander (Wiley-Interscience, 1994).

[0349] The polypeptides described herein can be made from commercially available starting materials or can be synthesized using known organic, inorganic and / or enzymatic processes.

[0350] Preparation of Polypeptides The polypeptides of the present disclosure can be prepared in many ways well known to those skilled in the art of organic synthesis. As an example, the polypeptides of the present disclosure can be synthesized using the following methods, along with synthetic methods known in the art of synthetic organic chemistry or variations thereof as will be understood by those skilled in the art. Preferred methods include, but are not limited to, the following methods. The polypeptides of the present disclosure can be synthesized by following the steps outlined in General Scheme 1, which includes different orders of construction intermediates Ia, Ib, Ic, Id, and Ie. The starting materials are either commercially available or can be made by known procedures in published literature or as exemplified.

[0351] General Scheme 1 [ka] In the formula, R 1 , X 1 , X 2 , X 3 X 4 , X 5 , X 6 , X 7 , X 8 X 9 , X 10 , X 11 , X 12 and X 13 is as defined in formula (I), and PG2, PG3, PG4, PG5, PG6, PG7, PG8, PG9, PG10, PG11, PG12 and PG13 are each selected from absent, tert-butyloxycarbonyl (Boc), 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl (Pbf), or tert-butyl (tBu).

[0352] A general method for preparing polypeptides of formula (I) by using intermediates Ia, Ib, Ic, Id and Ie is outlined in general Scheme 1. Synthesis of intermediate Ib can be accomplished by coupling an amine with an acid under standard coupling conditions using an amide coupling reagent (e.g., O-(1H-6-chlorobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HCTU), O-(7-azobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) or Oxyma Pure® (ethyl cyano(hydroxyimino)acetate)) and optionally a base (e.g., triethylamine or N,N-diisopropylethylamine (DIPEA)) in a solvent (e.g., dichloromethane (DCM) or dimethylformamide (DMF)) on a resin (e.g., TentaGel™ S RAM resin), optionally at elevated temperature. Solid phase peptide synthesis is a well-established method (see, for example: Stewart and Young, Solid Phase Peptide Synthesis, Pierce Chemical Co., Rockford, Ill., 1984; E. Atherton and R.C. Sheppard, Solid Phase Peptide Synthesis. A Practical Approach, Oxford-IRL Press, New York, 1989). For example, resin Ia can be washed with DMF and then deprotected by treatment with 4-methylpiperidine / DMF. Coupling of a protected amino acid to the deprotected amine I can be accomplished under standard coupling conditions, as described above. The deprotection and coupling steps are repeated to provide intermediate Ib.

[0353] Acylation of Ib with N-succinimidyl 2-chloroacetate Ic in a solvent such as N-methyl-2-pyrrolidone (NMP) provides Id. Simultaneous removal of the protecting groups and cleavage from the resin using an appropriate reagent, such as TFA, phenol, HO, thioanisole, and / or EDT (Reagent K), provides Ie (see DSK King, CG Fields, GB Fields, Int. J. Peptide Protein Res. 36, 1990, 255-266). Cyclization of Ie using a base such as triethylamine (TEA) in a solvent such as dimethyl sulfoxide (DMSO) provides the desired polypeptide of formula (I).

[0354] In the descriptions and formulae given above, the various groups R 1 , X 1 , X 2 , X 3 X 4 , X 5 , X 6 , X 7 , X 8 X 9 , X 10 , X 11 , X 12 and X 13 and other variables are to be understood as being as defined above unless otherwise specified. Furthermore, for purposes of synthesis, the polypeptides of General Scheme 1 are merely representative polypeptides with groups selected to illustrate the general method of synthesis of the polypeptides of Formula (I) as defined herein.

[0355] Methods of Using the Disclosed Polypeptides Another aspect of the present disclosure is directed to a method for modulating PCSK9, comprising administering to a patient in need thereof an effective amount of a cyclic polypeptide of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising a cyclic polypeptide of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier.

[0356] In another aspect, the present disclosure is directed to a method of inhibiting PCSK9, comprising administering to a patient in need thereof an effective amount of a cyclic polypeptide of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising a cyclic polypeptide of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier.

[0357] Another aspect of the present disclosure relates to a method of treating, preventing, inhibiting, or eliminating a disease or disorder in which PCSK9 contributes, comprising administering to a patient in need of treatment for a disease or disorder in which PCSK9 contributes an effective amount of a cyclic polypeptide of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising a cyclic polypeptide of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier.

[0358] Another aspect of the present disclosure relates to a method of treating, preventing, inhibiting, or eliminating a disease or disorder in a patient associated with inhibition of PCSK9, comprising administering to a patient in need thereof an effective amount of a cyclic polypeptide of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising a cyclic polypeptide of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier.

[0359] In another aspect, the disclosure relates to a method of treating, preventing, inhibiting, or eliminating a PCSK9-mediated disease or disorder, comprising administering to a patient in need of treatment for a PCSK9-mediated disease or disorder an effective amount of a cyclic polypeptide of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising the cyclic polypeptide of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier.

[0360] Another aspect of the present disclosure relates to a method of treating, preventing, inhibiting, or eliminating hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, vascular inflammation, xanthomas, peripheral arterial disease, sepsis, elevated Lp(a), elevated LDL, elevated TRL, or elevated triglycerides, comprising administering to a patient in need thereof an effective amount of a cyclic polypeptide of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising a cyclic polypeptide of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.

[0361] In another aspect, the disclosure relates to a method for lowering Lp(a), lowering Lp(a) plasma levels, lowering Lp(a) serum levels, lowering serum TRL or LDL levels, lowering serum triglyceride levels, lowering LDL-C, lowering total plasma apoB concentration, lowering LDL apoB, lowering TRL apoB, or lowering non-HDL-C, comprising administering to a patient in need thereof an effective amount of a cyclic polypeptide of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising a cyclic polypeptide of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier.

[0362] In another aspect, the disclosure relates to a cyclic polypeptide of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, or a pharmaceutical composition comprising a cyclic polypeptide of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof and a pharmaceutically acceptable carrier, for use in treating, preventing, inhibiting or eliminating a disease or disorder in which PCSK9 contributes.

[0363] Another aspect of the present disclosure relates to a cyclic polypeptide of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, or a pharmaceutical composition comprising a cyclic polypeptide of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof and a pharmaceutically acceptable carrier, for use in treating, preventing, inhibiting or eliminating diseases associated with PCSK9 inhibition.

[0364] Another aspect of the present disclosure relates to a cyclic polypeptide of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, or a pharmaceutical composition comprising a cyclic polypeptide of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof and a pharmaceutically acceptable carrier for use in the treatment, prevention, inhibition or elimination of hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, vascular inflammation, xanthomas, peripheral arterial disease, sepsis, elevated Lp(a), elevated LDL, elevated TRL or elevated triglycerides.

[0365] In another aspect, the disclosure relates to a cyclic polypeptide of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, or a pharmaceutical composition comprising a cyclic polypeptide of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof and a pharmaceutically acceptable carrier for use in lowering Lp(a), lowering Lp(a) plasma levels, lowering Lp(a) serum levels, lowering serum TRL or LDL levels, lowering serum triglyceride levels, lowering LDL apoB, lowering TRL apoB or lowering non-HDL-C.

[0366] Another aspect of the present disclosure relates to the use of a cyclic polypeptide of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, or a pharmaceutical composition comprising a cyclic polypeptide of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof and a pharmaceutically acceptable carrier, for treating, preventing, inhibiting or eliminating a disease or disorder in which PCSK9 contributes.

[0367] In another aspect, the disclosure relates to the use of a cyclic polypeptide of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, or a pharmaceutical composition comprising a cyclic polypeptide of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof and a pharmaceutically acceptable carrier in the manufacture of a medicament for inhibiting PCSK9.

[0368] In another aspect, the disclosure relates to the use of a cyclic polypeptide of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, or a pharmaceutical composition comprising a cyclic polypeptide of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof and a pharmaceutically acceptable carrier, in the manufacture of a medicament for treating, preventing, inhibiting or eliminating hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, vascular inflammation, xanthomas, peripheral arterial disease, sepsis, elevated Lp(a), elevated LDL, elevated TRL or elevated triglycerides.

[0369] Another aspect of the present disclosure relates to the use of a cyclic polypeptide of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, or a pharmaceutical composition comprising a cyclic polypeptide of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof and a pharmaceutically acceptable carrier, in the manufacture of a medicament for lowering Lp(a), lowering Lp(a) plasma levels, lowering Lp(a) serum levels, lowering serum TRL or LDL levels, lowering serum triglyceride levels, lowering LDL apoB, lowering TRL apoB, or lowering non-HDL-C.

[0370] In another aspect, the disclosure relates to a cyclic polypeptide of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, or a pharmaceutical composition comprising a cyclic polypeptide of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof and a pharmaceutically acceptable carrier, for use in the manufacture of a medicament for treating a disease associated with PCSK9 inhibition.

[0371] Another aspect of the present disclosure relates to a cyclic polypeptide of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, or a pharmaceutical composition comprising a cyclic polypeptide of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof and a pharmaceutically acceptable carrier, for use in the manufacture of a medicament for treating a disease in which PCSK9 contributes.

[0372] In another aspect, the present disclosure relates to a cyclic polypeptide of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, or a pharmaceutical composition comprising a cyclic polypeptide of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof and a pharmaceutically acceptable carrier, for use in the manufacture of a medicament for treating, preventing, inhibiting or eliminating hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, vascular inflammation, xanthomas, peripheral arterial disease, sepsis, elevated Lp(a), elevated LDL, elevated TRL or elevated triglycerides.

[0373] Another aspect of the present disclosure relates to a cyclic polypeptide of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, or a pharmaceutical composition comprising a cyclic polypeptide of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof and a pharmaceutically acceptable carrier, for use in the manufacture of a medicament for lowering Lp(a), lowering Lp(a) plasma levels, lowering Lp(a) serum levels, lowering serum TRL or LDL levels, lowering serum triglyceride levels, lowering LDL apoB, lowering TRL apoB, or lowering non-HDL-C.

[0374] In another aspect, the disclosure relates to the use of an inhibitor of PCSK9 for the preparation of a medicament for use in the treatment, prevention, inhibition, or elimination of hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, peripheral arterial disease, vascular inflammation, elevated Lp(a), elevated LDL, elevated TRL, elevated triglycerides, sepsis, or xanthomas.

[0375] Another aspect of the present disclosure relates to a cyclic polypeptide of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, or a pharmaceutical composition comprising a cyclic polypeptide of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier, for use in treating a PCSK9-mediated disease or disorder.

[0376] Another aspect of the present disclosure relates to a cyclic polypeptide of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising a cyclic polypeptide of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier, for use in treating a PCSK9-mediated disease or disorder selected from hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, peripheral arterial disease, vascular inflammation, elevated Lp(a), elevated LDL, elevated TRL, elevated triglycerides, sepsis, and xanthomas.

[0377] In another aspect, the disclosure relates to the use of a cyclic polypeptide of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, or a pharmaceutical composition comprising a cyclic polypeptide of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof and a pharmaceutically acceptable carrier in the manufacture of a medicament for treating a PCSK9-mediated disease or disorder.

[0378] Another aspect of the present disclosure relates to a cyclic polypeptide of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, or a pharmaceutical composition comprising a cyclic polypeptide of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof and a pharmaceutically acceptable carrier, for use in the manufacture of a medicament for treating a PCSK9-mediated disease or disorder.

[0379] In another aspect, the present disclosure relates to the use of a cyclic polypeptide of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, or a pharmaceutical composition comprising a cyclic polypeptide of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier, for use as a medicament.

[0380] The present disclosure also relates to the use of an inhibitor of PCSK9 for the preparation of a medicament for use in the treatment, prevention, inhibition, or elimination of a disease or condition in which PCSK9 contributes, the medicament comprising a cyclic polypeptide of formula (I).

[0381] In another aspect, the disclosure relates to a method for the manufacture of a medicament for treating, preventing, inhibiting, or eliminating a disease or condition mediated by PCSK9, the medicament comprising a cyclic polypeptide of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer.

[0382] In some embodiments of the above methods, the PCSK9-mediated disease or disorder, the disease or disorder in which PCSK9 contributes, the disease or disorder in a patient associated with inhibition of PCSK9, and the disease associated with PCSK9 inhibition is selected from hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, peripheral arterial disease, vascular inflammation, elevated Lp(a), elevated LDL, elevated TRL, elevated triglycerides, sepsis, and xanthomas.

[0383] Polypeptides of the present disclosure are useful for reducing or lowering low-density lipoprotein cholesterol (LDL-C) in individuals in need thereof. The individual may have persistently high levels of LDL-C. In some embodiments, the individual has LDL-C plasma levels consistently above 70 mg / dL, e.g., greater than or equal to 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 mg / dL. Polypeptides of the present disclosure may also be used to reduce or lower non-high-density lipoprotein cholesterol (non-HDL-C) or total cholesterol in individuals in need thereof.

[0384] The present disclosure also relates to methods for improving blood cholesterol markers associated with increased risk of heart disease. These markers include high total cholesterol, high LDL, high total cholesterol to HDL ratio, and high LDL to HDL ratio. Total cholesterol below 200 mg / dL is considered desirable, 200-239 mg / dL is considered borderline high, and above 240 mg / dL is considered high.

[0385] In a further aspect, the present disclosure provides a method of lowering LDL-C, non-HDL-C and / or total cholesterol in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a polypeptide as described herein.

[0386] In another embodiment, the present disclosure relates to a cyclic polypeptide of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising a cyclic polypeptide of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, of the present disclosure, and a pharmaceutically acceptable carrier, for use in treating diseases including, but not limited to, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, peripheral arterial disease, vascular inflammation, elevated Lp(a), elevated LDL, elevated TRL, elevated triglycerides, sepsis, and xanthomas.

[0387] In one embodiment, a method is provided for treating a disease or disorder in which PCSK9 contributes, including hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, peripheral arterial disease, vascular inflammation, elevated Lp(a), elevated LDL, elevated TRL, elevated triglycerides, sepsis, and xanthomas, comprising administering a cyclic polypeptide of Formula (I) to a patient suffering from at least one of said diseases or disorders.

[0388] The disclosed polypeptides can be administered in an effective amount to treat or prevent a disorder and / or prevent its onset in a subject.

[0389] The disclosed polypeptides can be administered in an effective amount to treat or prevent a disorder and / or prevent its onset in a subject.

[0390] Administration, Pharmaceutical Compositions, and Dosing of the Disclosed Polypeptides Administration of the disclosed polypeptides can be accomplished via any mode of administration for therapeutic agents, including systemic or local administration, such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal, or topical modes of administration.

[0391] Depending on the intended mode of administration, the disclosed compositions may be in solid, semi-solid, or liquid dosage forms, such as injectables, tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, solutions, suspensions, and the like, often in unit dosage amounts, consistent with conventional pharmaceutical practice. Likewise, they may also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous, or intramuscular form, and all using forms well known to those of skill in the pharmaceutical arts.

[0392] Another aspect of the present disclosure is directed to a pharmaceutical composition comprising a cyclic polypeptide of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may further comprise an excipient, diluent, or surfactant. In a further embodiment, the composition comprises at least two pharmaceutically acceptable carriers, such as those described herein. The pharmaceutical composition may be formulated for a specific route of administration, such as oral administration, parenteral administration (e.g., by injection, infusion, transdermal, or topical administration), and rectal administration. Topical administration may also refer to inhalation or intranasal application. The pharmaceutical compositions of the present disclosure may be configured in solid form (including, but not limited to, capsules, tablets, pills, granules, powders, or suppositories) or in liquid form (including, but not limited to, solutions, suspensions, or emulsions). Tablets may be film-coated or enteric-coated according to methods known in the art. Typically, the pharmaceutical composition is a tablet or gelatin capsule containing the active ingredient together with one or more of the following: a) diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) lubricants, such as silica, talc, stearic acid, its magnesium or calcium salts and / or polyethylene glycol; for tablets, c) binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; optionally d) disintegrants, such as starch, agar, alginic acid or its sodium salt or effervescent mixtures; and e) Absorbents, colorants, flavorings and sweeteners.

[0393] Liquid, particularly injectable, compositions can be prepared, e.g., by dissolving, dispersing, etc. For example, the disclosed polypeptides are dissolved in or mixed with a pharmaceutically acceptable solvent, e.g., water, saline, aqueous dextrose, glycerol, ethanol, etc., to thereby form an isotonic solution or suspension for injection. Proteins such as albumin, chylomicron particles, or serum proteins can be used to solubilize the disclosed polypeptides.

[0394] The disclosed polypeptides can also be formulated as suppositories which can be prepared from fatty emulsions or suspensions, using polyalkylene glycols, such as propylene glycol, as the carrier.

[0395] Parenteral injectable administration is generally used for subcutaneous, intramuscular, or intravenous injections and infusions. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, or as solid forms suitable for dissolving in liquid prior to injection.

[0396] The compositions can be prepared according to conventional mixing, granulating, or coating methods, respectively, and the pharmaceutical compositions can contain about 0.1% to about 99%, about 5% to about 90%, or about 1% to about 20% by weight or volume of the disclosed polypeptides.

[0397] Dosage regimens utilizing the disclosed polypeptides are selected according to a variety of factors, including the type, species, age, weight, sex, and medical condition of the patient; the severity of the condition to be treated; the route of administration; the patient's renal or hepatic function; and the particular disclosed polypeptide used. A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the drug required to prevent the progress of, counter, or arrest the condition.

[0398] When used for a designated effect, an effective dosage of the disclosed cyclic polypeptides, pharmaceutical compositions, or combinations ranges from about 0.5 mg to about 5,000 mg of the disclosed polypeptides, as needed to treat a condition. Compositions for in vivo or in vitro use can contain about 0.5, 5, 20, 50, 75, 100, 150, 250, 500, 750, 1,000, 1,250, 2,500, 3,500, or 5,000 mg of the disclosed polypeptides, or a range from one amount to another listed in the dosage table. In one embodiment, the composition is in the form of a scorable tablet. The therapeutically effective dosage of the cyclic peptides, pharmaceutical compositions, or combinations thereof depends on the species, weight, age, and individual condition of the subject, and the disorder or disease being treated, or its severity. A physician, clinician, or veterinarian of ordinary skill can readily determine the effective amount of each active ingredient required to prevent, treat, or inhibit the progression of a disorder or disease.

[0399] The above-cited dosage characteristics are demonstrable by in vitro and in vivo tests, preferably using mammals, e.g., mice, rats, dogs, monkeys, or isolated organs, tissues, and preparations thereof. The cyclic polypeptides of the present disclosure can be applied in vitro in the form of solutions, e.g., aqueous solutions, and in vivo enterally, parenterally, advantageously intravenously, e.g., as a suspension or in aqueous solution. In vitro dosages can range from about 10-3 molar to 10-9 molar concentrations. In vivo therapeutically effective amounts can range from about 0.1 to 500 mg / kg, or from about 1 to 100 mg / kg, depending on the route of administration.

[0400] Combination therapy The cyclic polypeptides of the present application can be administered in therapeutically effective amounts in combination therapy (pharmaceutical combinations) with one or more therapeutic agents, or in modalities, e.g., non-pharmacologic, such as synergistic effects with other cardiovascular drugs, antihypertensives, coronary vasodilators, and diuretics. When the polypeptides of the present application are administered in conjunction with other therapeutic agents, the dosage of the co-administered polypeptide will, of course, vary depending on the type of co-administered drug used, the specific drug used, the condition being treated, and the like.

[0401] Cyclic polypeptides of the present disclosure can be administered simultaneously with, before, or after one or more other therapeutic agents. Cyclic polypeptides of the present disclosure can be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition as other agents. A therapeutic agent is, for example, a chemical compound, peptide, antibody, antibody fragment, or nucleic acid that is therapeutically active or enhances therapeutic activity when administered to a patient in combination with a cyclic polypeptide of the present disclosure.

[0402] In one embodiment, the present disclosure provides a product comprising a cyclic polypeptide of the present disclosure and at least one other therapeutic agent as a combined preparation for simultaneous, separate, or sequential use in therapy. In one embodiment, the therapy is treatment of a disease or condition mediated by PCSK9. The product provided as a combined preparation may comprise a composition comprising a cyclic polypeptide of the present disclosure and another therapeutic agent together in the same pharmaceutical composition, or may comprise a cyclic polypeptide of the present disclosure and another therapeutic agent in separate forms, for example, in the form of a kit.

[0403] In another aspect, the present disclosure includes a cyclic polypeptide of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI) or a polypeptide according to any one of embodiments 1-50 or any embodiment of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), and / or Formula (VI) described herein, or a pharmaceutically acceptable salt thereof, for use in combination therapy. Compositions, agents, and polypeptides for use of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI) or a polypeptide according to any one of embodiments 1-50 or a polypeptide according to any embodiment of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), and / or Formula (VI) described herein, or a pharmaceutically acceptable salt thereof, may also be advantageously used in combination with one or more other therapeutic agents.

[0404] Another aspect of the present disclosure is directed to a pharmaceutical composition comprising a cyclic polypeptide of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, a pharmaceutically acceptable carrier, and one or more therapeutic agents. The pharmaceutically acceptable carrier may further comprise an excipient, diluent, or surfactant.

[0405] Combination therapy includes administration of the subject polypeptides in further combination with other biologically active ingredients (such as, but not limited to, a second drug, e.g., a cardiovascular drug, an adrenergic receptor blocker, an antihypertensive drug, an angiotensin system inhibitor, an angiotensin-converting enzyme (ACE) inhibitor, a coronary vasodilator, a diuretic or adrenergic stimulant, or a second drug targeting PCSK9) and non-drug therapies (such as, but not limited to, surgery or radiation therapy). For example, the subject polypeptides can be used in combination with other pharmaceutically active compounds or polypeptides, preferably compounds or polypeptides that can enhance the effects of the subject polypeptides. The subject polypeptides can be administered simultaneously (as a single preparation or separate preparations) or sequentially with other drug therapies or treatment modalities. Generally, combination therapy contemplates the administration of two or more drugs during a single cycle or series of treatment.

[0406] In some embodiments, the polypeptides of the present application may be used in combination with agents known to be beneficial for lowering cholesterol and total cholesterol and / or raising HDL-C, including LDL-C, non-HDL-C, and triglyceride lowering agents.

[0407] Representative therapeutic agents that may be used in combination with the polypeptides of the present disclosure include, but are not limited to, lipid-lowering agents, niacin and its analogs, bile acid sequestrants, thyroid hormone mimetics, thyroid hormone receptor (THR) β-selective agonists, microsomal triglyceride transfer protein (MTP) inhibitors, acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) inhibitors, Niemann-Pick C1-like 1 (NPC1-L1) inhibitors, agonists of ATP-binding cassette (ABC) proteins G5 or G8, inhibitory nucleic acids targeting PCSK9, inhibitory nucleic acids targeting apoB100, apoA-I upregulators / inducers, ABCA1 stabilizers or inducers, phospholipid transfer protein (PLTP) inhibitors, fish oil, antidiabetic agents, antiobesity agents, agonists of peroxisome proliferator-activated receptors, ATP citrate lyase (ACL) inhibitors, and antihypertensive agents.

[0408] Examples of lipid-lowering drugs that may be used in combination with the polypeptides of the present disclosure include, but are not limited to, HMG-CoA reductase inhibitors, squalene synthase inhibitors, LXR agonists, FXR agonists, fibrates, cholesterol absorption inhibitors, nicotinic acid bile acid binding resins, nicotinic acid and other GPR109 agonists, and aspirin.

[0409] HMG-CoA reductase inhibitors (i.e., statins) are a class of drugs used to lower cholesterol levels by inhibiting the enzyme HMG-CoA reductase, which plays a central role in cholesterol production in the liver. Elevated cholesterol levels are associated with cardiovascular disease, and therefore statins are used in the prevention of these diseases. Representative statins include, but are not limited to, atorvastatin, cerivastatin, compactin, dalvastatin, dihydrocompactin, fluindostatin, fluvastatin, lovastatin, pitavastatin, mevastatin, pravastatin, rivastatin, simvastatin, and velostatin, or pharmaceutically acceptable salts thereof.

[0410] Fibrates or fibric acid derivatives lower triglycerides and increase HDL cholesterol. They may have little effect on LDL cholesterol. For example, gemfibrozil or fenofibrate is prescribed for people with very high triglycerides or low HDL and high triglycerides. Gemfibrozil can be used to reduce the risk of heart attack in people with coronary artery disease (CAD) who have low HDL and elevated triglycerides. Examples of fibrates include, but are not limited to, clofibrate, gemfibrozil, fenofibrate, ciprofibrate, and bezafibrate.

[0411] Cholesterol absorption inhibitors are a class of compounds that prevent cholesterol from being absorbed into the circulation from the small intestine, and subsequently reduce plasma LDL-C levels. Elevated cholesterol levels are associated with increased CVD risk; therefore, cholesterol absorption inhibitors are used to reduce CVD risk. A non-limiting example of a cholesterol absorption inhibitor is ezetimibe, formerly known as "Sch-58235." Another example is Sch-48461. Both compounds are being developed by Schering-Plough.

[0412] Examples of bile acid sequestrants that may be used in combination with the polypeptides of the present disclosure include, but are not limited to, cholestyramine, colestipol, and colesevelam.

[0413] A non-limiting example of a thyromimetic drug that may be used in combination with the polypeptides of the present disclosure is the compound KB2115.

[0414] A non-limiting example of a thyroid hormone receptor (THR) β-selective agonist that may be used in combination with the polypeptides of the present disclosure is MGL-3196.

[0415] DGAT is an enzyme that catalyzes the final step in triacylglycerol biosynthesis. DGAT catalyzes the coupling of fatty acyl-CoA with 1,2-diacylglycerol, resulting in coenzyme A and triacylglycerol. Two enzymes exhibiting DGAT activity have been identified: DGAT1 (acyl-coA-diacylglycerol acyltransferase 1, see Cases et al., Proc. Natl. Acad. Sci. 95:13018-13023, 1998) and DGAT2 (acyl-coA-diacylglycerol acyltransferase 2, see Cases et al., J. Biol. Chem. 276:38870-38876, 2001). DGAT1 and DGAT2 do not share significant protein sequence homology. Importantly, DGAT1 knockout mice are protected from high-fat diet-induced weight gain and insulin resistance (Smith et al., Nature Genetics 25:87-90, 2000). The phenotype of DGAT1 knockout mice suggests that DGAT1 inhibitors are useful for treating obesity and obesity-related complications. DGAT1 inhibitors useful in the combination are, for example, the compounds and analogs generally and specifically disclosed in WO 2007 / 126957 and WO 2009 / 040410, particularly the compound claims and examples, the subject matter of the final products, pharmaceutical formulations and claims.

[0416] Examples of suitable DGAT1 inhibitors for use in combination with the polypeptides of the present disclosure include {4-[4-(3-methoxy-5-phenylamino-pyridin-2-yl)-phenyl]-cyclohexyl}-acetic acid, (4-{4-[5-(1-methyl-1H-pyrazol-3-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-acetic acid, (4-{4-[5-(5-fluoro-6-methoxy-pyridin-3-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-acetic acid, (4-{5-[5-(6-trifluoro- Methyl-pyridin-3-ylamino)-pyridin-2-yl]-spirocyclohexylidenyl-1,1'-indanyl}-acetic acid, (4-{4-[5-(benzoxazol-2-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-acetic acid, 4-(4-{4-[2-(3-chlorophenylamino)-oxazol-5-yl]-phenyl}-cyclohexyl)-butyric acid, (4-{4-[5-(6-trifluoromethyl-pyridin-3-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-acetic acid, (6-{ 4-[4-(2H-Tetrazol-5-ylmethyl)-cyclohexyl]-phenyl}-pyridazin-3-yl)-(6-trifluoromethyl-pyridin-3-yl)-amine, 3-(4-{4-[6-(6-trifluoromethyl-pyridin-3-ylamino)-pyridazin-3-yl]-phenyl}-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one, (1-{4-[6-(3-trifluoromethyl-phenylamino)-pyridazin-3-yl]-phenyl}-piperidin-4-yl)-acetic acid, (4-{4- [4-Methyl-6-(6-trifluoromethyl-pyridin-3-ylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-acetic acid, (4-{4-[5-(6-trifluoromethyl-pyridin-3-ylamino)-pyrazin-2-yl]-phenyl}-cyclohexyl)-acetic acid, 6-[5-(4-chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-2-(2,6-dichloro-phenyl)-1H-benzimidazole, 6-(5-cyclohexyl-[1,3,4]oxadiazol-2-yl)-2-(2,6-dichloro-phenyl)-1H-benzimidazole, 6-(5-butyl-[1,3,4]oxadiazol-2-yl)-2-(2,6-dichloro-phenyl)-1H-benzimidazole, 2-(2,6-dichloro-phenyl)-6-[5-(5-methyl-pyridin-3-yl)-[1,3,4]oxadiazol-2-yl]-1H-benzimidazole, 6-[5-(4-chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-2-(2,6-dimethyl-4-morpholin-4-yl-phenyl)-1H-benzimidazole, 6 -[5-(4-chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-2-(3,5-dichloro-pyridin-4-yl)-1H-benzimidazole, 3-(4-{5-[5-(4-methoxy-phenyl)-[1,3,4]oxadiazol-2-yl]-1H-benzimidazol-2-yl}-3,5-dimethyl-phenyl)-2,2-dimethyl-propionic acid, 3-(4-{6-[5-(4-methoxy-phenyl)-[1,3,4]oxadiazol-2-yl]-1H-benzimidazol-2-yl}-3,5-dimethyl-phenyl) phenyl)-propionic acid, 3-(4-{6-[5-(4-methoxyphenylamino)-[1,3,4]oxadiazol-2-yl]-1H-benzimidazol-2-yl}-3,5-dimethylphenyl)-propionic acid, [3-(4-{6-[5-(4-chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-1H-benzimidazol-2-yl}-3,5-dimethyl-phenyl)-propyl]-phosphonic acid, 2-(2,6-dichloro-phenyl)-6-(4,5-diphenyl-oxazol-2-yl)-1H-benzimidazole, ( Examples of suitable benzophenone-based compounds include, but are not limited to, 4-{6-[5-(4-chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-1H-benzimidazol-2-yl}-3,5-dimethyl-phenoxy)-acetic acid, 2-(2,6-dichloro-phenyl)-6-(5-pyrrolidin-1-yl-[1,3,4]oxadiazol-2-yl)-1H-benzimidazole, and 3,5-dimethyl-4-{6-[5-(4-trifluoromethyl-phenylamino)-[1,3,4]oxadiazol-2-yl]-1H-benzimidazol-2-yl}-phenol.

[0417] A non-limiting example of a Niemann-Pick C1-like 1 (NPC1-L1) inhibitor that may be used in combination with the polypeptides of the present disclosure is ezetimibe.

[0418] Apolipoprotein AI is a protein encoded by the APOA1 gene in humans. It plays a specific role in lipid metabolism. Apolipoprotein AI is the major protein component of high-density lipoprotein (HDL) in plasma. Chylomicrons secreted from enterocytes also contain ApoA-I, but it is rapidly converted to HDL in the bloodstream. This protein promotes cholesterol export from tissues to the liver for excretion. It is a cofactor for lecithin cholesterol acyltransferase (LCAT), which is responsible for the formation of most plasma cholesterol esters. Infusion of a mutant form of apoA-I in humans has been shown to resolve atherosclerotic plaques as assessed by intravascular ultrasound; therefore, apoA-I has the potential to both reduce CVD risk, slow progression, and induce the resolution of atherosclerosis. A non-limiting example of an apoA-I upregulator / inducer is RVX208.

[0419] ABCA1 (human transporter subfamily ABCA member 1), an ATP-binding cassette transporter, also known as cholesterol efflux control protein (CERP), is a protein encoded by the ABCA1 gene in humans. This transporter is a key regulator of cellular cholesterol and phospholipid homeostasis. A non-limiting example of an ABCA1 regulator is probucol. Probucol reduces cholesterol levels in the bloodstream by increasing the rate of LDL catabolism. Furthermore, probucol can inhibit cholesterol synthesis and slow cholesterol absorption. Probucol is a potent antioxidant that inhibits the oxidation of cholesterol in LDL; this slows the formation of foam cells that contribute to atherosclerotic plaques.

[0420] Liver X receptors (LXRs) are members of the nuclear receptor family of transcription factors and are closely related to nuclear receptors such as PPARs, FXRs, and RXRs. Liver X receptors (LXRs) are important regulators of cholesterol, fatty acid, and glucose homeostasis. LXR agonists are effective in treating mouse models of atherosclerosis, diabetes, anti-inflammation, and Alzheimer's disease. Treatment with LXR agonists (including, but not limited to, hypocholamide, T0901317, GW3965, or N,N-dimethyl-3-beta-hydroxy-cholenamide (DMHCA)) reduces serum and liver cholesterol levels and inhibits the development of atherosclerosis in mouse disease models. Examples of LXR agonists include, but are not limited to, GW3965 (a synthetic non-steroidal liver X receptor (LXR) agonist / activator) and T0901317 (a dual LXR, FXR agonist).

[0421] The farnesoid X receptor (FXR), also known as NR1H4 (nuclear receptor subfamily 1, group H, member 4), is an active nuclear hormone receptor similar to those found in other steroid receptors such as estrogen or progesterone, but more similar in form to PPARs, LXRs, and RXRs. Activation of the nuclear receptor FXR is known to ameliorate hyperglycemia and hyperlipidemia. A non-limiting example of an FXR agonist is GW4064 (3-(2,6-dichlorophenyl)-4-(3'-carboxy-2-chlorostilbene-4-yl)oxymethyl-5-isopropylisoxazole).

[0422] Phospholipid transfer protein (PLTP) is a protein encoded by the PLTP gene in humans. The protein encoded by this gene is one of at least two lipid transfer proteins found in human plasma, the other being CETP. The encoded protein transfers phospholipids from triglyceride-rich lipoproteins to HDL. In addition to regulating the size of HDL particles, this protein may be involved in cholesterol metabolism. At least two transcriptional variants encoding different isoforms have been discovered for this gene. Because PLTP affects the metabolism of both triglyceride-rich lipoproteins and HDL, modulation of this transport protein has the potential to alter cardiovascular disease risk.

[0423] Fish oil is derived from oily fish tissue. Fish oil contains the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), precursors of eicosanoids, which are known to have many health benefits. Fish oil and other omega-3 sources are most highly recommended for the following conditions: hypertriglyceridemia, secondary cardiovascular disease, and hypertension prevention. For example, Lovaza® is used in conjunction with a low-fat and low-cholesterol diet to reduce very high triglycerides (fats) in your blood. Examples of omega-3 fatty acids that can be used in combination with the polypeptides of the present disclosure include, but are not limited to, Lovaza® and Vascepa® (icosapent ethyl).

[0424] Examples of antidiabetic agents that may be used in combination with the polypeptides of the present disclosure include insulin, insulin derivatives and mimetics; insulin secretagogues, such as sulfonylureas; insulinotropic sulfonylurea receptor ligands, such as meglitinides, e.g., nateglinide and repaglinide; protein tyrosine phosphatase-1B (PTP-1B) inhibitors, including but not limited to PTP-112; GSK3 (glycogen synthase kinase-3) inhibitors, including but not limited to SB-517955, SB-4195052, SB-216763, NN-57-05441, and NN-57-05445; RXR ligands, including but not limited to GW-0791 and AGN-194204; sodium-dependent glucose cotransporter inhibitors, including but not limited to T-1095; These include, but are not limited to, glycogen phosphorylase A inhibitors, including but not limited to R3401; biguanides, including but not limited to metformin; alpha-glucosidase inhibitors, including but not limited to acarbose; GLP-1 (glucagon-like peptide-1), GLP-1 analogs, including but not limited to exendin-4 and GLP-1 mimetics; and DPPIV (dipeptidyl peptidase IV) inhibitors, including but not limited to vildagliptin.

[0425] Examples of sulfonylureas include, but are not limited to, tolbutamide, chlorpropamide, tolazamide, acetohexamide, 4-chloro-N-[(1-pyrrolidinylamino)carbonyl]-benzenesulfonamide (glycopyramide), glibenclamide (glyburide), gliclazide, 1-butyl-3-methanilyl urea, carbutamide, glibonuride, glipizide, gliquidone, glisoxepide, glybuthiazole, glybuzole, glyhexamide, glymidine, glipinamide, fenbutamide, amaryl, and tolylcyclamide) or pharmaceutically acceptable salts thereof.

[0426] DPP-IV (dipeptidyl peptidase IV) is involved in inactivating GLP-1. Specifically, DPP-IV generates a GLP-1 receptor antagonist, thereby shortening the physiological response to GLP-1. GLP-1 is the primary stimulator of pancreatic insulin secretion and has direct beneficial effects on glucose disposal.

[0427] DPP-IV inhibitors may be peptidic or, preferably, non-peptidic. DPP-IV inhibitors include, but are not limited to, those generally and specifically disclosed in, for example, WO 98 / 19998, DE 196 16 486 A1, WO 00 / 34241 and WO 95 / 15309, in each case in particular the compound claims and the final products of the examples, the subject matter of which, pharmaceutical formulations and claims are hereby incorporated into the present application by reference.

[0428] GLP-1 (glucagon-like peptide-1) is an insulinotropic protein, as described, for example, in W. E. Schmidt et al. in Diabetologia, 28, 1985, 704-707 and U.S. Pat. No. 5,705,483. The term "GLP-1 agonist" includes, in particular, variants and analogs of GLP-1(7-36)NH2, as disclosed in U.S. Pat. Nos. 5,120,712, 5,118,666, 5,512,549, WO 91 / 11457, and in C. Orskov et al. in J. Biol. Chem., 264 (1989) 12826. Further examples include GLP-1(7-37), in which Arg 36 The carboxy-terminal amide functionality of the GLP-1(7-36)NH2 molecule and the GLN 9 -GLP-1(7-37), D-GLN 9 -GLP-1(7-37), acetyl LYS 9 -GLP-1(7-37), LYS 18-GLP-1(7-37) and in particular GLP-1(7-37)OH, VAL 8 -GLP-1(7-37), GLY 8 -GLP-1(7-37), THR 8 -GLP-1(7-37), MET 8 -GLP-1(7-37) and its variants and analogs, including 4-imidazopropionyl-GLP-1, where Gly is substituted at position 37. Also particularly preferred is the GLP agonist analog exendin-4 described by Greig, et al. in Diabetologia, 1999, 42, 45-50.

[0429] Also included within the definition of "antidiabetic drug" are insulin sensitizers, which restore impaired insulin receptor function, thereby reducing insulin resistance and thereby enhancing insulin sensitivity. Examples include hypoglycemic thiazolidinedione derivatives (e.g., glitazones, (S)-((3,4-dihydro-2-(phenyl-methyl)-2H-1-benzopyran-6-yl)methyl-thiazolidine-2,4-dione (englitazone), 5-{[4-(3-(5-methyl-2-phenyl-4-oxazolyl)-1-oxopropyl)-phenyl]-methyl}-thiazolidine-2,4-dione (darglitazone)). ), 5-{[4-(1-methyl-cyclohexyl)methoxy)-phenyl]methyl}-thiazolidine-2,4-dione (ciglitazone), 5-{[4-(2-(1-indolyl)ethoxy)phenyl]methyl}-thiazolidine-2,4-dione (DRF2189), 5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)-ethoxy)]benzyl}-thiazolidine-2,4-dione (BM-13.1246), 5-(2-naphthylsulfonyl)-thiazolidine-2,4-dione (AY-31637), bis{4-[(2,4-dioxo-5-thiazolidinyl)methyl]phenyl}methane (YM268), 5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)-2-hydroxyethoxy]benzyl}-thiazolidine-2,4-dione (AD-5075), 5-[4-(1-phenyl-1-cyclopropanecarbonylamino)-benzyl]- Thiazolidine-2,4-dione (DN-108) 5-{[4-(2-(2,3-dihydroindol-1-yl)ethoxy)phenyl]methyl}-thiazolidine-2,4-dione, 5-[3-(4-chlorophenyl)-2-propynyl]-5-phenylsulfonyl)thiazolidine-2,4-dione, 5-[3-(4-chlorophenyl)-2-propynyl]-5-(4-fluorophenylsulfonyl)thiazolidine-2,4-dione, 5-{[4-(2 -(methyl-2-pyridinyl-amino)-ethoxy)phenyl]methyl}-thiazolidine-2,4-dione (rosiglitazone), 5-{[4-(2-(5-ethyl-2-pyridyl)ethoxy)phenyl]-methyl}thiazolidine-2,4-dione (pioglitazone), 5-{[4-((3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methoxy)-phenyl]-methyl}-thiazolidine-2,4- Dione (troglitazone), 5-[6-(2-fluoro-benzyloxy)naphthalen-2-ylmethyl]-thiazolidine-2,4-dione (MCC555), 5-{[2-(2-naphthyl)-benzoxazol-5-yl]-methyl}thiazolidine-2,4-dione (T-174), and 5-(2,4-dioxothiazolidin-5-ylmethyl)-2-methoxy-N-(4-trifluoromethyl-benzyl)benzamide (KRP297)).

[0430] Examples of anti-obesity agents that may be used in combination with the polypeptides of the present disclosure include, but are not limited to, orlistat, sibutramine, phentermine, and cannabinoid receptor 1 (CB1) antagonists such as rimonabant.

[0431] Examples of peroxisome proliferator-activated receptor agonists that may be used in combination with the polypeptides of the present disclosure include, but are not limited to, fenofibrate, pioglitazone, rosiglitazone, tesaglitazar, BMS-298585, L-796449, specifically the compounds described in patent application WO 2004 / 103995, i.e., the compounds of Examples 1 to 35 or the compounds specifically listed in claim 21, or the compounds specifically described in WO 03 / 043985, i.e., the compounds of Examples 1 to 7 or the compounds specifically listed in claim 19, and in particular (R)-1-{4-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-benzenesulfonyl}-2,3-dihydro-1H-indole-2-carboxyl or a salt thereof.

[0432] Examples of lipid-lowering drugs that may be used in combination with the polypeptides of the present disclosure include, but are not limited to, HMG-CoA reductase inhibitors, squalene synthase inhibitors, LXR agonists, FXR agonists, fibrates, cholesterol absorption inhibitors, nicotinic acid bile acid binding resins, bempedoic acid, nicotinic acid and other GPR109 agonists, and aspirin.

[0433] Examples of antihypertensive agents that may be used in combination with the polypeptides of the present disclosure include, but are not limited to, loop diuretics; angiotensin-converting enzyme (ACE); inhibitors of the Na-K-ATPase membrane pump; neutralendopeptidase (NEP) inhibitors; ACE / NEP inhibitors; angiotensin II antagonists; renin inhibitors; beta-adrenergic receptor blockers; inotropes; calcium channels; aldosterone receptor antagonists; and aldosterone synthase inhibitors.

[0434] Examples of loop diuretics that may be used in combination with the polypeptides of the present disclosure include, but are not limited to, ethacrynic acid, furosemide, and torsemide.

[0435] The term "ACE-inhibitors" (also called angiotensin-converting enzyme inhibitors) includes molecules that interfere with the enzymatic breakdown of angiotensin I to angiotensin II. Such compounds can be used for controlling blood pressure and for treating congestive heart failure. Examples include, but are not limited to, alacepril, benazepril, benazeprilat, captopril, ceronapril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, imidapril, lisinopril, moexipril, mobertopril, perindopril, quinapril, ramipril, spirapril, temocapril, and trandolapril, or pharmaceutically acceptable salts thereof.

[0436] A non-limiting example of an inhibitor of the Na-K-ATPase membrane pump is digoxin.

[0437] The term "NEP inhibitor" refers to a compound that inhibits neutral endopeptidase (NEP). Examples include, but are not limited to, candoxatril, candoxatrilat, dexecadotril, ecadotril, racecadotril, sampatrilat, fasidotril, omapatrilat, gemopatrilat, daglutril, SCH-42495, SCH-32615, UK-447841, AVE-0848, PL-37, and (2R,4s)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester or a pharmaceutically acceptable salt thereof. NEP inhibitors also include phosphono / biaryl-substituted dipeptide derivatives, such as those disclosed in U.S. Pat. No. 5,155,100. NEP inhibitors also include N-mercaptoacylphenylalanine derivatives such as those disclosed in WO 2003 / 104200. NEP inhibitors also include dual-action antihypertensive agents such as those disclosed in WO 2008 / 133896, WO 2009 / 035543, or WO 2009 / 134741. Other examples include compounds disclosed in U.S. Patent Application Nos. 12 / 788,794; 12 / 788,766; and 12 / 947,029. NEP inhibitors also include compounds disclosed in WO 2010 / 136474, WO 2010 / 136493, WO 2011 / 061271, WO 2012 / 065953, WO 2012 / 065956, WO 2014 / 126979, and WO 2014 / 015965. Other examples of NEP inhibitors are the compounds disclosed in WO2015116786, WO2015116760, WO2014138053, WO2014025891, WO2013184934, WO2013067163, WO2012166389, WO2012166387, WO2012112742, and WO2012082853.

[0438] The term "ACE / NEP inhibitor" refers to a compound that inhibits both angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP). Examples of ACE / NEP inhibitors that may be used in combination with the polypeptides of the present disclosure include, but are not limited to, omapatrilat, sampatrilat, and fasidotril.

[0439] The class of angiotensin II antagonists or AT1 receptor antagonists includes compounds with different structural characteristics, and essentially non-peptide ones are preferred. Examples of angiotensin II antagonists that can be used in combination with the polypeptides of the present disclosure include valsartan, losartan, candesartan, eprosartan, irbesartan, sapirisartan, tasosartan, telmisartan, compounds of the following formulas named E-1477 and ZD-8731: [ka] Or, in each case, includes, but is not limited to, a pharmaceutically acceptable salt thereof.

[0440] The term "renin inhibitor" includes ditekiren (chemical name: [1S-[1R,2R,4R(1R,2R)]]-1-[(1,1-dimethylethoxy)carbonyl]-L-prolyl-L-phenylalanyl-N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[[(2-pyridinylmethylamino]carbonyl]butyl]amino]carbonyl]hexyl]-N-alpha-methyl-L-histidineamide), tellurakiren (chemical name: [R-(R,S)]-N-(4-morpholinylcarbonyl)-L-phenylalanyl-N-[1-(cyclohexylmethyl)-2-hydroxy-3-(1-methylethoxy)-3-oxopropyl]-S-methyl-L-cysteinamide); aliskiren (chemical name: (2S,4s,5 S,7S)-5-amino-N-(2-carbamoyl-2,2-dimethylethyl)-4-hydroxy-7-{[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl}-8-methyl-2-(propan-2-yl)nonanamide) and Zankylene (chemical name: [1S-[1R[R(R)],2S,3r]]-N-[1-(cyclohexylmethyl)-2,3-dihydroxy-5-methylhexyl]-alpha-[[2-[[(4-methyl-1-piperazinyl)sulfonyl]methyl]-1-oxo-3-phenylpropyl]-amino]-4-thiazolepropanamide) or its hydrochloride salt, or SPP630, SPP635 and SPP800 developed by Speedel, or RO66-1132 and RO66-1168 of formula (A) and (B): [ka] or a pharmaceutically acceptable salt thereof. The term "aliskiren", unless otherwise defined, is to be understood as both the free base and a salt thereof, particularly a pharmaceutically acceptable salt thereof, most preferably the hemifumarate salt thereof.

[0441] Examples of beta-adrenergic receptor blockers that may be used in combination with the polypeptides of the present disclosure include, but are not limited to, acebutolol, atenolol, betaxolol, bisoprolol, metoprolol, nadolol, propranolol, sotalol, and timolol.

[0442] Examples of inotropic agents that may be used in combination with the polypeptides of the present disclosure include, but are not limited to, digoxin, dobutamine, and milrinone; inotropic agents as used herein include, for example, dobutamine, isoproterenol, milrinone, amilinone, levosimendan, epinephrine, norepinephrine, isoproterenol, and digoxin.

[0443] Examples of calcium channel blockers that may be used in combination with the polypeptides of the present disclosure include, but are not limited to, amlodipine, bepridil, diltiazem, felodipine, nicardipine, nimodipine, nifedipine, nisoldipine, and verapamil.

[0444] The class of aldosterone synthase inhibitors includes both steroidal and non-steroidal aldosterone synthase inhibitors, the latter being most preferred. The class of aldosterone synthase inhibitors includes compounds with a variety of structural characteristics. An example of an aldosterone synthase inhibitor that may be used in combination with the polypeptides of the present disclosure is the (+)-enantiomer of the hydrochloride salt of fadrozole (U.S. Pat. Nos. 4,617,307 and 4,889,861), of the formula: [ka] or, where appropriate, pharmaceutically acceptable salts thereof; and compounds and analogs, including but not limited to those compounds and analogs disclosed generically and specifically in U.S. Patent Application Publication No. 2007 / 0049616, the particular claimed compounds and end products, subject matter of the end products, pharmaceutical formulations, and claims of the Examples being hereby incorporated by reference into this application. Examples of aldosterone synthase inhibitors that may be used in combination with the polypeptides of the present disclosure include 4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-methylbenzonitrile; 5-(2-chloro-4-cyanophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylic acid (4-methoxybenzyl)methylamide; 4'-fluoro-6-(6,7,8,9-tetrahydro- -5H-Imidazo[1,5-a]azepin-5-yl)biphenyl-3-carbonitrile;5-(4-cyano-2-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylic acid butyl ester;4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-2-methoxybenzonitrile;5-(2-chloro-4-cyanophenyl)-6,7-dihydro-5H-pyrrolo[1, 2-c]imidazole-5-carboxylic acid 4-fluorobenzyl ester;5-(4-cyano-2-trifluoromethoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylic acid methyl ester;5-(4-cyano-2-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylic acid 2-isopropoxyethyl ester;4-(6,7-dihydro-5H-pyrrolo [1,2-c]imidazol-5-yl)-2-methylbenzonitrile; 4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-fluorobenzonitrile; 4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-2-methoxybenzonitrile; 3-fluoro-4-(7-methylene-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)benzonitrile;Cis-3-fluoro-4-[7-(4-fluoro-benzyl)-5,6,7,8-tetrahydro-imidazo[1,5-a]pyridin-5-yl]benzonitrile; 4'-fluoro-6-(9-methyl-6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepin-5-yl)biphenyl-3-carbonitrile; 4'-fluoro-6-(9-methyl-6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepin-5-yl)biphenyl-3-carbonitrile, or, in each case, its (R) or (S) enantiomer; or, as appropriate, a pharmaceutically acceptable salt thereof, but are not limited thereto.

[0445] The term aldosterone synthase inhibitor also includes, but is not limited to, compounds and analogs disclosed in WO 2008 / 076860, WO 2008 / 076336, WO 2008 / 076862, WO 2008 / 027284, WO 2004 / 046145, WO 2004 / 014914, WO 2001 / 076574.

[0446] Additionally, the term aldosterone synthase inhibitor also includes compounds described in U.S. Patent Application Publication Nos. 2007 / 0225232, 2007 / 0208035, 2008 / 0318978, 2008 / 0076794, 2009 / 0012068, 2009 / 0048241, and WO 2006 / 005726, WO 2006 / 006666, WO 2006 / 0066667, WO 2006 / 0066668, WO 2006 / 0066669, WO 2006 / 0066669, WO 2006 / 0066669, WO 2006 / 0066667, WO 2006 / 0066669 ... Also included are, but are not limited to, compounds and analogs disclosed in European Patent Nos. 128853, 2006128851, 2006 / 128852, 2007065942, 2007 / 116099, 2007 / 116908, 2008 / 119744 and EP 1886695.Preferred aldosterone synthase inhibitors suitable for use in the present disclosure include 8-(4-fluorophenyl)-5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazine; 4-(5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazin-8-yl)-2-fluorobenzonitrile; 4-(5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazin-8-yl)-2-fluorobenzonitrile [1,4]oxazin-8-yl)-2,6-difluorobenzonitrile;4-(5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazin-8-yl)-2-methoxybenzonitrile;3-(5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazin-8-yl)benzonitrile;4-(5,6-dihydro-8H-imidazo[5,1-c][1, 4-(8-(4-cyanophenyl)-5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazin-8-yl)phthalonitrile; 4-(5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazin-8-yl)benzonitrile; 4-(5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazin-8-yl)benzonitrile; 4-(5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazin-8-yl)naphthalene-1-carbonitrile; 8-[4-(1H-tetrazol-5-yl)phenyl 1-5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazine, developed by Speedel, or in each case its (R) or (S) enantiomer; or, where appropriate, a pharmaceutically acceptable salt thereof.

[0447] Aldosterone synthase inhibitors useful in the combination include, but are not limited to, compounds and analogs generally and specifically disclosed in WO 2009 / 156462 and WO 2010 / 130796, particularly the compound claims and examples, final products, subject matter of final products, pharmaceutical formulations and claims. Preferred aldosterone synthase inhibitors suitable for the combination in the present disclosure include 3-(6-fluoro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzonitrile hydrochloride, 1-(4-methanesulfonyl-benzyl)-3-methyl-2-pyridin-3-yl-1H-indole, 2-(5-benzyloxy-pyridin-3-yl)-6-chloro-1-methyl-1H-indole, 5-( 3-Cyano-1-methyl-1H-indol-2-yl)-nicotinic acid ethyl ester, N-[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-ethanesulfonamide, Pyrrolidine-1-sulfonic acid 5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-yl ester, N-methyl-N-[5-(1-methyl-1H-indol -2-yl)-pyridin-3-ylmethyl]-methanesulfonamide, 6-chloro-1-methyl-2-{5-[(2-pyrrolidin-1-yl-ethylamino)-methyl]-pyridin-3-yl}-1H-indole-3-carbonitrile, 6-chloro-2-[5-(4-methanesulfonyl-piperazin-1-ylmethyl)-pyridin-3-yl]-1-methyl-1H-indole-3-carbonitrile, 6-chloro-1-methyl- 2-{5-[(1-methyl-piperidin-4-ylamino)-methyl]-pyridin-3-yl}-1H-indole-3-carbonitrile, morpholine-4-carboxylic acid [5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-amide, N-[5-(6-chloro-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-ethanesulfonamide, C,C,C-trifluoro-N-[5-(1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-methanesulfonamide, N-[5-(3-chloro-4-cyano-phenyl)-pyridin-3-yl]-4-trifluoromethyl-benzenesulfonamide, N-[5-(3-chloro-4-cyano-phenyl)-pyridin-3-yl]-1-phenyl-methanesulfonamide, N-(5-(3-chloro-4-cyanophenyl)pyridin-3-yl)butane-1-sulfonamide, N-(1-(5-(4-cyano-3-methoxyphenyl)pyridin-3-yl)ethyl)ethanesulfonamide, N-((5-(3-chloro N-(cyclopropyl(5-(1H-indol-5-yl)pyridin-3-yl)methyl)ethanesulfonamide, N-(cyclopropyl(5-naphthalen-1-yl-pyridin-3-yl)methyl)ethanesulfonamide, ethanesulfonic acid [5-(6-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-pyridin-3-ylmethyl]-amide, and ethanesulfonic acid {[5-(3-chloro-4-cyano-phenyl)-pyridin-3-yl]-cyclopropyl-methyl}-ethyl-amide.

[0448] Lipid-lowering drugs are known in the art and are described, for example, in Goodman and Gilman's The Pharmacological Basis of Therapeutics, 11th Ed., Brunton, Lazo and Parker, Eds., McGraw-Hill (2006); 2009 Physicians' Desk Reference (PDR), e.g., 63rd (2008) Eds., Thomson PDR.

[0449] "Combination therapy" is intended to encompass the administration of these therapeutic agents sequentially, with each therapeutic agent administered at different times in any order, or alternating in any order, as well as substantially simultaneously administering these therapeutic agents, or at least two of the therapeutic agents. Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single capsule having a fixed ratio of each therapeutic agent, or multiple single capsules for each therapeutic agent. Sequential or substantially simultaneous administration of each therapeutic agent can be carried out by any suitable route, including, but not limited to, oral, intravenous, intramuscular, and direct absorption through mucosal tissue. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of a selected combination can be administered by intravenous injection, while other therapeutic agents of the combination can be administered orally. Alternatively, for example, all therapeutic agents can be administered orally, or all therapeutic agents can be administered by intravenous injection. The order in which the therapeutic agents are administered is not critical.

[0450] In accordance with the preceding, the present disclosure also provides a therapeutic combination, e.g., a kit, kit of parts, for use in any of the methods as defined herein, comprising a cyclic polypeptide of formula (I) or a pharmaceutically acceptable salt thereof, to be used simultaneously or sequentially with at least one pharmaceutical composition comprising at least another therapeutic agent selected from the following: a lipid-lowering drug, a niacin or analogue thereof, a bile acid sequestrant, a thyroid hormone mimetic, a thyroid hormone receptor (THR) β-selective agonist, a microsomal triglyceride transfer protein (MTP) inhibitor, an acyl C oA: diacylglycerol acyltransferase (DGAT) inhibitors, Niemann-Pick C1-like 1 (NPC1-L1) inhibitors, ATP-binding cassette (ABC) protein G5 or G8 agonists, inhibitory nucleic acids targeting PCSK9, inhibitory nucleic acids targeting apoB100, apoA-I upregulators / inducers, ABCA1 stabilizers or inducers, phospholipid transfer protein (PLTP) inhibitors, fish oil, antidiabetic agents, antiobesity agents, peroxisome proliferator-activated receptor agonists, ATP citrate lyase (ACL) inhibitors, and antihypertensive agents or pharmaceutically acceptable salts thereof. The kit may include instructions for administration. The combination may be a fixed combination (e.g., in the same pharmaceutical composition) or a free combination (e.g., in separate pharmaceutical compositions).

[0451] Similarly, the present disclosure provides a kit of parts comprising: (i) a pharmaceutical composition of the present disclosure; and (ii) a pharmaceutical composition comprising a compound selected from the following: a lipid-lowering agent, niacin or an analog thereof, a bile acid sequestrant, a thyroid hormone mimetic, a thyroid hormone receptor (THR) β-selective agonist, a microsomal triglyceride transfer protein (MTP) inhibitor, and an acyl-CoA:diacylglycerol acyltransferase (DGAT) inhibitor, in the form of two separate units of components (i)-(ii). agents, Niemann-Pick C1-like 1 (NPC1-L1) inhibitors, ATP-binding cassette (ABC) protein G5 or G8 agonists, inhibitory nucleic acids targeting PCSK9, inhibitory nucleic acids targeting apoB100, apoA-I upregulators / inducers, ABCA1 stabilizers or inducers, phospholipid transfer protein (PLTP) inhibitors, fish oil, antidiabetic agents, antiobesity agents, peroxisome proliferator-activated receptor agonists, ATP citrate lyase (ACL) inhibitors and antihypertensive agents or pharmaceutically acceptable salts thereof.

[0452] Similarly, the present disclosure provides a method as defined above, comprising the co-administration, e.g., simultaneous or sequential, of a therapeutically effective amount of a cyclic polypeptide of formula (I) or a pharmaceutically acceptable salt thereof and a second drug substance, wherein said second drug substance is selected from the group consisting of a lipid-lowering drug, a niacin or an analog thereof, a bile acid sequestrant, a thyromimetic drug, a thyroid hormone receptor (THR) β-selective agonist, a microsomal triglyceride transfer protein (MTP) inhibitor, an acyl-CoA:diacylglycerol acyltransferase (DGAT) inhibitor, a steroid hormone receptor (SHR ... inhibitors, Niemann-Pick C1-like 1 (NPC1-L1) inhibitors, agonists of ATP-binding cassette (ABC) protein G5 or G8, inhibitory nucleic acids targeting PCSK9, inhibitory nucleic acids targeting apoB100, apoA-I upregulators / inducers, ABCA1 stabilizers or inducers, phospholipid transfer protein (PLTP) inhibitors, fish oil, antidiabetic agents, antiobesity agents, agonists of peroxisome proliferator-activated receptors, ATP citrate lyase (ACL) inhibitors and antihypertensive agents, such as those set forth above. [Example]

[0453] The following examples and synthetic schemes further illustrate the present disclosure, but should not be construed as limiting the disclosure in scope or spirit of the specific procedures described herein. It should be understood that the examples are provided to illustrate particular embodiments and do not thereby limit the scope of the disclosure. Furthermore, it should also be understood that various other embodiments, modifications, and equivalents thereof, which may suggest themselves to those skilled in the art, may be used without departing from the spirit of the present disclosure and / or the scope of the appended claims.

[0454] Analytical methods, materials and measurement means Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Proton nuclear magnetic resonance (NMR) spectra were obtained using a Varian spectrometer at 400 MHz or a Bruker spectrometer at 300 MHz or 400 MHz. Spectra are given in parts per million (δ), and coupling constants, J, are reported in hertz. Tetramethylsilane (TMS) or the solvent peak was used as an internal standard. Purity and low-resolution mass spectrometry data were determined using a Thermo Finnigan Surveyor HPLC system with Surveyor photodiode array (PDA) detection and a Thermo LCQ Fleet™ ion trap mass spectrometer, unless otherwise noted. Column: Synergi 4 micron, hydro-RP80A, 30 x 2.0 mm; Flow rate: 0.500 mL / min; Solvent A (water + 0.1% formic acid), Solvent B (acetonitrile + 0.1% formic acid); Gradient: 2% B at t = 0 to 95% B in 3 min to 95% B in 3.3 min.

[0455] General preparative HPLC purification procedure and mass spectra The crude peptide was purified by preparative reversed-phase C18-HPLC using different column sizes and varying flow rates depending on the amount of crude peptide to be purified. For example, 0.1% TFA in water (A) and 0.1% TFA in acetonitrile (B) were used as eluents. Product-containing fractions were collected and lyophilized to obtain the purified product.

[0456] Conditions AA-1 (HRMS) - Column: Acquity UPLC® BEH C18, 130 Å, 1.7 μm, 2.1 x 50 mm, 50 °C; Flow rate: 1.0 mL / min; Mobile phase: (A) 0.1% formic acid in water + 3.75 mM ammonium acetate / (B) 0.04% formic acid + 3.75 mM ammonium acetate + 5% water in acetonitrile; Gradient: 0.2% to 98% in 7.5 min. Electrospray mass spectrum (+), DAD-UV chromatogram 214, 254 nm.

[0457] Conditions BB-1 (HRMS) - Column: Acquity UPLC® BEH C18, 130 Å, 1.7 μm 2.1 x 50 mm, 50 °C; Flow rate: 1.0 mL / min; Mobile phase: (A) 0.001% formic acid in water + 2% acetonitrile + 3.75 mM ammonium acetate / (B) 5% water in acetonitrile + 3.75 mM ammonium acetate; Gradient: 2% to 99.9% in 4.4 min; Electrospray mass spectrum (+), DAD-UV chromatogram 214, 254 nm.

[0458] Conditions CC-1 (HRMS) - Column: Acquity UPLC® BEH C18, 130 Å, 1.7 μm 2.1 x 50 mm, 50 °C; Flow rate: 1.0 mL / min; Mobile phase: (A) 0.1% formic acid in water / (B) 0.1% formic acid in acetonitrile; Gradient: 2% to 98% in 1.7 min; Electrospray mass spectrum (+), DAD-UV chromatogram 214 nm.

[0459] Condition A-1 (LCMS) - Column: Acquity UPLC® BEH C18, 300 Å, 1.7 μm 2.1×50 mm, 80° C.; Flow rate: 1.0 mL / min; Mobile phase: (A) 0.05% TFA in water / (B) 0.04% TFA in acetonitrile; Gradient: 5% to 98% in 4.4 min; Electrospray mass spectrum (+), DAD-UV chromatogram 214 nm.

[0460] Condition B-1 (LCMS) - Column: Acquity UPLC® HSS T3 100 Å, 1.8 μm 2.1 x 50 mm, 50°C; Flow rate: 1.2 mL / min; Mobile phase: (A) 0.05% formic acid in water + 3.75 mM ammonium acetate / (B) 0.04% formic acid in acetonitrile; Gradient: 2% to 98% in 1.4 min; Electrospray mass spectrum (+), DAD-UV chromatogram 214 nM

[0461] Condition C-1 (LCMS) - Column: Acquity UPLC® BEH C18, 130 Å, 1.7 μm 2.1×50 mm, 40° C.; Flow rate: 0.7 mL / min; Mobile phase: 5% to 95% in 2.8 min (A) 0.1% formic acid in water / (B) 0.1% formic acid in acetonitrile; Gradient: 5% to 95% in 2.8 min; Electrospray mass spectrum (+), DAD-UV chromatogram 214 nm.

[0462] Condition D-1 (LCMS) - Column: Acquity UPLC® BEH C18, 300 Å, 1.7 μm 2.1×50 mm, 50° C.; Flow rate: 0.1 mL / min; Mobile phase: (A) 0.05% TFA in water / (B) 0.04% TFA in acetonitrile; Gradient: 2 min hold at 5% B, 5 to 100% B in 11 min; Electrospray mass spectrum (+), DAD-UV chromatogram 214 nm.

[0463] Conditions E-1 (LCMS) - Column: Acquity UPLC® BEH C18, 300 Å, 1.7 μm 2.1×50 mm, 80° C.; Flow rate: 1.0 mL / min; Mobile phase: (A) 0.5% TFA in water / (B) 0.4% TFA in acetonitrile; Gradient: 5% to 98% in 4.4 min; Electrospray mass spectrum (+), DAD-UV chromatogram 214 nm.

[0464] Condition F-1 (LCMS) - Column: Ascentis Express C18, 2.7 μm 2.1 x 30 mm, 50 °C; Flow rate: 1.0 mL / min; Mobile phase: (A) 0.05% TFA in water / (B) 0.04% TFA in acetonitrile; Gradient: 5% to 95% in 1.9 min; Electrospray mass spectrum (+), DAD-UV chromatogram 212-216 nm.

[0465] Condition G-1 (LCMS) - Column: Acquity UPLC® BEH C18, 130 Å, 1.7 μm, 2.1×50 mm, 40° C.; Flow rate: 0.7 mL / min; Mobile phase: (A) 0.1% formic acid in water / (B) 0.1% formic acid in acetonitrile; Gradient: 20% to 25% in 1 min, then to 90% in 3.2 min; Electrospray mass spectrum (+), DAD-UV chromatogram 214 nm.

[0466] Condition H-1 (LCMS) - Column: Acquity UPLC® BEH C18 300 Å, 1.7 μm 2.1×50 mm, 80° C.; Flow rate: 1.0 mL / min; Mobile phase: (A) 0.05% TFA in water; (B) 0.04% TFA in acetonitrile; Gradient: 0% to 98% in 4.4 min; Electrospray mass spectrum (+), DAD-UV chromatogram 214 nm.

[0467] Abbreviations used in the following examples and elsewhere in this specification are as follows:

[0468] [Table 13]

[0469] [Table 14]

[0470] General procedure for cyclic peptide synthesis: Polypeptides of the present disclosure may also be synthesized by following the steps outlined in the general scheme shown below. [ka]

[0471] Step 1: Peptide synthesis Solid-phase peptide synthesis on a Liberty® peptide synthesizer from CEM, Inc. Synthesis Cycle A-1 The resin was washed with DMF and then deprotected by treatment with 4-methylpiperidine / DMF (1:4) for two cycles—the first cycle for 30 seconds and the second cycle for 3 minutes. Coupling was accomplished by adding Fmoc-amino acid (4-5 eq.; 0.2 M solution in DMF), HATU (4-5 eq.; 0.5 M solution in DMF), and DIPEA (4-6 eq.; 2 M solution in NMP). The coupling and deprotection steps were repeated until the desired cyclic polypeptide of Formula (I) was obtained. All Fmoc amino acids were coupled at 75°C for 5 minutes, except for the amino acids listed in Table 3 below. After the final coupling was completed, the Fmoc was removed by repeated treatment with 4-methylpiperidine / DMA (1:4) to provide the deprotected peptide.

[0472] [Table 15]

[0473] Solid-phase peptide synthesis on a Prelude® peptide synthesizer from Gyros Protein Technologies AB Alternatively, peptides were synthesized on a Prelude® peptide synthesizer as described in synthesis cycle B-1 or synthesis cycle B-2.

[0474] Synthesis Cycle B-1 The resin was washed with DMA. The Fmoc was then removed by repeated treatment of the resin with piperidine / DMA (1:4). The coupling was accomplished by the addition of Fmoc-amino acid (3 eq.; 0.2 M solution in NMP), HCTU (3 eq.; 0.3 M solution in NMP), and DIPEA (3–6 eq.; 0.66–0.9 M solution in NMP) followed by mixing the suspension with nitrogen for typically 15 min–4 h at rt, depending on the specific requirements. After washing with DMA, the coupling step was repeated. After washing with DMA, capping was performed by adding a mixture of AcO / pyridine / DMA (1:1:8) followed by mixing the suspension at rt. After the final coupling, the Fmoc was removed as described above in synthesis cycle A-1 to obtain the peptide.

[0475] Synthesis Cycle B-2 The resin was washed with DMA. Fmoc removal was achieved by repeated treatment with 4-methylpiperidine / DMA (1:4). Coupling was accomplished by the addition of a mixture of Fmoc-amino acid (3 eq.; 0.2 M solution in NMP), Oxyma Pure (3 eq.; 0.3 M solution in NMP), and DIPEA (6–7 eq.; 0.66 M solution in NMP) followed by mixing the suspension with nitrogen at room temperature for 15 min–4 h, depending on the specific requirements. After washing with DMA, the coupling step was repeated. After washing with DMA, capping was achieved by the addition of a mixture of AcO / pyridine / DMA (1:1:8) followed by mixing the suspension at room temperature. After the final coupling, Fmoc removal was achieved as described above in synthesis cycle A-1 to obtain the peptide.

[0476] Step 2: Peptide acylation The resin product from step 1 was suspended in N-methylpyrrolidine and N-succinimidyl 2-chloroacetate (5 equivalents) was added. The resulting resin mixture was shaken overnight at room temperature. The resin was then filtered and washed three times with dimethylformamide and dichloromethane, respectively, to obtain the acylated peptide product.

[0477] Step 3: Cleavage from the resin with or without concomitant removal of the protecting group (PG) The resin product from step 2 was shaken for 1-2 hours with one of the cleavage solutions listed below (1-5 mL for a 0.1 mmol scale). The resin was filtered and treated again with fresh cleavage solution for 0.5-1 hour. The cleavage cycle was repeated as necessary. The resin was then filtered, and the combined filtrate was slowly poured onto a mixture of cold heptane / diethyl ether (1:1) to obtain a precipitate. The suspension containing the precipitate was centrifuged, and the supernatant was discarded. The precipitate was suspended in cold ether, vortexed briefly, and then centrifuged. This washing step was repeated two more times. The crude peptide product was dried under high vacuum.

[0478] The following cleavage solutions were used: Cutting method 1: TFA / H2O / TIS / DTT(92.5:2.5:2.5:2.5) Cutting method 2:95%aq.TFA / EDT / TIS(95:2.5:2.5)

[0479] Step 4: Peptide cyclization The crude peptide product from Step 3 was dissolved in DMSO or DMA and treated with TEA or DIPEA. The reaction mixture was then shaken overnight at room temperature. The resulting reaction mixture containing the cyclized peptide was concentrated on a centrifugal evaporator to give the desired cyclic polypeptide of Formula (I).

[0480] Example 1: Synthesis of Ac*-FVDTTS-(N-Me)FB-(N-Me)ENSPC*-G-NH2 (1-1) [ka] Step 1: FVD(tBu)-T(tBu)-T(tBu)-S(tBu)-(N-Me)FB-(N-Me)E(tBu)-NS(tBu)-PC(Trt)-NH Resin-G (1b) Peptide sequence 1b was synthesized on Fmoc-Gly-RAM TentaGel™ resin (1a, 0.22 mmol / g loading, 0.25 mmol scale) on a Liberty® peptide synthesizer according to general peptide synthesis cycle A-1 (Fmoc-amino acid (4 eq.; 0.2 M solution in DMF), HATU (4 eq.; 0.5 M solution in DMF), and DIPEA (4.4 eq.; 2 M solution in NMP)). The resin was then filtered and washed with DMF (2x) and DCM (3x) to give the desired product 1b.

[0481] Step 2: ClCH2C(O)-FVD(tBu)-T(tBu)-T(tBu)-S(tBu)-(N-Me)FB-(N-Me)E(tBu)-NS(tBu)-PC(Trt) Resin-G (1d) To the peptide resin 1b from step 1 (0.25 mmol) was added a solution of N-succinimidyl 2-chloroacetate (1c, 287 mg, 1.5 mmol) in NMP (8 mL), and the resulting mixture was shaken overnight at room temperature. The resin was then drained, washed with DMF (3x) and DCM (4x), and dried to provide the desired product 1d.

[0482] Step 3: ClCHC(O)-FVDTTS-(N-Me)FB-(N-Me)ENSPCG (1e) Using cleavage method 1 described hereinabove, the peptide-resin product 1d from step 2 was cleaved from the resin and simultaneously deprotected to give crude peptide 1e (266 mg). ESI-MS m / z: 866.6 [M+2H] 2+ .

[0483] Step 4: 3-((3R,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S,39S,44aS)-30-([1,1'-biphenyl]-4-ylmethyl)-36-(2-amino-2-oxoethyl)-3-((2-amino-2-oxoethyl)carbamoyl)-9,27-dibenzyl-15-(carboxymethyl)-18,21-bis((R)-1-hydroxyethyl)-2 4,39-bis(hydroxymethyl)-12-isopropyl-26,32-dimethyl-1,7,10,13,16,19,22,25,28,31,34,37,40-tridecaoxodotetracontin-33-yl)propanoic acid (1-1) The crude peptide 1e from step 3 (266 mg) was dissolved in DMSO (20.5 mL). A few drops of TEA were added to bring the pH to 8-9. The resulting mixture was stirred overnight at room temperature. The reaction mixture was then concentrated to a few mL of DMSO on a centrifugal evaporator. The crude cyclic peptide was purified by preparative HPLC (Sunfire™ Prep C18 column, 130 Å, 5 μm, 30 × 50 mm, 15-40% in 6 min, 75 mL / min, ACN in water with 0.1% TFA) and then lyophilized to give the title polypeptide 1-1 (58 mg, 22%) as a white solid.

[0484] The following polypeptides in Table 4 were synthesized using a Prelude® peptide synthesizer according to the procedure described in Example 1 for polypeptide (1-1).

[0485] [Table 16]

[0486] [Table 17]

[0487] [Table 18]

[0488] The following polypeptides in Table 5 were synthesized using a Liberty® peptide synthesizer according to the procedure described in Example 1 for polypeptide (1-1).

[0489] [Table 19]

[0490] [Table 20]

[0491] The analytical data for the polypeptides of Examples 1-1 through 1-27 are summarized in Table 6 below and were generated using the HRMS* or UPLC-MS** analytical methods described herein above.

[0492] [Table 21]

[0493] [Table 22]

[0494] Example 2: Synthesis of Ac*-FVPTTF-(N-Me)A-(p-Cl)F-(N-Me)APAPC*-NH2 (2-1) [ka] Step 1: FVPT(tBu)-T(tBu)-F-(N-Me)A-(p-Cl)F-(N-Me)APAPC-(Trt)NH Resin (2b) Peptide sequence 2b was synthesized on Fmoc-NH TentaGel™ RAM resin (2a, 0.23 mmol / g loading, 0.1 mmol scale) on a Liberty® peptide synthesizer according to general peptide synthesis cycle A-1 (Fmoc-amino acid (5 eq.; 0.2 M solution in DMF), HATU (5 eq.; 0.5 M solution in DMF), and DIPEA (5.5 eq.; 2 M solution in NMP)). The resin was then filtered and washed with DMF (2x) and DCM (3x) to give the desired product 2b.

[0495] Step 2: ClCHC(O)-FVPT(tBu)-T(tBu)-F-(N-Me)A-(p-Cl)F-(N-Me)APAPC-(Trt)NH-Resin (2c) To the peptide resin 2b (0.1 mmol) from step 1 was added a solution of N-succinimidyl 2-chloroacetate (1c, 100 mg, 0.522 mmol) in NMP (6 mL), and the resulting mixture was shaken at room temperature for 18 h. The resin was then drained, washed with DMF (3x) and DCM (3x), and dried to give the desired product 2c.

[0496] Step 3: ClCH2C(O)-FVPTTF-(N-Me)A-(p-Cl)F-(N-Me)APAPC-NH2(2d) Using cleavage method 1 described hereinabove, the resin product 2c from step 2 was cleaved from the resin and simultaneously deprotected to give crude peptide 2d (106 mg) as a white solid. ESI-MS m / z: 1503.7 [M−H] - .

[0497] Step 4: (6S,8aS,14S,17S,20S,23S,26S,29S,31aS,37S,40S,46R,48aS)-23,40-dibenzyl-17-(4-chlorobenzyl)-26,29-bis((R)-1-hydroxyethyl)-37-isopropyl-6,14,15,20,21-pentamethyl-5,8,13,16,19,2 2,25,28,31,36,39,42,48-Tridecaoxohexatetracontahydro-13H-tripyrrolo[1,2-e1:1',2'-j:1'',2''-k1][1]thia[4,7,10,13,16,19,22,25,28,31,34,37,40]tridecaazacyclodo-tetracontin-46-carboxamide(2-1) Crude peptide 2d (106 mg) from step 3 was dissolved in DMSO (6 mL). TEA (50 μL, 0.359 mmol) was then added to bring the mixture to a pH of 8–9. The resulting mixture was stirred at rt for 18 h and then concentrated to a few mL of DMSO on a centrifugal evaporator. The crude cyclic peptide was purified by preparative HPLC (Sunfire™ Prep C18 column, 130 Å, 5 μm, 30 × 50 mm, 25–50% in 6 min, 75 mL / min, ACN in water with 0.1% TFA) and then lyophilized to give the title polypeptide 2-1 (10 mg, 9%) as a white solid.

[0498] The following polypeptides in Table 7 were synthesized using a Liberty® peptide synthesizer according to the procedure described in Example 2 for polypeptide (2-1).

[0499] [Table 23]

[0500] The analytical data for the polypeptides of Examples 2-1 through 2-6 is summarized below in Table 8, which was generated using the HRMS analytical method described hereinabove.

[0501] [Table 24]

[0502] Example 3: Synthesis of Ac*-FVNTTF-(N-Me)AB-(N-Me)A-(N-Me)EAPC*-NHEt (3-1) [ka] Step 1: FVNT(tBu)-T(tBu)-F-(N-Me)AB-(N-Me)A-(N-Me)E(tBu)-APC(Trt)N(Et) Resin (3b) Peptide sequence 3b was synthesized on {3-[(ethyl-Fmoc-amino)methyl]-indol-1-yl}-acetyl AM resin (3a, 0.93 mmol / g loading, 0.1 mmol scale) on a Prelude® peptide synthesizer according to general peptide synthesis as described herein below. The resin was then filtered and washed with DMA to give the desired product 3b.

[0503] [Table 25]

[0504] Synthesis cycle B-1: Fmoc-AA (3eq, 0.2M solution in NMP), HCTU (3eq. 0.3M solution in NMP) and DIPEA (3.3eq, 0.66M solution in NMP).

[0505] Synthesis cycle B-2: Fmoc-AA (3eq, 0.2M solution in NMP), PyOxim (3eq. 0.3M solution in NMP) and DIPEA (6.3eq, 0.66M solution in NMP). Step 2: ClCH2C(O)-FVNT(tBu)-T(tBu)-F-(N-Me)AB-(N-Me)A-(N-Me)E(tBu)-APC(Trt)N(Et)-Resin (3c) To the peptide resin 3b (0.1 mmol) from step 1 was added a solution of N-succinimidyl 2-chloroacetate (1c, 96 mg, 0.5 mmol) in NMP (3 mL), and the resulting mixture was shaken at room temperature for 16 h. The resin was then drained, washed with DMF (3x) and DCM (4x), and dried to give the desired product 3c.

[0506] Step 3: ClCH2C(O)-FVNTTF-(N-Me)AB-(N-Me)A-(N-Me)EAPCN(H)Et(3d) Using cleavage method 2 described hereinabove, the peptide-resin product 3c from step 2 was cleaved from the resin and simultaneously deprotected to give crude peptide 3d. The crude peptide was then purified by preparative HPLC (Atlantis® T3 OBD Prep column, 100 Å, 5 μm, 30×150 mm, 5–35% in 2.5 min, 35–55% in 12 min, ACN in water with 0.1% TFA). The product-containing fractions were lyophilized to give product 3d (36 mg, 22%) as a fluffy white solid. ESI-MS m / z: 1638.6 [M+H] + .

[0507] Step 4: 3-((3R,9S,12S,15S,18S,21S,24S,27S,30S,33S,36S,39S,44aS)-30-([1,1'-biphenyl]-4-ylmethyl)-15-(2-amino-2-oxoethyl)-9,24-dibenzyl-3-(ethylcarbamoyl)-18,21-bis((R)-1-hydroxyethyl)-12-isopropyl-26 ,27,32,33,35,39-Hexamethyl-1,7,10,13,16,19,22,25,28,31,34,37,40-tridecaoxodotetracontahydro-6H-pyrrolo[2,1-f][1]thia[4,7,10,13,16,19,22,25,28,31,34,37,40]tridecaazacyclodotetracontin-36-yl)propanoic acid (3-1) Peptide 3d (36 mg, 0.022 mmol) from step 3 was dissolved in DMA (22 mL) and DIPEA (220 μL, 1.26 mmol) was added. The resulting mixture was stirred at RT for 18 h and then concentrated in vacuo. The crude cyclic peptide was purified by preparative HPLC (SunFire™ C18 Prep column, 100 Å, 5 μm, 30 × 100 mm, 30 mL / min, 20–60% ACN in water with 0.1% TFA in 30 min), and the fractions containing the desired product were lyophilized to afford the title polypeptide 3-1 (27 mg, 76%) as a white solid.

[0508] The following polypeptides in Table 9 were synthesized according to the procedure described in Example 3 for polypeptide (3-1).

[0509] [Table 26]

[0510] The analytical data for the polypeptides of Examples 3-1 to 3-4 is summarized in Table 10 below and was generated using the UPLC-MS analytical method described hereinabove.

[0511] [Table 27]

[0512] Example 4: PCSK9 Ligand Binding Assay PCSK9 binding of cyclic polypeptides of the present disclosure was measured using a time-resolved fluorescence resonance energy transfer (TR-FRET) assay. This time-resolved fluorescence resonance energy transfer (TR-FRET) assay measures the ability of cyclic polypeptides of the present disclosure to interfere with the binding of human PCSK9 to human LDLR, and provides potency (IC 50 ) and effectiveness (A max ) gives a measure of both. material Human PCSK9 Human PCSK9 Alexa Fluor 647 Human LDLR extracellular domain - Europium Kryptate Proxi Plate Low Volume Assay Plates (PerkinElmer #6008280) ·Greiner V bottom (Greiner BioOne #781280) Assay buffer 20 mM HEPES, pH 7.5 150mM NaCl 1mM CaCl2 0.01% v / v Tween 20 0.01% w / v BSA

[0513] A master compound plate was prepared in a Greiner V-bottom plate by diluting the cyclic polypeptide of the present disclosure in dimethyl sulfoxide to the appropriate concentration relative to the desired top concentration based on the desired final concentration: for a 30 μM final concentration, the master plate concentration was 1.5 mM (68 μL DMSO + 12 μL 10 mM cyclic polypeptide of the present disclosure); for a 10 μM final concentration, the master plate concentration was 0.5 mM (76 μL DMSO + 4 μL 10 mM cyclic polypeptide of the present disclosure); and for a 3 μM final concentration, the master plate concentration was 150 μM (69 μL DMSO + 1 μL 10 mM cyclic peptide of the present disclosure). These solutions were pipetted into columns 1 and 11 of the compound plate. 3-fold serial dilutions were made in columns 2-10 and 12-20 of the compound plate by transferring 10 μL to 20 μL of DMSO. Columns 21 and 22 of the compound plate were negative controls containing DMSO only.

[0514] An intermediate plate was made in a Greiner V-bottom plate by transferring 8 μL from each well of the master plate to the corresponding well containing 92 μL of assay buffer and mixing thoroughly.

[0515] Proxi plates—low-volume assay plates—were used for the assay. Ten μL of 16 nM human PCSK9 Alexa Fluor 647 was added to all wells of the plate, followed by 5 μL from the middle plate. For a positive control, 5 μL of unlabeled human PCSK9 at 4 μM in assay buffer containing 8% DMSO was added to control wells in columns 23 and 24 of the plate. After a 30-minute incubation, 5 μL of 4 nM human LDLR extracellular domain—Europium Kryptate was added, and the mixture was incubated for an additional 2 hours.

[0516] TR-FRET signals were measured on an EnVision or PheraStar instrument with a 60 μs delay, 330 nm excitation and 665 nm emission (FRET) and 330 nm excitation and 615 nm (Europium). The FRET ratio (FRET / Europium) was used for calculations.

[0517] Data analysis No inhibition (0%) was observed from wells containing DMSO (control) in columns 21 and 22 of the compound plate. Complete inhibition (100%) was observed from wells containing 1 μM human PCSK9 (control) in columns 23 and 24 of the plate. Data are expressed as percent inhibition: (value - 0%) / (100% - 0%).

[0518] [Table 28]

[0519] equivalent Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments specifically described herein which equivalents are intended to be encompassed by the following claims. The present invention also provides the following. [1] Cyclic polypeptide of formula (I) (SEQ ID NO: 39): [ka] (In the formula, R 1 is H or (C 1 -C 4 ) alkyl; X 1 is absent, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * is NHR 1 Shows the connection point to; X 2 is L-Pro or D-Pro; X 3 is L-Arg, D-Arg, L-Ser, D-Ser, L-His, D-His, L-Ala or D-Ala; X 4 is L-Asp, D-Asp, L-Asn, D-Asn, L-Glu, D-Glu, L-Lys, D-Lys, L-Gln, D-Gln, L-Pro, D-Pro, L-Ala, D-Ala, L-(N-Me)Glu or D-(N-Me)Glu; X 5 is L-(N-Me)Ala, D-(N-Me)Ala, L-(N-Me)Glu or D-(N-Me)Glu; X 6 are L-Bip, D-Bip, L-(4-CF 3 )Phe, D-(4-CF 3 )Phe, L-(3,4-diCl)Phe, D-(3,4-diCl)Phe, L-(3-F)Phe, D-(3-F)Phe, L-(4-Cl)Phe or D-(4-Cl)Phe; X 7 is L-(N-Me)Ala, D-(N-Me)Ala, L-(N-Me)Phe or D-(N-Me)Phe; X 8 is L-Bip, D-Bip, L-Ser, D-Ser, L-Tyr, D-Tyr, L-(4-CF 3 )Phe, D-(4-CF 3 )Phe, L-Ala, D-Ala, L-Phe, D-Phe, L-Val or D-Val; X 9 is L-Thr or D-Thr; X 10 is L-Thr, D-Thr, L-Ser or D-Ser; X 11 is L-Ser, D-Ser, L-Asp, D-Asp, L-Asn, D-Asn, L-Pro, D-Pro, L-Ala, D-Ala, L-Hse or D-Hse; X 12 is L-Val, D-Val, L-Glu or D-Glu; X 13 is L-Phe or D-Phe; where: Bip is 4-phenyl-phenylalanine; Hse is homoserine; (4-CF 3 ) Phe is 4-trifluoromethyl-phenylalanine; (3,4-diCl)Phe is 3,4-dichloro-phenylalanine; (3-F)Phe is 3-fluoro-phenylalanine; (4-Cl)Phe is 4-chloro-phenylalanine) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof. [2] [1] The cyclic polypeptide according to the present invention (wherein: (SEQ ID NO: 40): R 1 is H or (C 1 -C 4 ) alkyl; X 1 is absent or is Gly; X 2 is L-Pro or D-Pro; X 3 is L-Arg, D-Arg, L-Ser, D-Ser, L-His, D-His, L-Ala or D-Ala; X 4 is L-Asp, D-Asp, L-Asn, D-Asn, L-Glu, D-Glu, L-Lys, D-Lys, L-Gln, D-Gln, L-Pro, D-Pro, L-Ala, D-Ala, L-(N-Me)Glu or D-(N-Me)Glu; X 5 is L-(N-Me)Ala, D-(N-Me)Ala, L-(N-Me)Glu or D-(N-Me)Glu; X 6 are L-Bip, D-Bip, L-(4-CF 3 )Phe, D-(4-CF 3 )Phe, L-(3,4-diCl)Phe, D-(3,4-diCl)Phe, L-(3-F)Phe, D-(3-F)Phe, L-(4-Cl)Phe or D-(4-Cl)Phe; X 7 is L-(N-Me)Ala, D-(N-Me)Ala, L-(N-Me)Phe or D-(N-Me)Phe; X 8 is L-Bip, D-Bip, L-Ser, D-Ser, L-Tyr, D-Tyr, L-(4-CF 3 )Phe, D-(4-CF 3 )Phe, L-Ala, D-Ala, L-Phe, D-Phe, L-Val or D-Val; X 9 is L-Thr or D-Thr; X 10 is L-Thr, D-Thr, L-Ser or D-Ser; X 11 is L-Ser, D-Ser, L-Asp, D-Asp, L-Asn, D-Asn, L-Pro, D-Pro, L-Ala, D-Ala, L-Hse or D-Hse; X 12 is L-Val, D-Val, L-Glu or D-Glu; X 13 is L-Phe or D-Phe; where: Bip is 4-phenyl-phenylalanine; Hse is homoserine; (4-CF 3 ) Phe is 4-trifluoromethyl-phenylalanine; (3,4-diCl)Phe is 3,4-dichloro-phenylalanine; (3-F)Phe is 3-fluoro-phenylalanine; (4-Cl)Phe is 4-chloro-phenylalanine) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof. [3] X 13 is L-Phe (SEQ ID NO: 41), [1] or [2]. [4] X 2 is L-Pro (SEQ ID NO: 42), [1] the cyclic polypeptide according to any one of [1] to [3]. [5] X 9 is L-Thr (SEQ ID NO: 43), the cyclic polypeptide according to any one of [1] to [4]. [6] The cyclic polypeptide according to [1] or [2], having the following formula (II) (SEQ ID NO: 44), (III) (SEQ ID NO: 45), (IV) (SEQ ID NO: 46), (V) (SEQ ID NO: 47), or (VI) (SEQ ID NO: 48):

change

[10] X 1 is Gly (SEQ ID NO: 52), the cyclic polypeptide according to any one of [1] to [8].

[11] X 10 is L-Thr or L-Ser (SEQ ID NO: 53), the cyclic polypeptide according to any one of [1] to

[10] .

[12] R 1 But H or (C 1 -C 3 ) alkyl (SEQ ID NO: 54). The cyclic polypeptide according to any one of [1] to

[11] .

[13] R 1 is H (SEQ ID NO: 55), the cyclic polypeptide according to any one of [1] to

[12] .

[14] The cyclic polypeptide according to [1], selected from the following:

change

change

change

change

change

change

change

change

[15] A pharmaceutical composition comprising a therapeutically effective amount of the cyclic polypeptide or a pharmaceutically acceptable salt thereof according to any one of [1] to

[14] , and one or more pharmaceutically acceptable carriers or excipients.

[16] A combination comprising the polypeptide or a pharmaceutically acceptable salt thereof according to any one of [1] to

[14] and one or more additional therapeutically active agents.

[17]

[16] The combination according to

[16] , wherein the further therapeutically active agent is a statin.

[18] The pharmaceutical composition or combination according to any one of

[15] to

[17] for use in the treatment, prevention, remission or delay of progression of a PCSK9-mediated disease or disorder.

[19] 18. The pharmaceutical composition or combination according to claim 17, wherein the PCSK9-mediated disease or disorder, or the disease or disorder requiring inhibition of PCSK9 activity, is selected from hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, peripheral arterial disease, vascular inflammation, elevated Lp(a), elevated LDL, elevated TRL, elevated triglycerides, sepsis, and xanthomas.

[20] A method for modulating PCSK9, comprising administering to a patient in need of PCSK9 modulation the cyclic polypeptide or a pharmaceutically acceptable salt thereof according to any one of [1] to

[14] .

[21] A method for inhibiting PCSK9, comprising administering to a patient in need of PCSK9 inhibition the cyclic polypeptide or a pharmaceutically acceptable salt thereof according to any one of [1] to

[14] .

[22] A method for treating, preventing, ameliorating, or delaying the progression of a PCSK9-mediated disease or disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a cyclic polypeptide or a pharmaceutically acceptable salt thereof according to any one of [1] to

[14] .

[23]

[22] The method of

[22] , wherein the PCSK9-mediated disease or disorder is selected from hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, peripheral arterial disease, vascular inflammation, elevated Lp(a), elevated LDL, elevated TRL, elevated triglycerides, sepsis, and xanthomas.

[24] 1. A method for (i) lowering Lp(a), (ii) lowering Lp(a) plasma levels, (iii) lowering Lp(a) serum levels, (iv) lowering serum TRL or LDL levels, (v) lowering serum triglyceride levels, (vi) lowering LDL-C, (vii) lowering total plasma apoB concentration, (viii) lowering LDL apoB, (ix) lowering TRL apoB, or (x) lowering non-HDL-C, comprising administering to a patient in need thereof a therapeutically effective amount of a cyclic polypeptide according to any one of [1] to

[14] or a pharmaceutically acceptable salt thereof, thereby lowering LDL-C in the patient.

[25] The method according to any one of

[20] to

[24] , wherein the administration is carried out orally, parenterally, subcutaneously, by injection, or by infusion.

[26] The cyclic polypeptide or a pharmaceutically acceptable salt thereof according to any one of [1] to

[14] , for use in treating a PCSK9-mediated disease or disorder.

[27] The cyclic polypeptide or a pharmaceutically acceptable salt thereof according to any one of [1] to

[14] , for use in the treatment, prevention, remission or delay of progression, or for use in the treatment, prevention, remission or delay of progression of a disease or disorder requiring inhibition of PCSK9.

[28] Use of the polypeptide or a pharmaceutically acceptable salt thereof according to any one of [1] to

[14] for the treatment, prevention, amelioration or delay of progression of a PCSK9-mediated disease or disorder, or for the treatment, prevention, amelioration or delay of progression of a disease or disorder requiring inhibition of PCSK9.

[29] Use of the polypeptide according to any one of [1] to

[14] or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment, prevention, amelioration or delay of progression of a PCSK9-mediated disease or disorder, or for the treatment, prevention, amelioration or delay of progression of a disease or disorder requiring inhibition of PCSK9.

[30] A method for treating, preventing, ameliorating, or delaying the progression of a PCSK9-mediated disease or disorder or a disease or disorder requiring inhibition of PCSK9 or PCSK9 activity, the method comprising administering to a patient in need thereof a therapeutically effective amount of the polypeptide or a pharmaceutically acceptable salt thereof according to any one of [1] to

[14] .

[31] The polypeptide for use according to

[27] , the use of the polypeptide according to

[28] or

[29] , or the method according to

[30] , wherein the PCSK9-mediated disease or disorder or the disease or disorder requiring inhibition of PCSK9 is selected from hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, peripheral arterial disease, vascular inflammation, elevated Lp(a), elevated LDL, elevated TRL, elevated triglycerides, sepsis, and xanthomas.

Claims

1. A cyclic polypeptide selected from: 【Chemistry 1】 (SEQ ID NO: 1) 【change】 (SEQ ID NO:2) 【Chemistry 2】 (SEQ ID NO: 3) 【change】 (SEQ ID NO: 4) 【change】 (SEQ ID NO:5) 【change】 (SEQ ID NO:6) 【change】 (SEQ ID NO:7) 【Chemistry 3】 (SEQ ID NO:8) 【change】 (SEQ ID NO:9) 【change】 (SEQ ID NO: 10) 【change】 (SEQ ID NO:11) 【change】 (SEQ ID NO: 12) 【change】 (SEQ ID NO: 13) 【Chemistry 4】 (SEQ ID NO: 14) 【change】 (SEQ ID NO: 15) 【change】 (SEQ ID NO: 16) 【change】 (SEQ ID NO: 17) 【change】 (SEQ ID NO: 18) 【Chemistry 5】 (SEQ ID NO: 19) 【change】 (SEQ ID NO: 20) 【change】 (SEQ ID NO:21) 【change】 (SEQ ID NO:22) 【change】 (SEQ ID NO:23) 【Chemistry 6】 (SEQ ID NO:24) 【change】 (SEQ ID NO:25) 【change】 (SEQ ID NO:26) 【change】 (SEQ ID NO:27) 【change】 (SEQ ID NO:28) 【change】 (SEQ ID NO:29) 【Chemistry 7】 (SEQ ID NO: 30) 【change】 (SEQ ID NO:31) 【change】 (SEQ ID NO:32) 【change】 (SEQ ID NO:33) 【change】 (SEQ ID NO:34) 【change】 (SEQ ID NO:35) 【change】 (SEQ ID NO:36) 【Chemistry 8】 (SEQ ID NO:37) 【change】 (SEQ ID NO:38) or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof.

2. A pharmaceutical composition comprising the cyclic polypeptide of claim 1 or a pharma- ceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, and one or more pharma- ceutically acceptable carriers or excipients.

3. 3. The pharmaceutical composition of claim 2 for use in the treatment, prevention, amelioration or delay of progression of a PCSK9-mediated disease or disorder or a disease or disorder requiring inhibition of PCSK9 activity.

4. 4. The pharmaceutical composition of claim 3, wherein the PCSK9-mediated disease or disorder or disease or disorder requiring inhibition of PCSK9 activity is selected from hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, peripheral arterial disease, vascular inflammation, elevated Lp(a), elevated LDL, elevated TRL, elevated triglycerides, sepsis, and xanthomas.

Images