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

Abstract

The present disclosure relates to PCSK9 inhibitors useful for treating lipid metabolism and other diseases in which PCSK9 plays a role, wherein the PCSK9 inhibitor has formula (I), 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 As described in this article.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 772,033, filed on November 27, 2018, the entire contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] The present disclosure relates to modulators of PCSK9 for treating diseases or disorders associated with proprotein convertase subtilisin / kexin type 9 (PCSK9) proteases. In particular, the present disclosure relates to peptides and compositions that inhibit PCSK9, methods for treating diseases or disorders associated with PCSK9, and methods for synthesizing these peptides. Background Art

[0004] 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, and is synthesized as a soluble 74 kDa precursor that undergoes autocatalytic cleavage in the endoplasmic reticulum. It has been shown that autocatalytic activity is required for secretion.

[0005] PCSK9 has a significant effect on plasma low-density lipoprotein cholesterol (LDL-C) levels by regulating the hepatic low-density lipoprotein receptor (LDLR), which is the main pathway for removing cholesterol from the circulation. PCSK9 binds to the LDLR and directs it to lysosomal degradation, thereby increasing plasma LDL-C levels and, in turn, 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 LDL-C levels and substantially reduce liver LDLR protein, without observed effects on mRNA, SREBP, or SREBP protein nuclear-cytoplasmic ratio. (Maxwell K.N., Proc. Natl. Acad. Sci. [Proceedings of the National Academy of Sciences of the United States] 101, 2004, 7100-7105). In addition, PCSK9 mutations 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. [New England Journal of Medicine], 354, 2006, 1264-1272). Therefore, the results indicate that modulation of PCSK9 leads to reduced LDLR protein levels.

[0006] Genetic deletion of PCSK9 has also been performed in mice. PCSK9 knockout mice show a reduction in plasma cholesterol levels of about 50% and an increased sensitivity to statins to reduce plasma cholesterol (Rashid, S., et al., Proc. Natl. Acad. Sci. [Proceedings of the National Academy of Sciences of the United States], 2005, 102: 5374-5379). Human genetic data strongly support the role of PCSK9 in LDL balance. The link between PCSK9 and plasma LDL-C levels was first established by the discovery of PCSK9 missense mutations in patients with autosomal dominant familial hypercholesterolemia (Abifadel, M. et al., Nature [Nature], 2003, 34: 154-6). Patients carrying PCSK9 gain-of-function alleles have increased plasma LDL-C levels and premature CHD, while patients with PCSK9 loss-of-function alleles have significantly reduced plasma LDL-C and are protected from CHD.

[0007] PCSK9 also plays a role in lipoprotein (a) (Lp (a)) metabolism. Lp (a) is a pro-atherogenic lipoprotein composed of LDL particles covalently linked to apoLp (a). Human genetic studies have shown that Lp (a) is causally related to CHD risk. PCSK9 therapeutic antibodies have been shown to significantly reduce Lp (a) levels in patients with hypercholesterolemia. (Desai, NR et al., Circulation. [Circulation] 2013, 128 (9): 962-969; Lambert, G. et al., Clin. Sci. [Clinical Science], 2017, 131, 261-268). Compared with placebo, patients receiving statin therapy treated with monoclonal antibodies against PCSK9 showed a reduction of up to 32% in Lp (a) levels. (Desai NR et al., Circulation. [Circulation] 2013, 128 (9): 962-969).

[0008] In addition to its cardiovascular effects, PCSK9 also plays an important role in sepsis, a life-threatening disease caused by the body's response to infection. Overexpression of PSCK9 in septic mice has been shown to aggravate sepsis by increasing inflammation, while inhibition of PCSK9 has been shown to reduce mortality. (Dwivedi, DJ et al., Shock, 2016, 46(6), 672–680). In addition, flow cytometric studies in human HepG2 cells have shown that PCSK9 negatively regulates hepatocyte uptake of Gram-negative lipopolysaccharide (LPS) through an LDL-dependent mechanism by regulating LDLR-mediated bacterial lipid uptake of lipoteichoic acid (LTA) and LPS. (Grin, PM et al., Nature, 2018, 8(1): 10496) Therefore, inhibition of PCSK9 has the potential to treat sepsis by reducing the body's immune response to infection.

[0009] Currently, there are no known small molecule inhibitors of PCSK9. The only known PCSK9 inhibitors on the market are anti-PCSK9 antibodies. Therefore, the use of small molecule inhibitors to inhibit PCSK9 has the potential to treat 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 lipoproteins (TRL), elevated triglycerides, sepsis, xanthomas and other disorders. For these reasons, there is still a need for novel and effective small molecule PCSK9 inhibitors. Summary of the invention

[0010] The first aspect of the present disclosure relates to a cyclic peptide having formula (I) (SEQ ID No.: 39):

[0011]

[0012] in:

[0013] R 1 is H or (C1-C4)alkyl;

[0014] X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point;

[0015] X 2 Is L-Pro or D-Pro;

[0016] X 3 is L-Arg, D-Arg, L-Ser, D-Ser, L-His, D-His, L-Ala, or D-Ala;

[0017] 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,

[0018] D-Pro, L-Ala, D-Ala, L-(N-Me)Glu or D-(N-Me)Glu;

[0019] X 5 Is L-(N-Me)Ala, D-(N-Me)Ala, L-(N-Me)Glu, or D-(N-Me)Glu;

[0020] X 6 It is L-Bip, D-Bip, L-(4-CF3)Phe, D-(4-CF3)Phe, L-(3,4-diCl)Phe, D-(3,4-diCl)Phe,

[0021] L-(3-F)Phe, D-(3-F)Phe, L-(4-Cl)Phe, or D-(4-Cl)Phe;

[0022] X 7 Is L-(N-Me)Ala, D-(N-Me)Ala, L-(N-Me)Phe, or D-(N-Me)Phe;

[0023] X 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, L-Val, or D-Val;

[0024] X 9 is L-Thr or D-Thr;

[0025] X 10 is L-Thr, D-Thr, L-Ser, or D-Ser;

[0026] 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;

[0027] X 12 is L-Val, D-Val, L-Glu, or D-Glu; and

[0028] X 13 is L-Phe or D-Phe;

[0029] in:

[0030] Bip is 4-phenyl-phenylalanine;

[0031] Hse is homoserine;

[0032] (4-CF3)Phe is 4-trifluoromethyl-phenylalanine;

[0033] (3,4-diCl)Phe is 3,4-dichloro-phenylalanine;

[0034] (3-F)Phe is 3-fluoro-phenylalanine; and

[0035] (4-Cl)Phe is 4-chloro-phenylalanine;

[0036] or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof.

[0037] In one embodiment, the disclosure relates to a polypeptide having formula (I) (SEQ ID No.: 40), wherein:

[0038] R 1 is H or (C1-C4)alkyl;

[0039] X 1 absent or Gly;

[0040] X 2 Is L-Pro or D-Pro;

[0041] X 3 is L-Arg, D-Arg, L-Ser, D-Ser, L-His, D-His, L-Ala, or D-Ala;

[0042] 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,

[0043] D-Pro, L-Ala, D-Ala, L-(N-Me)Glu or D-(N-Me)Glu;

[0044] X 5 Is L-(N-Me)Ala, D-(N-Me)Ala, L-(N-Me)Glu, or D-(N-Me)Glu;

[0045] X 6 It is L-Bip, D-Bip, L-(4-CF3)Phe, D-(4-CF3)Phe, L-(3,4-diCl)Phe, D-(3,4-diCl)Phe,

[0046] L-(3-F)Phe, D-(3-F)Phe, L-(4-Cl)Phe, or D-(4-Cl)Phe;

[0047] X 7 Is L-(N-Me)Ala, D-(N-Me)Ala, L-(N-Me)Phe, or D-(N-Me)Phe;

[0048] 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;

[0049] X 9 is L-Thr or D-Thr;

[0050] X 10 is L-Thr, D-Thr, L-Ser, or D-Ser;

[0051] X 11is 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;

[0052] X 12 is L-Val, D-Val, L-Glu, or D-Glu; and

[0053] X 13 is L-Phe or D-Phe;

[0054] in:

[0055] Bip is 4-phenyl-phenylalanine;

[0056] Hse is homoserine;

[0057] (4-CF3)Phe is 4-trifluoromethyl-phenylalanine;

[0058] (3,4-diCl)Phe is 3,4-dichloro-phenylalanine;

[0059] (3-F)Phe is 3-fluoro-phenylalanine; and

[0060] (4-Cl)Phe is 4-chloro-phenylalanine;

[0061] or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof.

[0062] Another aspect of the present disclosure relates to a cyclic polypeptide having formula (I) or a pharmaceutically acceptable salt thereof for use in treating, preventing, ameliorating or delaying the progression of a disease or disorder mediated by PCSK9 or for use in treating, preventing, ameliorating or delaying the progression of a disease or disorder requiring inhibition of PCSK9 or PCSK9 activity.

[0063] In another aspect, the present disclosure relates to the use of a cyclic polypeptide having formula (I) or a pharmaceutically acceptable salt thereof for treating, preventing, ameliorating or delaying the progression of a disease or disorder mediated by PCSK9 or for treating, preventing, ameliorating or delaying the progression of a disease or disorder requiring inhibition of PCSK9 or PCSK9 activity.

[0064] Another aspect of the present disclosure relates to the use of a cyclic polypeptide having formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating, preventing, ameliorating or delaying the progression of a disease or disorder mediated by PCSK9 or for treating, preventing, ameliorating or delaying the progression of a disease or disorder requiring inhibition of PCSK9 or PCSK9 activity.

[0065] 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, the method comprising the steps of administering to a patient in need thereof a therapeutically effective amount of a cyclic polypeptide having formula (I) according to the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

[0066] 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, the method comprising the steps of administering to a patient in need thereof a therapeutically effective amount of a cyclic polypeptide having formula (I) according to the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

[0067] In another aspect, the present disclosure relates to a method 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, the method comprising the steps of administering to a patient in need thereof a therapeutically effective amount of a cyclic polypeptide having formula (I) or a pharmaceutically acceptable salt thereof.

[0068] Another aspect of the present disclosure relates to 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, the method comprising the steps of administering to a patient in need thereof a therapeutically effective amount of a cyclic polypeptide having formula (I) or a pharmaceutically acceptable salt thereof.

[0069] In another aspect, the present disclosure also relates to a method for (i) lowering LDL-C, (ii) lowering total apolipoprotein B (apoB) concentration, (iii) lowering LDL apoB, (iv) lowering TRL apoB, or (v) lowering non-HDL-C, and combinations thereof, in a patient in need thereof, wherein the method comprises administering to the patient a therapeutically effective amount of a cyclic polypeptide having formula (I) or a pharmaceutically acceptable salt thereof.

[0070] Another aspect of the 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, wherein the method comprises administering to the patient a therapeutically effective amount of a cyclic polypeptide having formula (I) or a pharmaceutically acceptable salt thereof.

[0071] In another aspect, the disclosure relates to a pharmaceutical composition comprising (eg, a therapeutically effective amount of) a cyclic polypeptide having formula (I) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0072] Another aspect of the present disclosure relates to a pharmaceutical composition comprising (e.g., a therapeutically effective amount of) a cyclic polypeptide having 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.

[0073] In another aspect, the disclosure relates to a method of modulating PCSK9 comprising administering to a patient in need thereof a cyclic polypeptide having formula (I) or a pharmaceutically acceptable salt thereof.

[0074] Another aspect of the disclosure relates to a method of inhibiting PCSK9, the method comprising administering a cyclic polypeptide of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need thereof. In another aspect, the disclosure relates to a method of inhibiting PCSK9 activity, the method comprising administering a cyclic polypeptide of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0075] In another aspect, the disclosure relates to a method for treating a PCSK9-mediated disease or disorder, comprising the step of administering to a patient in need thereof a therapeutically effective amount of a cyclic polypeptide having formula (I) or a pharmaceutically acceptable salt thereof.

[0076] Another aspect of the disclosure relates to a method of lowering LDL-C in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a cyclic polypeptide having formula (I) or a pharmaceutically acceptable salt thereof, thereby lowering LDL-C in the patient.

[0077] In another aspect, the disclosure relates to a cyclic polypeptide having formula (I) or a pharmaceutically acceptable salt thereof for use in treating a PCSK9-mediated disease or disorder.

[0078] Another aspect of the present disclosure relates to a cyclic polypeptide having formula (I) or a pharmaceutically acceptable salt thereof for use in treating a PCSK9-mediated disease or disorder selected from the group consisting 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, and xanthomas.

[0079] In another aspect, the disclosure relates to the use of a cyclic polypeptide having 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.

[0080] Another aspect of the present disclosure relates to a cyclic polypeptide having formula (I) or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for treating a disease associated with inhibition of PCSK9 activity.

[0081] In another aspect, the disclosure relates to the use of a cyclic polypeptide having formula (I) or a pharmaceutically acceptable salt thereof in treating a disease associated with inhibition of PCSK9 activity.

[0082] In certain aspects, the cyclic polypeptides of the disclosure that modulate or inhibit PCSK9 can be administered alone or in combination with other compounds (including other PCSK9 modulators or inhibitors) or other therapeutic agents.

[0083] Thus, in another aspect, the disclosure relates to a combination comprising (eg, a therapeutically effective amount of) a cyclic polypeptide having formula (I) or a pharmaceutically acceptable salt thereof, and one or more therapeutically active agents.

[0084] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those of ordinary skill in the art to which this disclosure belongs. In this specification, the singular also includes the plural, unless the context clearly states otherwise. Although methods and materials similar or equivalent to those described herein can be used for the practice and testing of this disclosure, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. The references cited herein are not considered to be the prior art of the disclosure claimed. In the event of a conflict, the present specification including the definition shall prevail. In addition, materials, methods and examples are illustrative only and are not intended to be limiting.

[0085] Other features and advantages of the disclosure will be apparent from the following detailed description, and from the claims. DETAILED DESCRIPTION

[0086] The present disclosure relates to peptides and compositions capable of regulating PCSK9 activity. The present disclosure is characterized by treating, preventing or improving a disease or disorder in which PCSK9 plays a role by administering a therapeutically effective amount of a cyclic polypeptide having formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof to a patient in need. The method disclosed herein can be used to treat a variety of PCSK9-dependent diseases and disorders by regulating or inhibiting PCSK9. Inhibiting or regulating PCSK9 provides novel methods for treating, preventing or improving 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.

[0087] The cyclic polypeptides disclosed herein have utility in 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 by inhibiting PCSK9.

[0088] For example, the cyclic polypeptides of formula (I) disclosed herein bind to PCSK9 and thus inhibit PCSK9 and / or PCSK9 activity because PCSK9 is no longer able to bind to the low-density lipoprotein receptor (LDLR) or any other target receptor. For example, if PCSK9 is blocked, more LDLR is circulated and present on the cell surface to remove LDL particles from the extracellular fluid. Therefore, blocking PCSK9 can reduce the concentration of LDL particles in the blood.

[0089] Therefore, the polypeptides of the present disclosure can potentially be used to treat, prevent, ameliorate or delay the progression of a disease or disorder mediated by PCSK9, or a disease or disorder in which PCSK9 plays a role, as well as the progression of conditions, diseases and disorders that benefit from modulation of PCSK9 or PCSK9 activity.

[0090] Furthermore, the cyclic polypeptides of the present disclosure are therefore potentially useful for treating, preventing, ameliorating or delaying the progression of diseases or disorders requiring inhibition of PCSK9 or PCSK9 activity.

[0091] Such diseases and disorders include those selected from the group consisting 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 (e.g., elevated VLDL and / or chylomicrons), elevated triglycerides, sepsis, and xanthomas.

[0092] Various embodiments of the present disclosure are described herein. It will be appreciated that features specified in each embodiment may be combined with other specified features of other embodiments to provide further embodiments.

[0093] In a first aspect of the present disclosure, a cyclic polypeptide having formula (I) is described:

[0094]

[0095] 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 As described above.

[0096] The details of the present disclosure are set forth in the specification attached below. Although methods and materials similar or equivalent to those described herein can be used for the practice or testing of the present disclosure, illustrative methods and materials are now described. According to the specification and according to the claims, other features, objects and advantages of the present disclosure will be clear. In this specification and the appended claims, the singular form also includes the plural form, unless the context clearly indicates otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those of ordinary skill in the art to which the present disclosure belongs. All patents and public documents cited in this specification are incorporated herein by reference in their entirety.

[0097] Definitions of terms and conventions used

[0098] Terms that are not explicitly defined herein should be understood to have the meanings that would be derived by a person skilled in the art based on this disclosure and context. However, unless otherwise indicated to the contrary, the following terms as used in this specification and the appended claims have the indicated meanings and follow the following conventions.

[0099] Chemical Nomenclature, Terminology and Conventions

[0100] Unless otherwise indicated, conventional definitions of terms and conventional stable atom valencies are assumed and reflected in all formulae and radicals.

[0101] As used in this disclosure, the articles "a" and "an" refer to one or more than one (e.g., at least one) of the grammatical object of the article. For example, "an element" means one element or more than one element.

[0102] The term "and / or" used in this disclosure means "and" or "or" unless otherwise indicated.

[0103] "Alkyl" means a straight or branched chain saturated hydrocarbon containing 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.

[0104] As used herein, the terms "polypeptide" and "peptide" are used interchangeably and refer to two or more amino acids linked together. In addition to the abbreviations for uncommon or non-natural amino acids listed in Table 1 below, three-letter or single-letter abbreviations recognized in the art are used to represent the amino acid residues that make up the peptides and polypeptides of the present disclosure. When it begins with "D", the amino acid is a D-amino acid. When it begins with "L", the amino acid is an L-amino acid. When the single-letter abbreviation is capitalized, it refers to an L-amino acid. When the single-letter abbreviation is lowercase, it refers to a D-amino acid. Groups or strings of amino acid abbreviations are used to represent peptides. The left side of the peptide is represented by the N-terminus, and the sequence is written from the N-terminus to the C-terminus.

[0105] Any of the above amino acid residues of formula (I) or its related formulae described herein (e.g., formula (I), (II), (III), (IV), (V), and (VI)) may be substituted in a conservative manner, provided that the peptide or polypeptide of the present disclosure still retains functional activity and structural properties (e.g., half-life extension, protection against degradation, conformational restriction). The principles and examples of permitted conservative amino acid substitutions are further explained herein.

[0106] The peptides of the present disclosure contain unnatural amino acids (ie, compounds that do not occur in nature), and other amino acid analogs known in the art may be used instead.

[0107] Those of ordinary skill in the art will appreciate that various amino acid substitutions, such as conservative amino acid substitutions, can be made in the sequence of any cyclic polypeptide described herein without reducing its activity. As used herein, "amino acids commonly used as their substituents" include conservative substitutions (i.e., substitutions with amino acids having similar chemical properties). For the purpose of conservative substitutions, non-polar (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 substitution of an L-amino acid with a corresponding D-amino acid, substitution of cysteine ​​with homocysteine ​​or other non-natural amino acids having a thiol-containing side chain, substitution of lysine with homolysine, diaminobutyric acid, diaminopropionic acid, ornithine or other non-natural amino acids having an amino-containing side chain, or substitution of alanine with norvaline, etc.

[0108] As used herein, the term "amino acid" refers to naturally occurring amino acids, unnatural amino acids, amino acid analogs, and amino acid mimetics (which function similarly to the naturally occurring amino acids), both in their D and L stereoisomeric forms (if their structures permit such stereoisomeric forms). Amino acids may be referred to herein by their name, their well-known three letter symbols, or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission.

[0109] The term "naturally occurring" refers to materials found in nature and not manipulated by humans. Similarly, "non-naturally occurring", "non-natural", etc. as used herein refer to materials that are not found in nature or have been structurally modified or synthesized by humans. When used in conjunction with amino acids, the term "naturally occurring" refers to 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)).

[0110] As used herein, the terms "non-natural amino acid" and "unnatural amino acid" are interchangeably intended to refer to amino acid structures that cannot be biosynthetically produced in any organism using the same or different unmodified or modified genes from any organism. These include, but are not limited to, modified amino acids and / or amino acid analogs (which are not one of the 20 naturally occurring amino acids), selenocysteine, pyrrolysine (Pyl), or pyrroline-carboxyl-lysine (Pcl, described, for example, in PCT Patent Publication WO 2010 / 48582).

[0111] Modified encoded amino acids include, but are not limited to, hydroxyproline, γ-carboxyglutamate, O-phosphoserine, azetidine carboxylic acid, 2-aminoadipic acid, 3-aminoadipic acid, β-alanine, aminopropionic acid, 2-aminobutyric acid, 4-aminobutyric acid, 6-aminohexanoic acid, 2-aminoheptanoic acid, 2-aminoisobutyric acid, 3-aminoisobutyric acid, 2-aminopimelic acid, tert-butylglycine, 2,4-diaminoisobutyric acid, desmosine, 2,2'-diaminopimelic acid, 2 The term "amino acid" also includes naturally occurring amino acids that are metabolites in certain organisms but are not encoded by the genetic code and are incorporated into proteins. Such amino acids include, but are not limited to, ornithine, D-ornithine, and D-arginine.

[0112] A peptide is defined herein as an organic compound comprising two or more amino acids covalently linked by peptide bonds. Peptides may be referred to with respect to the number of amino acid components, i.e., a dipeptide or dimer contains two amino acid residues, a tripeptide or trimer contains three amino acids, etc. Peptides containing ten or fewer amino acids may be referred to as oligopeptides, and peptides with more than ten amino acid residues are polypeptides.

[0113] The term "peptide" as used herein means two or more amino acids linked together via peptide bonds.

[0114] Table 1: Examples of unnatural amino acids described in this disclosure:

[0115]

[0116]

[0117] Table 2: Examples of protected amino acids described in this disclosure:

[0118] Salt, Prodrug, Derivative, and Solvate Terms and Conventions

[0119] "Prodrug" or "prodrug derivative" means a covalently bonded derivative or carrier of a parent polypeptide or active drug substance that undergoes at least some biotransformation before exhibiting one or more of its pharmacological effects. Generally speaking, such prodrugs have metabolically cleavable groups and are rapidly transformed in vivo to produce the parent polypeptide, such as by hydrolysis in the blood, and generally include ester and amide analogs of the parent polypeptide. Prodrugs are formulated with the goal of improving chemical stability, improving patient acceptance and compliance, improving bioavailability, extending duration of action, improving organ selectivity, improving formulations (e.g., increased water solubility) and / or reducing side effects (e.g., toxicity). Generally speaking, the prodrug itself has weak biological activity 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, in particular 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, in particular, pages 309-396; Burger's Medicinal Chemistry and Drug Discovery, 5th edition, M. Wolff (ed.), John Wiley & Sons, 1995, in particular, volume 1 and pages 172-178 and 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.

[0120] As used herein, "pharmaceutically acceptable prodrug" means a prodrug of the polypeptides of the present disclosure that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, etc., commensurate with a reasonable benefit / risk ratio, and, where possible, effective for its intended use as well as in zwitterionic form.

[0121] "Salt" means the product of the reaction between the ionic form of the parent polypeptide or the parent polypeptide and a suitable acid or base to prepare an acid salt or basic salt of the parent polypeptide. The salt of the polypeptide of the present disclosure can be synthesized from the parent polypeptide containing the basic or acidic part by conventional chemical methods. Typically, the salt is prepared by reacting the free basic or acidic parent polypeptide with a stoichiometric amount or with an excess of the desired salt-forming inorganic or organic acid or base in a suitable solvent or different solvent combinations.

[0122] "Pharmaceutically acceptable salt" means a salt of the polypeptide of the present disclosure which is, within the scope of reasonable medical judgment, suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, etc., commensurate with a reasonable benefit / risk ratio, generally water-soluble or oil-soluble or dispersible, and effective for its intended use. The term includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. Since the polypeptide of the present disclosure is useful in both free base form and salt form, in practice, using the salt form is equivalent to using the base form. A list of suitable salts is found, for example, in SM Birge et al., J. Pharm. Sci. [Journal of Pharmaceutical Sciences], 1977, 66, pp. 1-19, which is hereby incorporated by reference in its entirety.

[0123] "Pharmaceutically acceptable acid addition salts" means those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable and are prepared by addition of an inorganic acid (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, aminosulfonic acid, nitric acid, phosphoric acid, etc.) and an organic acid (e.g., 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, The present invention can be used to prepare the present invention comprises amino acid, glycolic acid, glycerophosphoric acid, hemisulfuric acid, heptanoic acid, hexanoic acid, formic acid, fumaric acid, 2-hydroxyethanesulfonic acid (hydroxyethylsulfonic 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, pectic acid, phenylacetic acid, 3-phenylpropionic acid, picric acid, pivalic acid, propionic acid, pyruvic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, p-aminobenzenesulfonic acid, tartaric acid, p-toluenesulfonic acid, undecanoic acid, etc.).

[0124] "Pharmaceutically acceptable base addition salts" means salts that retain the biological effectiveness and properties of the free acids and are not biologically or otherwise undesirable, and are formed with inorganic bases (e.g., ammonia or hydroxides, carbonates, or ammonium bicarbonate) or metal cations (e.g., sodium, potassium, lithium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc.). Particularly preferred are ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary 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, histidine, Caffeine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, tetramethylammonium compounds, tetraethylammonium compounds, pyridine, N,N-methylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, dibenzylamine, N,N-dibenzylphenethylamine, 1-diphenylhydroxymethylamine, N,N'-dibenzylethylenediamine, polyamine resins, etc. Particularly preferred organic non-toxic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0125] "Solvate" means a complex of variable stoichiometry formed by a solute (e.g., a polypeptide of Formula (I)) and a solvent (e.g., water, ethanol, or acetic acid). This physical association may involve varying degrees of ionic and covalent bonds, including hydrogen bonds. In some cases, the solvate is capable of separation (e.g., when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid). In general, 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 separable solvates. Representative solvates include hydrates, ethanolates, methanolates, and the like.

[0126] "Hydrate" means a solvate wherein one or more of the solvent molecules is water.

[0127] The polypeptides of the present disclosure as discussed below include free bases or acids thereof, salts, solvates and prodrugs thereof, and may include oxidized sulfur atoms or quaternized nitrogen atoms in their structures (although not explicitly described or shown), particularly pharmaceutically acceptable forms thereof. Such forms (particularly pharmaceutically acceptable forms) are intended to be included in the appended claims.

[0128] Isomer terms and conventions

[0129] "Isomers" refers to compounds or polypeptides that have the same number and kind of atoms, and therefore the same molecular weight, but differ in the arrangement or configuration of the atoms in space. The term includes stereoisomers and geometric isomers.

[0130] "Stereoisomer" or "optical isomer" means a stable isomer having at least one chiral atom or restricted rotation resulting in a vertical asymmetric plane (e.g., certain biphenyls, allenes, and spiro compounds) and can rotate plane polarized light. Because asymmetric centers and other chemical structures are present in the polypeptides of the present disclosure that can cause stereoisomerism, the present disclosure contemplates stereoisomers and mixtures thereof. The polypeptides of the present disclosure and their salts include asymmetric carbon atoms and can therefore exist as single stereoisomers, racemates, and mixtures of enantiomers and diastereomers. Typically, such compounds or polypeptides will be prepared as racemic mixtures. However, if desired, such compounds or polypeptides can be prepared or separated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as a mixture enriched in stereoisomers. As discussed in more detail below, individual stereoisomers of compounds or polypeptides 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 (such as conversion into a mixture of diastereomers followed by separation or recrystallization, chromatography techniques, use of a chiral resolving agent, or direct separation of enantiomers on a chiral chromatographic column). Starting compounds or amino acids of specific stereochemistry are commercially available or prepared by the methods described below and resolved by techniques well known in the art.

[0131] "Enantiomers" means a pair of stereoisomers that are non-superimposable mirror images of one another.

[0132] "Diastereomers" or "diastereomers" means optical isomers that are not mirror images of one another.

[0133] "Racemic mixture" or "racemate" means a mixture containing equal parts of individual enantiomers.

[0134] "Non-racemic mixture" means a mixture containing unequal parts of individual enantiomers.

[0135] Some polypeptides of the present disclosure can exist in more than one tautomeric form. As mentioned above, the polypeptides of the present disclosure include all such tautomers.

[0136] It is well known in the art that the biological and pharmacological activities of compounds or polypeptides are sensitive to the stereochemistry of the compounds or polypeptides. Thus, for example, enantiomers generally exhibit significantly different biological activities, including differences in pharmacokinetic properties (including metabolism, protein binding, etc.) and pharmacological properties (including the type of activity displayed, degree of activity, toxicity, etc.). Therefore, it will be understood by those skilled in the art that one enantiomer may be more active or may exhibit a beneficial effect when enriched relative to the other enantiomers or when separated from the other enantiomers. Additionally, those skilled in the art will know how to separate, enrich, or selectively prepare the enantiomers of the polypeptides of the present disclosure from the knowledge of the present disclosure and the prior art.

[0137] Therefore, although the racemic form of the drug can be used, it is generally not as effective as administering an equal amount of enantiomerically pure drug; in fact, in some cases, one enantiomer may be pharmacologically inactive and only act as a simple diluent. For example, although ibuprofen has previously been administered as a racemate, it has been found that only the S-isomer of ibuprofen can be effectively used as an anti-inflammatory agent (however, in the case of ibuprofen, although the R-isomer is inactive, it is converted to the S-isomer in the body, so the racemic form of the drug is slower to take effect than the pure S-isomer). In addition, the pharmacological activity of enantiomers can have significantly different biological activities. For example, S-penicillamine is a therapeutic agent for chronic arthritis, while R-penicillamine is toxic. In fact, some purified enantiomers are more advantageous than racemates because it has been reported that purified individual isomers have faster transdermal penetration rates than racemic mixtures. See U.S. Patent Nos. 5,114,946 and 4,818,541.

[0138] Therefore, if one enantiomer is pharmacologically more active, less toxic, or has a more favorable in vivo distribution than the other enantiomer, it would be more beneficial to administer that enantiomer preferentially. In this way, the patient being treated would be exposed to a lower total dose of the drug and a lower dose of the potentially toxic enantiomer or other enantiomer inhibitors.

[0139] The preparation of pure enantiomers or mixtures having the desired enantiomeric excess (ee) or enantiomeric purity can be accomplished by one or more of a number of methods known to those skilled in the art for (a) separation or resolution of enantiomers, or (b) enantioselective synthesis, or a combination of these methods. These resolution methods typically 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; TE Beesley and RPW Scott, Chiral Chromatography, John Wiley & Sons, 1999; and Satinder Ahuja, Chiral Separations by Chromatography, Am. Chem. Soc., 2000. In addition, there are equally well-known methods for quantifying enantiomeric excess or purity (e.g., GC, HPLC, CE, or NMR) and for identifying absolute configuration and conformation (e.g., CDORD, X-ray crystallography, or NMR).

[0140] In general, all tautomeric and isomeric forms and mixtures of a chemical structure or compound, whether individual geometric isomers or stereoisomers or racemic or non-racemic mixtures, are contemplated unless a specific stereochemistry or isomeric form is explicitly indicated in the compound name or structure.

[0141] Drug administration and treatment terminology and conventions

[0142] A "patient" or "subject" is a mammal, e.g., 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 yet other embodiments, the subject is a human.

[0143] The term "pharmaceutically effective amount" or "therapeutically effective amount" or "effective amount" means an amount of a polypeptide according to the disclosure that, when administered to a patient in need thereof, is sufficient to achieve treatment of a disease state, condition or disorder in which the polypeptide has utility. Such an amount is sufficient to elicit the biological or medical response of a tissue, system or patient sought by a researcher or clinician. The amount of a polypeptide according to the disclosure that constitutes a therapeutically effective amount will vary according to factors such as the polypeptide and its biological activity, the composition used for administration, the time of administration, the route of administration, the excretion rate of the polypeptide, the duration of treatment, the type of disease state or disorder being treated and its severity, the drugs combined or used with the polypeptide of the disclosure, and the age, weight, general health, sex and diet of the patient. Such a therapeutically effective amount can be routinely determined by those of ordinary skill in the art based on their own knowledge, the prior art and the disclosure.

[0144] 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 in a form suitable for oral or parenteral administration, and at least one pharmaceutically acceptable carrier.

[0145] "Carrier" encompasses carriers, excipients, and diluents, and means a material, composition, or vehicle involved in carrying or transporting a pharmaceutical agent from one organ or part of a subject's body to another, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material.

[0146] "Combination" refers to a fixed combination in the form of one dosage unit, or a combined administration in which the cyclic polypeptide of the present disclosure and at least one combination partner (e.g., another drug, also referred to as "therapeutic agent" or "co-agent") explained below can be administered independently at the same time or separately within time intervals, particularly where these time intervals allow the combination partners to show the beneficial effects of the therapeutic agents acting together. The beneficial effects of the combination include, but are not limited to, synergistic effects, such as synergistic effects and / or pharmacokinetic or pharmacodynamic co-actions, or any combination thereof, resulting from the combination of therapeutic agents. In one embodiment, the combined administration of these therapeutic agents is performed over a defined period of time (e.g., minutes, hours, days or weeks, depending on the combination selected). "

[0147] The individual components can be packaged in a kit or packaged separately. One or both components (e.g., powder or liquid) can be reconstituted or diluted to the desired dose prior to administration. The terms "co-administration" or "combination administration" etc. as used herein are intended to encompass administration of the selected combination partner 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 are administered simultaneously.

[0148] As used herein, the term "drug combination" means a product produced by a mixture or combination of more than one therapeutic agent, and includes both fixed and non-fixed combinations of therapeutic agents. The term "fixed combination" means that therapeutic agents (e.g., cyclic polypeptides and combination partners of the present disclosure) are administered to patients simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that therapeutic agents (e.g., cyclic polypeptides and combination partners of the present disclosure) are administered to patients simultaneously, in parallel or sequentially as separate entities (without specific time limits), wherein such administration provides two compounds at therapeutically effective levels in the patient's body. The latter is also applicable to cocktail therapy, such as the administration of three or more therapeutic agents.

[0149] A subject (preferably a human) is "in need of" a treatment if the subject would benefit biologically, medically, or in quality of life from such treatment.

[0150] The term "PCSK9" or "proprotein convertase subtilisin / kexin type 9" refers interchangeably to a naturally occurring human proprotein convertase that belongs to the proteinase K subfamily of the secreted subtilisin family. PCSK9 is synthesized as a soluble zymogen that undergoes autocatalytic intramolecular processing in the endoplasmic reticulum and is thought to function as a proprotein convertase. PCSK9 plays a role in cholesterol homeostasis and may play a role in the differentiation of cortical neurons. Mutations in the PCSK9 gene are responsible for autosomal dominant familial hypercholesterolemia. (Burnett and Hooper, Clin. Biochem. Rev. (2008) 29(1): 11-26)

[0151] As used herein, the terms "inhibit," "inhibition," or "inhibiting" refer to the reduction 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.

[0152] As used herein, the terms "treat," "treating," or "treatment" of any disease or disorder refers to alleviating or relieving the disease or disorder (i.e., slowing or arresting the progression of the disease or at least one clinical symptom thereof); or alleviating or improving at least one physical parameter or biomarker associated with the disease or disorder, including those that may not be discernible by the patient.

[0153] As used herein, the terms "prevent," "preventing," or "prevention" of any disease or disorder refers to prophylactic treatment of; or delaying the onset or progression of; a disease or disorder.

[0154] "Pharmaceutically acceptable" means 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.

[0155] Unless otherwise indicated, "disorder" means, and is used interchangeably with, the terms disease, condition, or ailment.

[0156] "Administer," "administering," or "administration" means administering a disclosed polypeptide, or a pharmaceutically acceptable salt or composition of a disclosed polypeptide directly to a subject, or administering a prodrug derivative or analog of a polypeptide, or a pharmaceutically acceptable salt or composition of a polypeptide to a subject, which can form an equivalent amount of active polypeptide in the subject.

[0157] "Prodrug" means a polypeptide that is convertible in vivo to a disclosed polypeptide by metabolic means (eg, by hydrolysis).

[0158] "Polypeptide of the present disclosure", "polypeptide of formula (I)", "polypeptide of the present disclosure", "cyclic polypeptide of the present disclosure", "cyclic polypeptide of formula (I)", "cyclic polypeptide of the present disclosure" and equivalent expressions (unless otherwise specifically indicated) refer to polypeptides of formula (I), (II), (III), (IV), (V) and (VI) as described herein, including tautomers, prodrugs, salts (particularly pharmaceutically acceptable salts), and solvates and hydrates thereof, (where the context permits) and all stereoisomers (including diastereomers and enantiomers), rotational isomers, tautomers, and isotopically labeled polypeptides (including deuterium substitution), as well as inherently formed moieties (e.g., solvates and / or hydrates). For the purposes of the present disclosure, solvates and hydrates are generally considered to be compositions. Generally and preferably, polypeptides of the present disclosure and formulas representing polypeptides of the present disclosure should be understood to include only stable polypeptides thereof and exclude unstable polypeptides, even if unstable polypeptides can be considered to be actually included in the polypeptide formula. Similarly, where the context permits, references to intermediates (whether or not they themselves are claimed) are intended to include their salts and solvates. For clarity, specific instances where the context permits are sometimes indicated in the text, but these are purely illustrative and are not intended to exclude other instances where the context permits.

[0159] By "stable polypeptide" or "stable structure" is meant a polypeptide that is sufficiently robust 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 with "dangling valencies" or carbanions are not polypeptides contemplated by the present disclosure.

[0160] In specific embodiments, the term "about" or "approximately" means within 20%, preferably within 10%, and more preferably within 5% of a given value or range.

[0161] As used herein, "modulator of PCSK9" refers to a peptide or polypeptide that is capable of modulating the biological activity or function of PCSK9 and / or one or more downstream pathways mediated by PCSK9 activity.

[0162] As used herein, "inhibitors of PCSK9" refers to peptides or polypeptides that can inhibit PCSK9 biological activity or function and / or one or more downstream pathways mediated by PCSK9 signaling. Inhibitors of PCSK9 activity include polypeptides that block, antagonize, inhibit or reduce (to any extent, including significantly) PCSK9 biological activity (including downstream pathways mediated by PCSK9 activity).

[0163] As used herein, "disorders or diseases responsive to inhibition of PCSK9," "disorders and conditions responsive to inhibition of PCSK9," "disorders and conditions responsive to inhibition of PCSK9 activity," "disorders responsive to inhibition of PCSK9," "disorders responsive to inhibition of PCSK9 activity," "disorders in which PCSK9 plays a role" and the like terms 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.

[0164] As used herein, "inhibiting PCSK9 activity" or "inhibiting PCSK9" refers to a decrease in PCSK9 activity, such as by administering the peptides and polypeptides of the disclosure.

[0165] The term "hypercholesterolemia" or "dyslipidemia" includes, for example, familial and non-familial hypercholesterolemia. Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder characterized by elevated serum cholesterol bound to low-density lipoprotein (LDL). Familial hypercholesterolemia includes heterozygous FH and homozygous FH. Hypercholesterolemia (or dyslipidemia) is the presence of high levels of cholesterol in the blood. It is a form of hyperlipidemia (elevated lipid levels in the blood) and hyperlipoproteinemia (elevated lipoprotein levels in the blood).

[0166] Hyperlipidemia is an increase in lipids in the blood. These lipids include cholesterol, cholesterol esters, phospholipids and triglycerides. Hyperlipidemia includes, for example, type I, type IIa, type IIb, type III, type IV and type V.

[0167] Hypertriglyceridemia means high levels of triglycerides in the blood. Elevated triglyceride levels are associated with atherosclerosis (even in the absence of hypercholesterolemia) and predispose to cardiovascular disease.

[0168] "Sitosterolemia" or "phytosterolemia" is a rare autosomal recessive lipid metabolism disorder characterized by excessive absorption of sitosterol in the gastrointestinal tract and reduced biliary excretion of dietary sterols (i.e., leading to hypercholesterolemia, tendon and tuberous xanthomas, premature development of atherosclerosis), and altered cholesterol synthesis.

[0169] "Atherosclerosis" includes hardening of the arteries involving the deposition of fatty substances, cholesterol, cellular waste products, calcium, and fibrin in the lining of the arteries. The resulting accumulation is called plaque.

[0170] "Atherosclerosis" or "atherosclerotic vascular disease (ASVD)" is a specific form of arteriosclerosis that involves thickening, hardening, and loss of elasticity of the arterial wall due to the invasion and accumulation of leukocytes, including live, active leukocytes (producing inflammation), and remnants of dead cells, including cholesterol and triglycerides. Thus, atherosclerosis is a syndrome that affects the arterial blood vessels due to a chronic inflammatory response of leukocytes in the arterial wall.

[0171] Coronary heart disease, also known as atherosclerotic heart disease, atherosclerotic cardiovascular disease, coronary artery disease or ischemic heart disease, is the most common type of heart disease and cause of heart attacks. The disease is caused by a buildup of plaque along the inner walls of the heart's arteries, which narrows the arteries and reduces blood flow to the heart.

[0172] "Xanthomas" are cutaneous manifestations of lipid hyperplasia in which lipids accumulate in large foam cells within the skin. Xanthomas are associated with hyperlipidemia.

[0173] As used herein, the term "elevated Lp(a) concentration" refers to a serum Lp(a) concentration above 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, 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, the patient's serum Lp(a) is considered elevated and the patient's serum Lp(a) level can be checked after a meal. In some embodiments, the Lp(a) level is measured after a period of fasting (e.g., after fasting for 8 hours, 8 hours, 10 hours, 12 hours, or more). Exemplary methods for measuring patient serum Lp(a) include, but are not limited to, rate immunoturbidimetry, ELISA, turbidimetry, immunoturbidimetry, and dissociation-enhanced lanthanide fluorescence immunoassay, although any clinically acceptable diagnostic method may be used in the context of the present disclosure.

[0174] "Elevated triglyceride levels" or "ETL" refers to any level of triglyceride levels determined to be undesirable or targeted for regulation.

[0175] "Sepsis" is a systemic response characterized by arterial hypotension, metabolic acidosis, decreased systemic vascular resistance, tachypnea, and organ dysfunction. Sepsis can result from sepsis (i.e., an organism, its metabolic end products or toxins in the blood) including bacteremia (i.e., bacteria in the blood) as well as toxemia (i.e., toxins in the blood) including endotoxemia (i.e., endotoxins in the blood). The term "sepsis" also includes fungemia (i.e., fungi in the blood), viremia (i.e., viruses or viral particles in the blood), and parasitemia (i.e., helminth or protozoan parasites in the blood). Thus, sepsis and septic shock (acute circulatory failure caused by sepsis, often associated with multi-organ failure and high mortality) can be caused by many organisms.

[0176] Specific embodiments of polypeptides having formula (I)

[0177] The present disclosure relates to polypeptides capable of regulating PCSK9 or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof (which can be used to treat diseases and disorders associated with the regulation of PCSK9 proteins or enzymes). In another embodiment, the present disclosure relates to polypeptides capable of inhibiting PCSK9 or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, which can be used to treat diseases and disorders associated with the inhibition of PCSK9 proteins or enzymes. The present disclosure further relates to polypeptides or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, which can be used to inhibit PCSK9.

[0178] In one embodiment, the polypeptide having formula (I) has the structure of formula (II): Formula (II) (SEQ ID No.: 44):

[0179]

[0180] and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers and tautomers thereof.

[0181] In another embodiment, the polypeptide having formula (I) has the structure of formula (III) (SEQ ID No.: 45):

[0182]

[0183] and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers and tautomers thereof.

[0184] In another embodiment, the polypeptide having formula (I) has the structure of formula (IV) (SEQ ID No.: 46):

[0185]

[0186] and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers and tautomers thereof.

[0187] In another embodiment, the polypeptide having formula (I) has the structure of formula (V) (SEQ ID No.: 47):

[0188]

[0189] and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers and tautomers thereof.

[0190] In another embodiment, the polypeptide having formula (I) has the structure of formula (VI) (SEQ ID No.: 48):

[0191]

[0192] and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers and tautomers thereof.

[0193] In some embodiments of the above formulae (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 In another embodiment, R 1 is H. In yet another embodiment, R 1 is H, methyl, or ethyl.

[0194] In some embodiments of the above formula, X 1 In another embodiment, X 1 In another embodiment, X 1 In another embodiment, X 1 In another embodiment, X 1 In another embodiment, X 1 In another embodiment, X 1 Does not exist.

[0195] In some embodiments of the above formula, X 2 In another embodiment, X 2 It's L-Pro.

[0196] In some embodiments of the above formula, X 3 X is D-Arg, D-Ser, D-His, or D-Ala. In another embodiment, X 3 In yet another embodiment, X 3 X is L-Arg, L-Ser, or L-His. 3 In yet another embodiment, X 3 In another embodiment, X 3 In yet another embodiment, X 3In another embodiment, X 3 In yet another embodiment, X 3 In another embodiment, X 3 is L-Arg, L-Ser, or L-Ala.

[0197] In some embodiments of the above formula, X 4 X is D-Asp, D-Asn, D-Glu, D-Lys, D-Gln, D-Pro, D-Ala, or D-(N-Me)Glu. In another embodiment, X 4 In yet another embodiment, X 4 In another embodiment, X 4 In yet another embodiment, X 4 In another embodiment, X 4 In yet another embodiment, X 4It 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.

[0198] In another embodiment, X 4 In yet another embodiment, X 4 In another embodiment, X 4 In yet another embodiment, X 4 In another embodiment, X 4 In yet another embodiment, X 4 In another embodiment, X 4 In yet another embodiment, X 4 In another embodiment, X 4 In yet another embodiment, X 4 X is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, or L-Ala. 4It is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu.

[0199] In some embodiments of the above formula, X 5 In another embodiment, X 5 In yet another embodiment, X 5 In another embodiment, X 5 In yet another embodiment, X 5 In another embodiment, X 5 It is L-(N-Me)Ala or L-(N-Me)Glu.

[0200] 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. In another embodiment, X 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. In yet another embodiment, X 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. In another embodiment, X 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. In another embodiment, X 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. In yet another embodiment, X 6 It 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.

[0201] 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. 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, L-(3-F)Phe, L-(4-Cl)Phe, or D-(4-Cl)Phe. In yet 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, L-(3-F)Phe, D-(3-F)Phe, or D-(4-Cl)Phe. 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, L-(3-F)Phe, D-(3-F)Phe, or L-(4-Cl)Phe. In yet another embodiment, X 6 is D-Bip, D-(4-CF3)Phe, D-(3,4-diCl)Phe, D-(3-F)Phe, or D-(4-Cl)Phe. In another embodiment, X 6 It is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe.

[0202] In some embodiments of the above formula, X 7In another embodiment, X 7 In yet another embodiment, X 7 In another embodiment, X 7 In yet another embodiment, X 7 In another embodiment, X 7 It is L-(N-Me)Ala or L-(N-Me)Phe.

[0203] In some embodiments of the above formula, X 8 In another embodiment, X 8 In yet another embodiment, X 8 In another embodiment, X 8 In yet another embodiment, X 8 In another embodiment, X 8In yet another embodiment, X 8 In another embodiment, X 8 In yet 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, D-Ala, L-Phe, D-Phe, L-Val, or D-Val.

[0204] In another embodiment, X 8 In another embodiment, X 8 In yet another embodiment, X 8 In another embodiment, X 8 In yet another embodiment, X 8In another embodiment, X 8 In yet another embodiment, X 8 It is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val.

[0205] In some embodiments of the above formula, X 9 In another embodiment, X 9 It's L-Thr.

[0206] In some embodiments of the above formula, X 10 In another embodiment, X 10 In yet another embodiment, X 10 In yet another embodiment, X 10 In another embodiment, X 10 In yet another embodiment, X 10 It is L-Thr or L-Ser.

[0207] In some embodiments of the above formula, X 11 X is D-Ser, L-Asp, D-Asp, L-Asn, D-Asn, L-Pro, D-Pro, L-Ala, D-Ala, L-Hse, or D-Hse. In another embodiment, X 11 In yet another embodiment, X 11 In another embodiment, X 11In yet another embodiment, X 11 X is L-Ser, D-Ser, L-Asp, D-Asp, D-Asn, L-Pro, D-Pro, L-Ala, D-Ala, L-Hse, or D-Hse. In another embodiment, X 11 In yet another embodiment, X 11 X is L-Ser, D-Ser, L-Asp, D-Asp, L-Asn, D-Asn, D-Pro, L-Ala, D-Ala, L-Hse, or D-Hse. In another embodiment, X 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.

[0208] In another embodiment, X 11 In yet another embodiment, X 11 In another embodiment, X 11 In yet another embodiment, X 11 X is L-Ser, D-Ser, L-Asp, D-Asp, L-Asn, D-Asn, L-Pro, D-Pro, L-Ala, D-Ala, or L-Hse. In another embodiment, X 11 In yet another embodiment, X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala, or L-Hse.

[0209] In some embodiments of the above formula, X 12X is L-Val, D-Val, L-Glu, or D-Glu. In another embodiment, X 12 In yet another embodiment, X 12 X is D-Val, L-Glu, or D-Glu. In another embodiment, X 12 In yet another embodiment, X 12 X is L-Val, D-Val, or D-Glu. In another embodiment, X 12 In yet another embodiment, X 12 In another embodiment, X 12 In yet another embodiment, X 12 In another embodiment, X 12 It is L-Val or L-Glu.

[0210] In some embodiments of the above formula, X 13 In another embodiment, X 13 It is L-Phe.

[0211] In some embodiments of the above formula, X 13 is L-Phe and X 2 In another embodiment, X 13 is L-Phe and X 9 In another embodiment, X 13 is L-Phe and X 12 In yet another embodiment, X 13 is L-Phe and X 12 In another embodiment, X 13 is L-Phe and X 1 In yet another embodiment, X 13 is L-Phe and X 10 In another embodiment, X 13 is L-Phe and R 1 is H or (C1-C3) alkyl. In yet another embodiment, X 13 is L-Phe and R 1 It's H.

[0212] In some embodiments of the above formula, X 2Is L-Pro and X 9 In yet another embodiment, X 2 Is L-Pro and X 12 In another embodiment, X 2 Is L-Pro and X 12 In yet another embodiment, X 2 Is L-Pro and X 1 In another embodiment, X 2 Is L-Pro and X 10 In yet another embodiment, X 2 It is L-Pro and R 1 is H or (C1-C3) alkyl. In another embodiment, X 2 It is L-Pro and R 1 It's H.

[0213] In some embodiments of the above formula, X 9 Is L-Thr and X 12 In another embodiment, X 9 Is L-Thr and X 12 In yet another embodiment, X 9 Is L-Thr and X 1 In another embodiment, X 9 Is L-Thr and X 10 In yet another embodiment, X 9 is L-Thr and R 1 is H or (C1-C3) alkyl. In another embodiment, X 9 is L-Thr and R 1 It's H.

[0214] In some embodiments of the above formula, X 12 is L-Val or L-Glu and X 1 In another embodiment, X 12 is L-Val or L-Glu and X 10 In yet another embodiment, X 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 1is H. In yet another embodiment, X 12 Is L-Val and X 1 In another embodiment, X 12 Is L-Val and X 10 In yet another embodiment, X 12 is L-Val and R 1 is H or (C1-C3) alkyl. In another embodiment, X 12 is L-Val and R 1 It's H.

[0215] In some embodiments of the above formula, X 1 Not present or Gly and X 10 In another embodiment, X 1 Absent or Gly and R 1 is H or (C1-C3) alkyl. In yet another embodiment, X 1 Absent or 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 yet another embodiment, X 10 is L-Thr or L-Ser and R 1 It's H.

[0216] In some embodiments of the above formula, X 13 It is L-Phe, X 2 It is L-Pro, and X 9 In yet another embodiment, X 13 It is L-Phe, X 2 It is L-Pro, and X 12 In another embodiment, X 13 It is L-Phe, X 2 It is L-Pro, and X 12 In another embodiment, X 13 It is L-Phe, X 2 It is L-Pro, and X 1 In another embodiment, X 13 It is L-Phe, X 2 It is L-Pro, and X 10 In another embodiment, X 13 It is L-Phe, X 2It is L-Pro, and R 1 is H or (C1-C3) alkyl. In another embodiment, X 13 It is L-Phe, X 2 It is L-Pro, and R 1 It's H.

[0217] In some embodiments of the above formula, X 13 It is L-Phe, X 9 is L-Thr, and X 12 In another embodiment, X 13 It is L-Phe, X 9 is L-Thr, and X 12 In yet another embodiment, X 13 It is L-Phe, X 9 is L-Thr, and X 1 In another embodiment, X 13 It is L-Phe, X 9 is L-Thr, and X 10 In yet another embodiment, X 13 It is L-Phe, X 9 is L-Thr, and R 1 is H or (C1-C3) alkyl. In another embodiment, X 13 It is L-Phe, X 9 is L-Thr, and R 1 It's H.

[0218] In some embodiments of the above formula, X 9 It is L-Thr, X 12 is L-Val or L-Glu, and X 1 In another embodiment, X 9 It is L-Thr, X 12 is L-Val or L-Glu, and X 10 In yet another embodiment, X 9 It is L-Thr, X 12 is L-Val or L-Glu, and R 1 is H or (C1-C3) alkyl. In another embodiment, X 9 It is L-Thr, X 12 is L-Val or L-Glu, and R 1 It's H.

[0219] In some embodiments of the above formula, X9 It is L-Thr, X 12 is L-Val, and X 1 In another embodiment, X 9 It is L-Thr, X 12 is L-Val, and X 10 In yet another embodiment, X 9 It is L-Thr, X 12 is L-Val, and R 1 is H or (C1-C3) alkyl. In another embodiment, X 9 It is L-Thr, X 12 is L-Val, and R 1 is H. In yet another embodiment, X 12 Is L-Val or L-Glu, X 1 Not present or Gly, and X 10 In another embodiment, X 12 Is L-Val or L-Glu, X 1 Absent or Gly, and R 1 is H or (C1-C3) alkyl. In yet another embodiment, X 12 Is L-Val or L-Glu, X 1 Absent or Gly, and R 1 is H. In another embodiment, X 1 Not present or Gly, X 10 is L-Thr or L-Ser, and R 1 is H or (C1-C3) alkyl. In yet another embodiment, X 1 Not present or Gly, X 10 is L-Thr or L-Ser, and R 1 It's H.

[0220] In some embodiments of the above formula, X 13 It is L-Phe, X 2 It is L-Pro, X 9 is L-Thr, and X 12 In another embodiment, X 13 It is L-Phe, X 2 It is L-Pro, X 9 is L-Thr, and X 12 In yet another embodiment, X 13 It is L-Phe, X 2 It is L-Pro, X9 is L-Thr, and X 1 In another embodiment, X 13 It is L-Phe, X 2 It is L-Pro, X 9 is L-Thr, and X 10 In yet another embodiment, X 13 It is L-Phe, X 2 It is L-Pro, X 9 is L-Thr, and R 1 is H or (C1-C3) alkyl. In another embodiment, X 13 It is L-Phe, X 2 It is L-Pro, X 9 is L-Thr, and R 1 is H. In yet another embodiment, X 13 It is L-Phe, X 2 It is L-Pro, X 9 is L-Thr, and X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 attachment point.

[0221] In some embodiments of the above formula, X 13 It is L-Phe, X 2 It is L-Pro, X 12 is L-Val or L-Glu, and X 1 In another embodiment, X 13 It is L-Phe, X 2 It is L-Pro, X 12 is L-Val or L-Glu, and X 10 In another embodiment, X 13 It is L-Phe, X 2 It is L-Pro, X 12 is L-Val or L-Glu, and R 1 is H or (C1-C3) alkyl. In another embodiment, X 13 It is L-Phe, X 2 It is L-Pro, X 12 is L-Val or L-Glu, and R 1 is H. In yet another embodiment, X 13 It is L-Phe, X 2 It is L-Pro, X 12is L-Val, and X 1 In another embodiment, X 13 It is L-Phe, X 2 It is L-Pro, X 12 is L-Val, and X 10 In yet another embodiment, X 13 It is L-Phe, X 2 It is L-Pro, X 12 is L-Val, and R 1 is H or (C1-C3) alkyl. In another embodiment, X 13 It is L-Phe, X 2 It is L-Pro, X 12 is L-Val, and R 1 is H. In yet another embodiment, X 13 It is L-Phe, X 2 It is L-Pro, X 1 Not present or Gly, and X 10 In another embodiment, X 13 It is L-Phe, X 2 It is L-Pro, X 1 Absent or Gly, and R 1 is H or (C1-C3) alkyl. In yet another embodiment, X 13 It is L-Phe, X 2 It is L-Pro, X 1 Absent or Gly, and R 1 It's H.

[0222] In some embodiments of the above formula, X 13 It is L-Phe, X 2 It is L-Pro, X 12 is L-Val or L-Glu, and X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 In another embodiment, X 13 It is L-Phe, X 2 It is L-Pro, X 12 is L-Val, and X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 In yet another embodiment, X 13 It is L-Phe, X 2It is L-Pro, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 The attachment point, and X 10 In another embodiment, X 13 It is L-Phe, X 2 It is L-Pro, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 The attachment point, and R 1 is H or (C1-C3) alkyl. In yet another embodiment, X 13 It is L-Phe, X 2 It is L-Pro, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 The attachment point, and R 1 It's H.

[0223] In some embodiments of the above formula, X 13 It is L-Phe, X 9 It is L-Thr, X 12 is L-Val or L-Glu, and X 1 In another embodiment, X 13 It is L-Phe, X 9 It is L-Thr, X 12 is L-Val or L-Glu, and X 10 In yet another embodiment, X 13 It is L-Phe, X 9 It is L-Thr, X 12 is L-Val or L-Glu, and R 1 is H or (C1-C3) alkyl. In another embodiment, X 13 It is L-Phe, X 9 It is L-Thr, X 12 is L-Val or L-Glu, and R 1 is H. In yet another embodiment, X 13 It is L-Phe, X 9 It is L-Thr, X 12 is L-Val, and X 1 In another embodiment, X 13 It is L-Phe, X 9 It is L-Thr, X12 is L-Val, and X 10 In yet another embodiment, X 13 It is L-Phe, X 9 It is L-Thr, X 12 is L-Val, and R 1 is H or (C1-C3) alkyl. In another embodiment, X 13 It is L-Phe, X 9 It is L-Thr, X 12 is L-Val, and R 1 It's H.

[0224] In some embodiments of the above formula, X 13 It is L-Phe, X 9 It is L-Thr, X 12 is L-Val or L-Glu, and X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 In yet another embodiment, X 13 It is L-Phe, X 9 It is L-Thr, X 12 is L-Val, and X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 attachment point.

[0225] In some embodiments of the above formula, X 13 It is L-Phe, X 12 Is L-Val or L-Glu, X 1 Not present or Gly, and X 10 In another embodiment, X 13 It is L-Phe, X 12 Is L-Val or L-Glu, X 1 Absent or Gly, and R 1 is H or (C1-C3) alkyl. In yet another embodiment, X 13 It is L-Phe, X 12 Is L-Val or L-Glu, X 1 Absent or Gly, and R 1 is H. In another embodiment, X 13 It is L-Phe, X 12 It is L-Val, X 1 Not present or Gly, and X10 In yet another embodiment, X 13 It is L-Phe, X 12 It is L-Val, X 1 Absent or Gly, and R 1 is H or (C1-C3) alkyl. In another embodiment, X 13 It is L-Phe, X 12 It is L-Val, X 1 Absent or Gly, and R 1 It's H.

[0226] In some embodiments of the above formula, X 13 It is L-Phe, X 1 Not present or Gly, X 10 is L-Thr or L-Ser, and R 1 is H or (C1-C3) alkyl. In another embodiment, X 13 It is L-Phe, X 1 Not present or Gly, X 10 is L-Thr or L-Ser, and R 1 It's H.

[0227] In some embodiments of the above formula, X 13 It is L-Phe, X 12 Is L-Val or L-Glu, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 The attachment point, and X 10 In another embodiment, X 13 It is L-Phe, X 12 Is L-Val or L-Glu, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 The attachment point, and R 1 is H or (C1-C3) alkyl. In yet another embodiment, X 13 It is L-Phe, X 12 Is L-Val or L-Glu, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 The attachment point, and R 1 is H. In another embodiment, X 13 It is L-Phe, X 12It is L-Val, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 The attachment point, and X 10 In yet another embodiment, X 13 It is L-Phe, X 12 It is L-Val, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 The attachment point, and R 1 is H or (C1-C3) alkyl. In another embodiment, X 13 It is L-Phe, X 12 It is L-Val, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 The attachment point, and R 1 It's H.

[0228] In some embodiments of the above formula, X 13 It is L-Phe, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 10 is L-Thr or L-Ser, and R 1 is H or (C1-C3) alkyl. In another embodiment, X 13 It is L-Phe, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 10 is L-Thr or L-Ser, and R 1 It's H.

[0229] In some embodiments of the above formula, X 13 It is L-Phe, X 2 It is L-Pro, X 9 It is L-Thr, X 12 is L-Val or L-Glu, and X 1 In another embodiment, X 13 It is L-Phe, X 2 It is L-Pro, X 9 It is L-Thr, X 12 is L-Val or L-Glu, and X10 In yet another embodiment, X 13 It is L-Phe, X 2 It is L-Pro, X 9 It is L-Thr, X 12 is L-Val or L-Glu, and R 1 is H or (C1-C3) alkyl. In another embodiment, X 13 It is L-Phe, X 2 It is L-Pro, X 9 It is L-Thr, X 12 is L-Val or L-Glu, and R 1 is H. In yet another embodiment, X 13 It is L-Phe, X 2 It is L-Pro, X 9 It is L-Thr, X 12 is L-Val, and X 1 In another embodiment, X 13 It is L-Phe, X 2 It is L-Pro, X 9 It is L-Thr, X 12 is L-Val, and X 10 In yet another embodiment, X 13 It is L-Phe, X 2 It is L-Pro, X 9 It is L-Thr, X 12 is L-Val, and R 1 is H or (C1-C3) alkyl. In another embodiment, X 13 It is L-Phe, X 2 It is L-Pro, X 9 It is L-Thr, X 12 is L-Val, and R 1 It's H.

[0230] In some embodiments of the above formula, X 13 It is L-Phe, X 2 It is L-Pro, X 9 It is L-Thr, X 12 is L-Val or L-Glu, and X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 In yet another embodiment, X 13 It is L-Phe, X 2It is L-Pro, X 9 It is L-Thr, X 12 is L-Val, and X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 attachment point.

[0231] In some embodiments of the above formula, X 13 It is L-Phe, X 2 It is L-Pro, X 9 It is L-Thr, X 12 Is L-Val or L-Glu, X 1 Not present or Gly, and X 10 In another embodiment, X 13 It is L-Phe, X 2 It is L-Pro, X 9 It is L-Thr, X 12 Is L-Val or L-Glu, X 1 Absent or Gly, and R 1 is H or (C1-C3) alkyl. In yet another embodiment, X 13 It is L-Phe, X 2 It is L-Pro, X 9 It is L-Thr, X 12 Is L-Val or L-Glu, X 1 Absent or Gly, and R 1 is H. In another embodiment, X 13 It is L-Phe, X 9 It is L-Thr, X 12 Is L-Val or L-Glu, X 1 Not present or Gly, X 10 is L-Thr or L-Ser and R 1 is H or (C1-C3) alkyl. In yet another embodiment, X 13 It is L-Phe, X 9 It is L-Thr, X 12 Is L-Val or L-Glu, X 1 Not present or Gly, X 10 is L-Thr or L-Ser and R 1 is H. In another embodiment, X 13 It is L-Phe, X 2 It is L-Pro, X 9 It is L-Thr, X 12 It is L-Val, X1 Not present or Gly, and X 10 In yet another embodiment, X 13 It is L-Phe, X 2 It is L-Pro, X 9 It is L-Thr, X 12 It is L-Val, X 1 Absent or Gly, and R 1 is H or (C1-C3) alkyl. In another embodiment, X 13 It is L-Phe, X 2 It is L-Pro, X 9 It is L-Thr, X 12 It is L-Val, X 1 Absent or Gly, and R 1 is H. In yet another embodiment, X 13 It is L-Phe, X 9 It is L-Thr, X 12 It is L-Val, X 1 Not present or Gly, X 10 is L-Thr or L-Ser and R 1 is H or (C1-C3) alkyl. In another embodiment, X 13 It is L-Phe, X 9 It is L-Thr, X 12 Is L-Val or L-Glu, X 1 Not present or Gly, X 10 is L-Thr or L-Ser and R 1 It's H.

[0232] In some embodiments of the above formula, X 13 It is L-Phe, X 2 It is L-Pro, X 9 It is L-Thr, X 12 Is L-Val or L-Glu, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 The attachment point, and X 10 In another embodiment, X 13 It is L-Phe, X 2 It is L-Pro, X 9 It is L-Thr, X 12 Is L-Val or L-Glu, X 1Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 The attachment point, and R 1 is H or (C1-C3) alkyl. In yet another embodiment, X 13 It is L-Phe, X 2 It is L-Pro, X 9 It is L-Thr, X 12 Is L-Val or L-Glu, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 The attachment point, and R 1 is H. In another embodiment, X 13 It is L-Phe, X 9 It is L-Thr, X 12 Is L-Val or L-Glu, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 10 is L-Thr or L-Ser and R 1 is H or (C1-C3) alkyl. In yet another embodiment, X 13 It is L-Phe, X 9 It is L-Thr, X 12 Is L-Val or L-Glu, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 10 is L-Thr or L-Ser and R 1 is H. In another embodiment, X 13 It is L-Phe, X 2 It is L-Pro, X 9 It is L-Thr, X 12 It is L-Val, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 The attachment point, and X 10 In yet another embodiment, X 13 It is L-Phe, X 2 It is L-Pro, X 9 It is L-Thr, X 12 It is L-Val, X 1Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 The attachment point, and R 1 is H or (C1-C3) alkyl. In another embodiment, X 13 It is L-Phe, X 2 It is L-Pro, X 9 It is L-Thr, X 12 It is L-Val, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 The attachment point, and R 1 is H. In yet another embodiment, X 13 It is L-Phe, X 9 It is L-Thr, X 12 It is L-Val, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 10 is L-Thr or L-Ser and R 1 is H or (C1-C3) alkyl. In another embodiment, X 13 It is L-Phe, X 9 It is L-Thr, X 12 Is L-Val or L-Glu, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 10 is L-Thr or L-Ser and R 1 It's H.

[0233] In some embodiments of the above formula, X 13 It is L-Phe, X 9 It is L-Thr, X 12 Is L-Val or L-Glu, X 1 Not present or Gly, X 10 is L-Thr or L-Ser and R 1 is H or (C1-C3) alkyl. In another embodiment, X 13 It is L-Phe, X 9 It is L-Thr, X 12 Is L-Val or L-Glu, X 1 Not present or Gly, X 10 is L-Thr or L-Ser and R 1is H. In yet another embodiment, X 13 It is L-Phe, X 9 It is L-Thr, X 12 It is L-Val, X 1 Not present or Gly, X 10 is L-Thr or L-Ser and R 1 is H or (C1-C3) alkyl. In another embodiment, X 13 It is L-Phe, X 9 It is L-Thr, X 12 It is L-Val, X 1 Not present or Gly, X 10 is L-Thr or L-Ser and R 1 It's H.

[0234] In some embodiments of the above formula, X 13 It is L-Phe, X 9 It is L-Thr, X 12 Is L-Val or L-Glu, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 10 is L-Thr or L-Ser and R 1 is H or (C1-C3) alkyl. In another embodiment, X 13 It is L-Phe, X 9 It is L-Thr, X 12 Is L-Val or L-Glu, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 10 is L-Thr or L-Ser and R 1 is H. In yet another embodiment, X 13 It is L-Phe, X 9 It is L-Thr, X 12 It is L-Val, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 10 is L-Thr or L-Ser and R 1 is H or (C1-C3) alkyl. In another embodiment, X 13 It is L-Phe, X 9 It is L-Thr, X 12 It is L-Val, X1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 10 is L-Thr or L-Ser and R 1 It's H.

[0235] In some embodiments of the above formula, X 13 It is L-Phe, X 2 It is L-Pro, X 9 It is L-Thr, X 12 Is L-Val or L-Glu, X 1 Not present or Gly, X 10 is L-Thr or L-Ser and R 1 is H or (C1-C3) alkyl. In another embodiment, X 13 It is L-Phe, X 2 It is L-Pro, X 9 It is L-Thr, X 12 Is L-Val or L-Glu, X 1 Not present or Gly, X 10 is L-Thr or L-Ser and R 1 is H. In yet another embodiment, X 13 It is L-Phe, X 2 It is L-Pro, X 9 It is L-Thr, X 12 It is L-Val, X 1 Not present or Gly, X 10 is L-Thr or L-Ser and R 1 is H or (C1-C3) alkyl. In another embodiment, X 13 It is L-Phe, X 2 It is L-Pro, X 9 It is L-Thr, X 12 It is L-Val, X 1 Not present or Gly, X 10 is L-Thr or L-Ser and R 1 It's H.

[0236] In some embodiments of the above formula, X 13 It is L-Phe, X 2 It is L-Pro, X 9 It is L-Thr, X 12 Is L-Val or L-Glu, X 1Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 10 is L-Thr or L-Ser and R 1 is H or (C1-C3) alkyl. In another embodiment, X 13 It is L-Phe, X 2 It is L-Pro, X 9 It is L-Thr, X 12 Is L-Val or L-Glu, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 10 is L-Thr or L-Ser and R 1 is H. In yet another embodiment, X 13 It is L-Phe, X 2 It is L-Pro, X 9 It is L-Thr, X 12 It is L-Val, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 10 is L-Thr or L-Ser and R 1 is H or (C1-C3) alkyl. In another embodiment, X 13 It is L-Phe, X 2 It is L-Pro, X 9 It is L-Thr, X 12 It is L-Val, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 10 is L-Thr or L-Ser and R 1 It's H.

[0237] In some embodiments of the above formula, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It is L-Pro, and X 3 is L-Arg, L-Ser, L-His, or L-Ala. In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It 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. In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, 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 In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 It is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe.

[0238] In some embodiments of the above formula, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It is L-Pro, and X 3 is L-Arg, L-Ser, L-His, or L-Ala. In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It 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. In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, 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 In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 It is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe.

[0239] In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, and X 7 It is L-(N-Me)Ala or L-(N-Me)Phe.

[0240] In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 It is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val.

[0241] In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, and X 9 It's L-Thr.

[0242] In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 is L-Thr, and X 10 It is L-Thr or L-Ser.

[0243] In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 It is L-Thr, X 10 is L-Thr or L-Ser, and X 11is 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, X 1 Not present or Gly, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 It is L-Thr, X 10 Is L-Thr or L-Ser, X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala, or L-Hse, and X 12 It is L-Val or L-Glu.

[0245] In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 It is L-Thr, X 10 Is L-Thr or L-Ser, X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala, or L-Hse, X 12 is L-Val or L-Glu, and X 13 It is L-Phe.

[0246] In some embodiments of the above formula, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, and X 3 is L-Arg, L-Ser, L-His, or L-Ala. In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 3 is L-Arg, L-Ser, L-His, or L-Ala, and X 4 In yet another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 3 is L-Arg, L-Ser, L-His, or L-Ala, 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 In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 It is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe.

[0247] In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, and X 7 In yet another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 It is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val.

[0248] In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, and X 9 In yet another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 is L-Thr, and X 10 It is L-Thr or L-Ser.

[0249] In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 It is L-Thr, X 10 is L-Thr or L-Ser, and X 11 In yet another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 It is L-Thr, X 10 Is L-Thr or L-Ser, X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala, or L-Hse, and X 12 It is L-Val or L-Glu.

[0250] In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 It is L-Thr, X 10 Is L-Thr or L-Ser, X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala, or L-Hse, X 12 is L-Val or L-Glu, and X 13 It is L-Phe.

[0251] In some embodiments of the above formula, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It is L-Pro, and X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu. In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It 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 In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It 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, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 It is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe.

[0252] In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It is L-Pro, X 4is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, and X 7 It is L-(N-Me)Ala or L-(N-Me)Phe.

[0253] In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It 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, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 In yet another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It 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, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, and X 9 It's L-Thr.

[0254] In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It 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, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 is L-Thr, and X 10 In yet another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It 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, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 It is L-Thr, 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.

[0255] In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X2 It 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, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 It is L-Thr, X 10 Is L-Thr or L-Ser, X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala, or L-Hse, and X 12 In yet another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It 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, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 It is L-Thr, X 10 Is L-Thr or L-Ser, X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala, or L-Hse, X 12 is L-Val or L-Glu, and X 13 It is L-Phe.

[0256] In some embodiments of the above formula, R 1is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, and X 5 In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, 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. In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, and X 7 It is L-(N-Me)Ala or L-(N-Me)Phe.

[0257] In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8In yet another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, and X 9 It's L-Thr.

[0258] In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 is L-Thr, and X 10 In yet another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 It is L-Thr, 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.

[0259] In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 It is L-Thr, X 10 Is L-Thr or L-Ser, X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala, or L-Hse, and X 12 In yet another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 It is L-Thr, X 10 Is L-Thr or L-Ser, X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala, or L-Hse, X 12 is L-Val or L-Glu, and X 13 It is L-Phe.

[0260] In some embodiments of the above formula, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, 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. In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, and X 7 It is L-(N-Me)Ala or L-(N-Me)Phe.

[0261] In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 In yet another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, and X 9 It's L-Thr.

[0262] In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 is L-Thr, and X 10 In yet another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 It is L-Thr, 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.

[0263] In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 It is L-Thr, X 10Is L-Thr or L-Ser, X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala, or L-Hse, and X 12 In yet another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 It is L-Thr, X 10 Is L-Thr or L-Ser, X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala, or L-Hse, X 12 is L-Val or L-Glu, and X 13 It is L-Phe.

[0264] In some embodiments of the above formula, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, 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. In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It is L-Pro, X3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 It is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val.

[0265] In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, and X 9 In yet another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 is L-Thr, and X10 It is L-Thr or L-Ser.

[0266] In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 It is L-Thr, X 10 is L-Thr or L-Ser, and X 11 In yet another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 It is L-Thr, X 10 Is L-Thr or L-Ser, X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala, or L-Hse, and X 12 It is L-Val or L-Glu.

[0267] In another embodiment, R 1is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 It is L-Thr, X 10 Is L-Thr or L-Ser, X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala, or L-Hse, X 12 is L-Val or L-Glu, and X 13 It is L-Phe.

[0268] In some embodiments of the above formula, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val. In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, and X 9 It's L-Thr.

[0269] In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 is L-Thr, and X 10 In yet another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 It is L-Thr, 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.

[0270] In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 It is L-Thr, X 10 Is L-Thr or L-Ser, X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala, or L-Hse, and X 12 In yet another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 It is L-Thr, X 10 Is L-Thr or L-Ser, X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala, or L-Hse, X 12 is L-Val or L-Glu, and X 13 It is L-Phe.

[0271] In some embodiments of the above formula, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 9 In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7is L-(N-Me)Ala or L-(N-Me)Phe, X 9 is L-Thr, and X 10 It is L-Thr or L-Ser.

[0272] In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 9 It is L-Thr, X 10 is L-Thr or L-Ser, and X 11 In yet another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 9 It is L-Thr, X 10 Is L-Thr or L-Ser, X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala, or L-Hse, and X 12It is L-Val or L-Glu.

[0273] In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 9 It is L-Thr, X 10 Is L-Thr or L-Ser, X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala, or L-Hse, X 12 is L-Val or L-Glu, and X 13 It is L-Phe.

[0274] In some embodiments of the above formula, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, and X 10In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, 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.

[0275] In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 10 Is L-Thr or L-Ser, X 11is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala, or L-Hse, and X 12 In yet another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 10 Is L-Thr or L-Ser, X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala, or L-Hse, X 12 is L-Val or L-Glu, and X 13 It is L-Phe.

[0276] In some embodiments of the above formula, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 is L-Thr, and X 11 In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 It is L-Thr, X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala, or L-Hse, and X 12 It is L-Val or L-Glu.

[0277] In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 It is L-Thr, X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala, or L-Hse, X 12 is L-Val or L-Glu, and X 13 It is L-Phe.

[0278] In some embodiments of the above formula, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 It is L-Thr, X 10 Is L-Thr or L-Ser, X 12 is L-Val or L-Glu, and X 13 It is L-Phe.

[0279] In some embodiments of the above formula, R 1 is H or (C1-C4) alkyl, X 1 Not present or Gly, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 It is L-Thr, X 10 Is L-Thr or L-Ser, X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala, or L-Hse, and X 13 It is L-Phe.

[0280] In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, and X 7 It is L-(N-Me)Ala or L-(N-Me)Phe.

[0281] In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 It is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val.

[0282] In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, and X 9 It's L-Thr.

[0283] In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 is L-Thr, and X 10 It is L-Thr or L-Ser.

[0284] In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 It is L-Thr, 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.

[0285] In another embodiment, R 1 is H or (C1-C4) alkyl, X 1Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 It is L-Thr, X 10 Is L-Thr or L-Ser, X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala, or L-Hse, and X 12 It is L-Val or L-Glu.

[0286] In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 It is L-Thr, X 10 Is L-Thr or L-Ser, X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala, or L-Hse, X 12 is L-Val or L-Glu, and X 13 It is L-Phe.

[0287] In some embodiments of the above formula, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 The attachment point, and X 3 is L-Arg, L-Ser, L-His, or L-Ala. In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 3 is L-Arg, L-Ser, L-His, or L-Ala, and X 4 In yet another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 3 is L-Arg, L-Ser, L-His, or L-Ala, 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 In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 3is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 It is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe.

[0288] In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, and X 7 In yet another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8It is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val.

[0289] In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, and X 9 In yet another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 is L-Thr, and X10 It is L-Thr or L-Ser.

[0290] In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 It is L-Thr, X 10 is L-Thr or L-Ser, and X 11 In yet another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 It is L-Thr, X 10 Is L-Thr or L-Ser, X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala, or L-Hse, and X 12 It is L-Val or L-Glu.

[0291] In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 It is L-Thr, X 10 Is L-Thr or L-Ser, X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala, or L-Hse, X 12 is L-Val or L-Glu, and X 13 It is L-Phe.

[0292] In some embodiments of the above formula, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It is L-Pro, and X 4is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu. In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It 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 In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It 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, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, and X 6 It is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe.

[0293] In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It 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, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, and X 7 It is L-(N-Me)Ala or L-(N-Me)Phe.

[0294] In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It 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, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 In yet another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It 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, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, and X 9 It's L-Thr.

[0295] In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1Attachment point, X 2 It 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, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 is L-Thr, and X 10 In yet another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It 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, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 It is L-Thr, 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.

[0296] In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR1 Attachment point, X 2 It 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, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 It is L-Thr, X 10 Is L-Thr or L-Ser, X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala, or L-Hse, and X 12 In yet another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It 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, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 It is L-Thr, X 10 Is L-Thr or L-Ser, X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala, or L-Hse, X 12 is L-Val or L-Glu, and X13 It is L-Phe.

[0297] In some embodiments of the above formula, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, and X 5 In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, 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. In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, and X 7 It is L-(N-Me)Ala or L-(N-Me)Phe.

[0298] In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 In yet another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, and X 9 It's L-Thr.

[0299] In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 is L-Thr, and X 10 In yet another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 It is L-Thr, 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.

[0300] In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 It is L-Thr, X 10 Is L-Thr or L-Ser, X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala, or L-Hse, and X 12 In yet another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 It is L-Thr, X 10 Is L-Thr or L-Ser, X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala, or L-Hse, X 12 is L-Val or L-Glu, and X 13 It is L-Phe.

[0301] In some embodiments of the above formula, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, 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. In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, and X 7 It is L-(N-Me)Ala or L-(N-Me)Phe.

[0302] In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 In yet another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It is L-Pro, X 3is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, and X 9 It's L-Thr.

[0303] In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 is L-Thr, and X 10 In yet another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 It is L-Thr, 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.

[0304] In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 It is L-Thr, X 10 Is L-Thr or L-Ser, X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala, or L-Hse, and X 12 In yet another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR1 Attachment point, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 It is L-Thr, X 10 Is L-Thr or L-Ser, X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala, or L-Hse, X 12 is L-Val or L-Glu, and X 13 It is L-Phe.

[0305] In some embodiments of the above formula, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, 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. In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 8 It is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val.

[0306] In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, and X 9 In yet another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 is L-Thr, and X 10 It is L-Thr or L-Ser.

[0307] In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 It is L-Thr, X 10 is L-Thr or L-Ser, and X 11 In yet another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X9 It is L-Thr, X 10 Is L-Thr or L-Ser, X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala, or L-Hse, and X 12 It is L-Val or L-Glu.

[0308] In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 It is L-Thr, X 10 Is L-Thr or L-Ser, X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala, or L-Hse, X 12 is L-Val or L-Glu, and X 13 It is L-Phe.

[0309] In some embodiments of the above formula, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, and X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val. In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, and X 9 It's L-Thr.

[0310] In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 8is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 is L-Thr, and X 10 In yet another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 It is L-Thr, 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.

[0311] In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 It is L-Thr, X 10 Is L-Thr or L-Ser, X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala, or L-Hse, and X 12 In yet another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 It is L-Thr, X 10 Is L-Thr or L-Ser, X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala, or L-Hse, X 12 is L-Val or L-Glu, and X 13 It is L-Phe.

[0312] In some embodiments of the above formula, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, and X 9 In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 9 is L-Thr, and X 10 It is L-Thr or L-Ser.

[0313] In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 9 It is L-Thr, X 10 is L-Thr or L-Ser, and X 11 In yet another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 9 It is L-Thr, X 10 Is L-Thr or L-Ser, X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala, or L-Hse, and X 12 It is L-Val or L-Glu.

[0314] In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 9 It is L-Thr, X 10 Is L-Thr or L-Ser, X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala, or L-Hse, X 12 is L-Val or L-Glu, and X 13 It is L-Phe.

[0315] In some embodiments of the above formula, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, and X 10 In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, 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.

[0316] In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 10 Is L-Thr or L-Ser, X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala, or L-Hse, and X 12 In yet another embodiment, R 1 is H or (C1-C4) alkyl, X 1Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 10 Is L-Thr or L-Ser, X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala, or L-Hse, X 12 is L-Val or L-Glu, and X 13 It is L-Phe.

[0317] In some embodiments of the above formula, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 is L-Thr, and X 11 In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 It is L-Thr, X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala, or L-Hse, and X 12 It is L-Val or L-Glu.

[0318] In another embodiment, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 It is L-Thr, X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala, or L-Hse, X 12 is L-Val or L-Glu, and X 13 It is L-Phe.

[0319] In some embodiments of the above formula, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1 Attachment point, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 It is L-Thr, X 10 Is L-Thr or L-Ser, X 12 is L-Val or L-Glu, and X 13 It is L-Phe.

[0320] In some embodiments of the above formula, R 1 is H or (C1-C4) alkyl, X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1Attachment point, X 2 It is L-Pro, X 3 is L-Arg, L-Ser, L-His, or L-Ala, X 4 is L-Asp, L-Asn, L-Glu, L-Lys, L-Gln, L-Pro, L-Ala, or L-(N-Me)Glu, X 5 is L-(N-Me)Ala or L-(N-Me)Glu, X 6 is L-Bip, L-(4-CF3)Phe, L-(3,4-diCl)Phe, L-(3-F)Phe, or L-(4-Cl)Phe, X 7 is L-(N-Me)Ala or L-(N-Me)Phe, X 8 is L-Bip, L-Ser, L-Tyr, L-(4-CF3)Phe, L-Ala, L-Phe, or L-Val, X 9 It is L-Thr, X 10 Is L-Thr or L-Ser, X 11 is L-Ser, L-Asp, L-Asn, L-Pro, L-Ala, or L-Hse, and X 13 It is L-Phe.

[0321] Example 1. A polypeptide according to formula (I):

[0322] in:

[0323] R 1 is H or (C1-C4)alkyl;

[0324] X 1 absent or Gly;

[0325] X 2 Is L-Pro or D-Pro;

[0326] X 3 is L-Arg, D-Arg, L-Ser, D-Ser, L-His, D-His, L-Ala, or D-Ala;

[0327] 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;

[0328] X 5Is L-(N-Me)Ala, D-(N-Me)Ala, L-(N-Me)Glu, or D-(N-Me)Glu;

[0329] 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;

[0330] X 7 Is L-(N-Me)Ala, D-(N-Me)Ala, L-(N-Me)Phe, or D-(N-Me)Phe;

[0331] 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;

[0332] X 9 is L-Thr or D-Thr;

[0333] X 10 is L-Thr, D-Thr, L-Ser, or D-Ser;

[0334] 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;

[0335] X 12 is L-Val, D-Val, L-Glu, or D-Glu; and

[0336] X 13 is L-Phe or D-Phe;

[0337] in:

[0338] Bip is 4-phenyl-phenylalanine;

[0339] Hse is homoserine;

[0340] (4-CF3)Phe is 4-trifluoromethyl-phenylalanine;

[0341] (3,4-diCl)Phe is 3,4-dichloro-phenylalanine;

[0342] (3-F)Phe is 3-fluoro-phenylalanine; and

[0343] (4-Cl)Phe is 4-chloro-phenylalanine;

[0344] or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof.

[0345] Embodiment 2. The polypeptide according to embodiment 1, wherein X 13 It is L-Phe.

[0346] Embodiment 3. The polypeptide according to embodiment 1 or 2, wherein X 2 It's L-Pro.

[0347] Embodiment 4. The polypeptide according to any one of embodiments 1-3, wherein X 9 It's L-Thr.

[0348] Embodiment 5. The polypeptide according to embodiment 1, which has formula (II), formula (III), formula (IV), formula (V), or formula (VI).

[0349] Embodiment 6. The polypeptide according to any one of embodiments 1-5, wherein X 12 It is L-Val or L-Glu.

[0350] Embodiment 7. The polypeptide according to any one of embodiments 1-6, wherein X 12 It is L-Val or L-Glu.

[0351] Embodiment 8. The polypeptide according to any one of embodiments 1-7, wherein X 12 It's L-Val.

[0352] Embodiment 9. The polypeptide according to any one of embodiments 1-8, wherein X 1 Does not exist.

[0353] Embodiment 10. The polypeptide according to any one of embodiments 1-9, wherein X 1 It's Gly.

[0354] Embodiment 11. The polypeptide according to any one of embodiments 1-10, wherein X 10 It is L-Thr or L-Ser.

[0355] Embodiment 12. The polypeptide according to any one of embodiments 1-11, wherein R 1 It is H or (C1-C3) alkyl.

[0356] Embodiment 13. The polypeptide according to any one of embodiments 1-12, wherein R 1 It's H.

[0357] Non-limiting illustrative polypeptides of the present disclosure include:

[0358]

[0359]

[0360]

[0361]

[0362]

[0363]

[0364]

[0365]

[0366]

[0367] wherein Ac is an acetyl group, and wherein the acetyl group marked with "*" and the amino acid marked with "*" are linked via a sulfide bond formed via the side chains or terminals thereof.

[0368] Embodiment 51. A pharmaceutical composition comprising a therapeutically effective amount of the cyclic polypeptide according to any one of Embodiments 1-50 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0369] Embodiment 52. A combination comprising a polypeptide according to any one of embodiments 1-50 or a pharmaceutically acceptable salt thereof, and one or more additional therapeutically active agents.

[0370] Embodiment 53. The combination according to embodiment 52, wherein the additional therapeutically active agent is a statin.

[0371] Embodiment 54. The pharmaceutical composition according to embodiment 51 or the combination according to any one of embodiments 52 or 53, for use in treating, preventing, ameliorating, or delaying the progression of a PCSK9-mediated disease or disorder.

[0372] Embodiment 55. A pharmaceutical composition or combination according to embodiment 54, 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.

[0373] Embodiment 56. A method of regulating PCSK9, the method comprising administering to a patient in need thereof a cyclic polypeptide according to any one of embodiments 1-50 or a pharmaceutically acceptable salt thereof.

[0374] Embodiment 57. A method of inhibiting PCSK9, the method comprising administering to a patient in need thereof the cyclic polypeptide according to any one of embodiments 1-50 or a pharmaceutically acceptable salt thereof.

[0375] Embodiment 58. A method for treating, preventing, ameliorating or delaying the progression of a disease or disorder mediated by PCSK9, the method comprising the following steps: administering a therapeutically effective amount of a cyclic polypeptide or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1-50 to a patient in need thereof.

[0376] Example 59. A method according to Example 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.

[0377] Embodiment 60. 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 concentration, (viii) lowering LDL apoB, (ix) lowering TRL apoB, or (x) lowering non-HDL-C, the method 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 Embodiments 1-50, thereby lowering the patient's LDL-C.

[0378] Embodiment 61. The method of any one of embodiments 56-60, wherein administration is performed orally, parenterally, subcutaneously, by injection, or by infusion.

[0379] Embodiment 62. The cyclic polypeptide or pharmaceutically acceptable salt thereof according to any one of embodiments 1-50, for use in treating a disease or disorder mediated by PCSK9.

[0380] Embodiment 63. A cyclic polypeptide or a pharmaceutically acceptable salt thereof according to any one of embodiments 1-50, for use in treating, preventing, improving or delaying progression, or for use in treating, preventing, improving or delaying progression of a disease or disorder requiring inhibition of PCSK9.

[0381] Embodiment 64. Use of a polypeptide according to any one of Embodiments 1-50 or a pharmaceutically acceptable salt thereof for treating, preventing, ameliorating or delaying the progression of a disease or disorder mediated by PCSK9 or for treating, preventing, ameliorating or delaying the progression of a disease or disorder requiring inhibition of PCSK9.

[0382] Example 65. Use of a polypeptide or a pharmaceutically acceptable salt thereof according to any one of Examples 1-50 in the manufacture of a medicament for treating, preventing, ameliorating or delaying the progression of a disease or disorder mediated by PCSK9 or for treating, preventing, ameliorating or delaying the progression of a disease or disorder requiring inhibition of PCSK9.

[0383] Example 66. 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 the following steps: administering a therapeutically effective amount of a polypeptide according to any one of Examples 1-50 or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0384] 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.

[0385] Embodiment 68. A polypeptide according to formula (I), wherein:

[0386] R 1 is H or (C1-C4)alkyl;

[0387] X 1 Not present, Gly, Gly-L-Lys*, or Gly-D-Lys*, where * indicates NHR 1Attachment point;

[0388] X 2 Is L-Pro or D-Pro;

[0389] X 3 is L-Arg, D-Arg, L-Ser, D-Ser, L-His, D-His, L-Ala, or D-Ala;

[0390] 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;

[0391] X 5 Is L-(N-Me)Ala, D-(N-Me)Ala, L-(N-Me)Glu, or D-(N-Me)Glu;

[0392] 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;

[0393] X 7 Is L-(N-Me)Ala, D-(N-Me)Ala, L-(N-Me)Phe, or D-(N-Me)Phe;

[0394] 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;

[0395] X 9 is L-Thr or D-Thr;

[0396] X 10 is L-Thr, D-Thr, L-Ser, or D-Ser;

[0397] X 11is 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;

[0398] X 12 is L-Val, D-Val, L-Glu, or D-Glu; and

[0399] X 13 is L-Phe or D-Phe;

[0400] in:

[0401] Bip is 4-phenyl-phenylalanine;

[0402] Hse is homoserine;

[0403] (4-CF3)Phe is 4-trifluoromethyl-phenylalanine;

[0404] (3,4-diCl)Phe is 3,4-dichloro-phenylalanine;

[0405] (3-F)Phe is 3-fluoro-phenylalanine; and

[0406] (4-Cl)Phe is 4-chloro-phenylalanine;

[0407] or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof.

[0408] Embodiment 69. The polypeptide according to embodiment 68, wherein:

[0409] R 1 is H or (C1-C4)alkyl;

[0410] X 1 absent or Gly;

[0411] X 2 Is L-Pro or D-Pro;

[0412] X 3 is L-Arg, D-Arg, L-Ser, D-Ser, L-His, D-His, L-Ala, or D-Ala;

[0413] 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;

[0414] X 5 Is L-(N-Me)Ala, D-(N-Me)Ala, L-(N-Me)Glu, or D-(N-Me)Glu;

[0415] 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;

[0416] X 7 Is L-(N-Me)Ala, D-(N-Me)Ala, L-(N-Me)Phe, or D-(N-Me)Phe;

[0417] 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;

[0418] X 9 is L-Thr or D-Thr;

[0419] X 10 is L-Thr, D-Thr, L-Ser, or D-Ser;

[0420] 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;

[0421] X 12 is L-Val, D-Val, L-Glu, or D-Glu; and

[0422] X 13 is L-Phe or D-Phe;

[0423] in:

[0424] Bip is 4-phenyl-phenylalanine;

[0425] Hse is homoserine;

[0426] (4-CF3)Phe is 4-trifluoromethyl-phenylalanine;

[0427] (3,4-diCl)Phe is 3,4-dichloro-phenylalanine;

[0428] (3-F)Phe is 3-fluoro-phenylalanine; and

[0429] (4-Cl)Phe is 4-chloro-phenylalanine;

[0430] or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof.

[0431] Embodiment 70. The polypeptide according to embodiment 68 or 69, wherein X 13 It is L-Phe.

[0432] Embodiment 71. A polypeptide according to any one of embodiments 68-70, wherein X 2 It's L-Pro.

[0433] Embodiment 72. The polypeptide according to any one of embodiments 68-71, wherein X 9 It's L-Thr.

[0434] Embodiment 73. A polypeptide according to embodiment 68 or 69, which has formula (II), formula (III), formula (IV), formula (V), or formula (VI).

[0435] Embodiment 74. A polypeptide according to any one of embodiments 68-73, wherein X 12 It is L-Val or L-Glu.

[0436] Embodiment 75. The polypeptide according to any one of embodiments 68-74, wherein X 12 It is L-Val or L-Glu.

[0437] Embodiment 76. The polypeptide according to any one of embodiments 68-75, wherein X 12 It's L-Val.

[0438] Embodiment 77. The polypeptide according to any one of embodiments 68-76, wherein X 1 Does not exist.

[0439] Embodiment 78. A polypeptide according to any one of embodiments 68-77, wherein X 1 It's Gly.

[0440] Embodiment 79. The polypeptide according to any one of embodiments 68-78, wherein X 10 It is L-Thr or L-Ser.

[0441] Embodiment 80. A polypeptide according to any one of embodiments 68-79, wherein R1 It is H or (C1-C3) alkyl.

[0442] Embodiment 81. A compound according to any one of embodiments 68-80, wherein R 1 It's H.

[0443] Embodiment 82. A pharmaceutical composition comprising a therapeutically effective amount of the cyclic polypeptide according to any one of Embodiments 68-81 and 14-51 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0444] Embodiment 83. A combination comprising a polypeptide according to any one of embodiments 68-81 and 14-51 or a pharmaceutically acceptable salt thereof, and one or more additional therapeutically active agents.

[0445] Embodiment 84. The combination according to Embodiment 83, wherein the additional therapeutically active agent is a statin.

[0446] Embodiment 85. The pharmaceutical composition according to Embodiment 82 or the combination according to any one of Embodiments 83 or 84, for use in treating, preventing, ameliorating, or delaying the progression of a PCSK9-mediated disease or disorder.

[0447] Embodiment 86. A pharmaceutical composition or combination according to Embodiment 85, 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.

[0448] Embodiment 87. A method of regulating PCSK9, the method comprising administering to a patient in need thereof a cyclic polypeptide according to any one of embodiments 68-81 and 14-51 or a pharmaceutically acceptable salt thereof.

[0449] Embodiment 88. A method of inhibiting PCSK9, the method comprising administering to a patient in need thereof a cyclic polypeptide according to any one of embodiments 68-81 and 14-51 or a pharmaceutically acceptable salt thereof.

[0450] Embodiment 89. A method for treating, preventing, ameliorating or delaying the progression of a disease or disorder mediated by PCSK9, the method comprising the following steps: administering a therapeutically effective amount of a cyclic polypeptide or a pharmaceutically acceptable salt thereof according to any one of Embodiments 68-81 and 14-51 to a patient in need thereof.

[0451] Example 90. A method according to Example 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.

[0452] Embodiment 91. 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 concentration, (viii) lowering LDL apoB, (ix) lowering TRL apoB, or (x) lowering non-HDL-C, the method 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 Embodiments 68-81 and 14-51, thereby lowering the patient's LDL-C.

[0453] Embodiment 92. The method of any one of embodiments 87-91, wherein administration is performed orally, parenterally, subcutaneously, by injection, or by infusion.

[0454] Embodiment 93. A cyclic polypeptide or a pharmaceutically acceptable salt thereof according to any one of embodiments 68-81 and 14-51 for use in treating a disease or disorder mediated by PCSK9.

[0455] Embodiment 94. A cyclic polypeptide or a pharmaceutically acceptable salt thereof according to any one of embodiments 68-81 and 14-51, for use in treating, preventing, ameliorating or delaying progression, or for use in treating, preventing, ameliorating or delaying progression of a disease or disorder requiring inhibition of PCSK9.

[0456] Embodiment 95. Use of a polypeptide or a pharmaceutically acceptable salt thereof according to any one of embodiments 68-81 and 14-51 for treating, preventing, ameliorating or delaying the progression of a disease or disorder mediated by PCSK9 or for treating, preventing, ameliorating or delaying the progression of a disease or disorder requiring inhibition of PCSK9.

[0457] Example 96. Use of a polypeptide or a pharmaceutically acceptable salt thereof according to any one of Examples 68-81 and 14-51 in the manufacture of a medicament for treating, preventing, ameliorating or delaying the progression of a disease or disorder mediated by PCSK9 or for treating, preventing, ameliorating or delaying the progression of a disease or disorder requiring inhibition of PCSK9.

[0458] Example 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, the method comprising the following steps: administering a therapeutically effective amount of a polypeptide according to any one of Examples 68-81 and 14-51 or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0459] 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.

[0460] 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.

[0461] In another embodiment, the polypeptides having Formula (I) are diastereomers.

[0462] It should be understood that all isomeric forms are included in the present disclosure, including mixtures thereof. If the polypeptide contains a double bond, the substituents may be in the E or Z configuration. If the polypeptide contains a disubstituted cycloalkyl, the cycloalkyl substituents may have a cis configuration or a trans configuration. All tautomeric forms are also intended to be included.

[0463] The polypeptides of the present disclosure and their pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, and prodrugs can exist in their tautomeric forms (e.g., as amides or imino ethers). All such tautomeric forms are considered herein as part of the present disclosure.

[0464] The polypeptide of the present disclosure may contain an asymmetric center or a chiral center, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the polypeptide of the present disclosure and mixtures thereof (including racemic mixtures) all constitute a part of the present disclosure. In addition, the present disclosure includes all geometric isomers and positional isomers. For example, if the polypeptide of the present disclosure contains a double bond or a fused ring, both the cis form and the trans form and the mixture are included in the scope of the present disclosure. Each polypeptide disclosed herein includes all enantiomers that conform to the general structure of the polypeptide. The polypeptide may be in a racemic or enantiomerically pure form, or any other form in terms of stereochemistry. The assay result may reflect data collected for a racemic form, an enantiomerically pure form, or any other form in terms of stereochemistry.

[0465] A diastereomeric mixture can be separated into its individual diastereomers based on its physicochemical differences by methods well known to those skilled in the art (such as, for example, by chromatography and / or fractional crystallization). Enantiomers can be separated as follows: by reacting the enantiomeric mixture with an appropriate optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acidchlorid), converting the enantiomeric mixture into a diastereomeric mixture, separating the diastereomers, and converting (e.g., hydrolyzing) the individual diastereomers into the corresponding pure enantiomers. In addition, some polypeptides disclosed herein can be atropisomers (e.g., substituted biaryls) and are considered to be part of the disclosure. Enantiomers can also be separated using a chiral HPLC column.

[0466] The polypeptides of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. In addition, for example, all keto-enol and imine-enamine forms of the polypeptides are included in the present disclosure.

[0467] All stereoisomers (e.g., geometric isomers, optical isomers, etc.) of the polypeptides disclosed herein (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 different substituents (including enantiomeric forms (which may even exist without asymmetric carbons), rotational isomers, atropisomers, and diastereomeric forms), are included within the scope of the disclosure, and positional isomers (such as, for example, 4-pyridyl and 3-pyridyl) are also included within the scope of the disclosure. (For example, if the polypeptide having formula (I) contains a double bond or a fused ring, both the cis form and the trans form, as well as mixtures, are included within the scope of the disclosure. In addition, for example, all keto-enol and imine-enamine forms of the polypeptide are included in the disclosure). Individual stereoisomers of the polypeptides disclosed herein may, for example, be substantially free of other isomers, or may, for example, be present as a racemate or mixed with all other, or other selected, stereoisomers. The chiral centers of the present disclosure may have the S or R configuration as defined by the IUPAC Recommendations 1974. The use of the terms "salt," "solvate," "ester," "prodrug," and the like are intended to apply equally to enantiomers, stereoisomers, rotational isomers, tautomers, positional isomers, racemates, or salts, solvates, esters, and prodrugs of the inventive polypeptides.

[0468] Polypeptides having formula (I) may form salts, which are also within the scope of the present disclosure. Unless otherwise indicated, reference to a polypeptide having a formula herein is understood to include reference to a salt thereof.

[0469] The present disclosure relates to polypeptides that are modulators of PCSK9. In one embodiment, the polypeptides of the present disclosure are inhibitors of PCSK9.

[0470] The present disclosure relates 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.

[0471] Activity of peptides

[0472] The activity of the cyclic polypeptides according to the present disclosure as PCSK9 can be evaluated using a time-resolved fluorescence resonance energy transfer (TR-FRET) assay. The time-resolved fluorescence resonance energy transfer (TR-FRET) assay measures the ability of the cyclic polypeptides of the present disclosure to interfere with the binding of human PCSK9 to human LDLR, providing a measurement of potency (IC50) and efficacy (Amax).

[0473] Solutions of varying concentrations are prepared by diluting the cyclic polypeptide of the present disclosure in dimethyl sulfoxide (DMSO), and the resulting solutions are pipetted onto the plate. DMSO is used as a negative control. An intermediate plate is prepared by transferring a known amount of each polypeptide solution and control from a compound plate to corresponding wells containing assay buffer and mixing thoroughly. A third plate is then prepared for 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 an assay buffer containing DMSO is used as a positive control for the assay. After incubation, human LDLR extracellular domain-Europium Kryptate is added to each well of the assay plate, and the resulting mixture is incubated for another period of time. The TR-FRET signal is measured, and the IC of the cyclic polypeptide is calculated using the FRET ratio (FRET / Europium). 50 and Amax.

[0474] Synthesis of peptides

[0475] The polypeptides of the present disclosure can be prepared by a variety of methods, including standard chemistry. Suitable synthetic routes are described in the schemes given below.

[0476] 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 (such as "for example") provided herein is intended only to better illustrate this disclosure, without limiting the scope of this disclosure otherwise claimed.

[0477] The peptides and polypeptides disclosed herein can be produced by procedures known per se for peptide synthesis. The method for peptide synthesis can be any of solid phase synthesis and liquid phase synthesis. Therefore, the target peptides and polypeptides can be produced by condensing a partial peptide or amino acid capable of constituting a protein with the remaining part, and when the product has a protecting group, the protecting group is separated, thereby the desired peptide can be manufactured. Known condensation and deprotection methods include the procedures described in the following documents (1)-(5): (1) M. Bodanszky and MA 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.

[0478] After the reaction, the peptide can be purified and isolated by a combination of conventional purification techniques (e.g., solvent extraction, column chromatography, liquid chromatography, and recrystallization). In the case where the peptide isolated as above is a free polypeptide, it can be converted into a suitable salt by known methods. On the contrary, in the case where the isolated product is a salt, it can be converted into a free peptide by known methods.

[0479] The amide of the polypeptide can be obtained by using a resin suitable for peptide synthesis of amidation. The resin includes 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, 2-chlorotrityl chloride resin, etc. Using such resins, by various condensation techniques known per se, according to the sequence of the target peptide, amino acids in which the α-amino group and the functional groups of the side chains are appropriately protected are condensed on the resin. At the end of a series of reactions, the peptide or protected peptide is removed from the resin, the protecting group is removed, and if necessary, a disulfide bond is formed to obtain the target polypeptide.

[0480] In order to condense the above-mentioned protected amino acids, a variety of activators for peptide synthesis can be used, such as HATU, HCTU or, for example, carbodiimides. Carbodiimides include DCC (N, N'-dicyclohexylcarbodiimide), N, N'-diisopropylcarbodiimide, and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide. In order to activate with this reagent, a racemization inhibitor additive, such as HOBt or Oxyma Pure, can be used. The protected amino acid can be added directly to the resin together with the activator and the racemization inhibitor, or the protected amino acid can be pre-activated as a symmetrical anhydride, HOBt (hydroxybenzotriazole) ester or HOOBt ester and then added to the resin. The solvent for activating the protected amino acid or condensing with the resin can be appropriately selected from those solvents known to be useful for peptide condensation reactions. For example, N,N-dimethylformamide, N-methylpyrrolidone, chloroform, trifluoroethanol, dimethyl sulfoxide, DMF, pyridine, dioxane, dichloromethane, tetrahydrofuran, acetonitrile, ethyl acetate or their suitable mixture can be mentioned. The reaction temperature can be selected from the useful range known so far 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 usually used in a ratio of about 1.5 times to about 6 times excess. If the test conducted by utilizing the ninhydrin reaction finds that the condensation is insufficient, the condensation reaction can be repeated to achieve sufficient condensation without removing the protecting group. If repeated condensation still cannot provide enough condensation degree, the unreacted amino group can be acetylated with acetic anhydride or acetylimidazole.

[0481] The amino group protecting group of the starting material amino acid includes Z, Boc, tert-pentyloxycarbonyl, isocamphenyloxycarbonyl, 4-methoxybenzyloxycarbonyl, CI-Z, Br-Z, adamantyloxycarbonyl, trifluoroacetyl, phthaloyl, formyl, 2-nitrophenylsulfinyl, diphenylphosphinosulfinyl, or Fmoc. The carboxyl protecting group that can be used includes but is not limited to the above-mentioned (C1-C6) alkyl, (C3-C8) cycloalkyl and (C6-C8) cycloalkyl. 10 )aryl-(C1-C2)alkyl, and 2-adamantyl, 4-nitrobenzyl, 4-methoxybenzyl, 4-chlorobenzyl, phenacyl, benzyloxycarbonylhydrazide, tert-butyloxycarbonylhydrazide, and tritylhydrazide.

[0482] The hydroxyl groups of serine and threonine can be protected by esterification or etherification. Suitable groups for the esterification include carbon-derived groups, such as lower alkanoyl groups (e.g., acetyl, etc.), aromatic acyl groups (e.g., benzoyl, etc.), benzyloxycarbonyl and ethoxycarbonyl. Suitable groups for the etherification include benzyl, tetrahydropyranyl and tert-butyl. The protecting group of the phenolic hydroxyl group of tyrosine includes Bzl or Z (carboxybenzyl), Cl2-Bzl, 2-nitrobenzyl, Br-Z and tert-butyl.

[0483] The protecting groups of the imidazole of histidine include Tos or Ts (Tosyl), 4-methoxy-2,3,6-triethylbenzenesulfonyl, DNP (2,4-dinitrophenol), benzyloxymethyl, Bum (tert-butyloxymethyl), Boc (tert-butyloxycarbonyl), Trt (triphenylmethane) and Fmoc (fluorenylmethyloxycarbonyl).

[0484] The activated carboxyl group of the starting amino acid includes the corresponding anhydride, azide and active ester, for example, ester with 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.

[0485] The method of eliminating the protecting group includes catalytic reduction using hydrogen in the presence of a catalyst such as palladium black or palladium carbon, acid treatment with anhydrous hydrogen fluoride, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid or a mixture of such acids, alkali treatment with diisopropylethylamine, triethylamine, piperidine, piperazine, and reduction with metallic sodium in liquid ammonia. The elimination reaction by the above acid treatment is usually carried out at a temperature of -20°C to 40°C, and can be advantageously carried out with the addition of a cation acceptor (such as anisole, phenol, anisole thioether, m-cresol, p-cresol, dimethyl sulfide, 1,4-butanedithiol, 1,2-ethanedithiol). The 2,4-dinitrophenyl group used to protect the imidazole group of histidine can be removed by thiophenol treatment, and the formyl group used to protect the indole group of tryptophan can be removed by alkali treatment with dilute sodium hydroxide solution or dilute ammonia and the above acid treatment in the presence of 1,2-ethanedithiol, 1,4-butanedithiol.

[0486] The method for protecting the functional groups not participating in the reaction of the starting materials, the protecting groups which can be used, the method for removing the protecting groups, and the method for activating the functional groups to participate in the reaction can all be appropriately selected from known groups and methods.

[0487] Polypeptides of formula (I) can also be prepared by methods known in the art of organic synthesis, as described in part by the following synthesis scheme. In the schemes described below, it is well understood that, according to general principles or chemistry, protecting groups for sensitive or reactive groups are used when necessary. Protecting groups are manipulated according to standard methods for organic synthesis (TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", 3rd edition, Wiley, New York 1999). These groups are removed at a convenient stage of polypeptide synthesis using methods that are obvious to those skilled in the art. The selection process and reaction conditions and the order in which they are implemented should be consistent with the preparation of polypeptides of formula (I).

[0488] Those skilled in the art will recognize whether there is a stereocenter in a polypeptide with formula (I). Therefore, the present disclosure includes two possible stereoisomers (unless indicated in the synthesis) and not only includes racemic polypeptides, but also includes individual enantiomers and / or diastereomers. When a polypeptide is needed as a single enantiomer or diastereomer, it can be obtained by stereospecific synthesis or by splitting the final product or any convenient intermediate. The splitting 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 EL Elel, SH Wilen, and LN Mander (Wiley-lnterscience, 1994).

[0489] The polypeptides described herein can be prepared from commercially available starting materials or synthesized using known organic, inorganic and / or enzymatic methods.

[0490] Preparation of peptides

[0491] The polypeptides disclosed herein can be prepared by a variety of methods well known to those skilled in the art of organic synthesis. For example, the polypeptides disclosed herein can be synthesized using the methods described below, as well as synthetic methods known in the field of synthetic organic chemistry or variants thereof understood by those skilled in the art. Preferred methods include, but are not limited to, those described below. The polypeptides disclosed herein can be synthesized by following the steps outlined in General Scheme 1, which include assembling different orders of intermediates Ia, Ib, Ic, Id, and Ie. The starting materials are commercially available or prepared by known procedures reported in the literature or as described.

[0492] General solution 1

[0493]

[0494] Where 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 13As defined in formula (I), PG2, PG3, PG4, PG5, PG6, PG7, PG8, PG9, PG10, PG11, PG12 and PG13 are absent or selected from tert-butyloxycarbonyl (Boc), 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl (Pbf), or tert-butyl (tBu).

[0495] A general method for preparing polypeptides of formula (I) by using intermediates Ia, Ib, Ic, Id and Ie is outlined in General Scheme 1. The synthesis of intermediate Ib can be achieved by 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 (ethyl cyano(hydroxyimino)acetate) and optionally a base such as triethylamine or N,N-diisopropylethylamine (DIPEA) in a solvent such as dichloromethane (DCM) or dimethylformamide (DMF) on a resin such as TentaGel TM S RAM resin), optionally at elevated temperature, the acid is coupled to the amine. Solid phase peptide synthesis is a well-recognized method (see, e.g., Stewart and Young, Solid Phase Peptide Synthesis, Pierce Chemical Co., Rockford, Ill., 1984; E. Atherton and RC 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 the protected amino acid with the deprotected amine Ia can be accomplished under standard coupling conditions as described above. Repeating the deprotection and coupling steps provides intermediate Ib.

[0496] Acylation of Ib with N-succinimidyl 2-chloroacetate Ic in a solvent such as N-methyl-2-pyrrolidone (NMP) provides Id. Removal of the protecting group and cleavage from the resin using an appropriate reagent such as TFA, phenol, H2O, thioanisole, and / or EDT (reagent K) provides Ie. (See, DSKing, CGFields, GBFields, 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).

[0497] It should be understood that in the description and formula shown above, each group 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 as defined above unless otherwise indicated. In addition, for synthetic purposes, the polypeptides of General Scheme 1 are merely representative polypeptides with selected groups to illustrate the general synthetic methods of polypeptides having Formula (I) as defined herein.

[0498] Methods of using the disclosed polypeptides

[0499] Another aspect of the present disclosure relates to a method for regulating PCSK9. The method comprises 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 (the pharmaceutical composition comprises a cyclic polypeptide of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier).

[0500] In another aspect, the disclosure relates to a method for inhibiting PCSK9. The method involves 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 (the pharmaceutical composition comprises a cyclic polypeptide of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier).

[0501] Another aspect of the present disclosure relates to a method for treating, preventing, inhibiting or eliminating a disease or disorder in which PCSK9 plays a role. The method comprises administering 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 (the pharmaceutical composition comprises a cyclic polypeptide of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier) to a patient in need of treatment for a disease or disorder in which PCSK9 plays a role.

[0502] Another aspect of the present disclosure relates to a method for treating, preventing, inhibiting or eliminating a disease or disorder associated with inhibition of PCSK9 in a patient, the method comprising administering to a patient in need thereof an effective amount of a cyclic polypeptide having formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, or a pharmaceutical composition (the pharmaceutical composition comprising a cyclic polypeptide having formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier).

[0503] In another aspect, the present disclosure relates to a method for treating, preventing, inhibiting or eliminating a disease or disorder mediated by PCSK9. The method comprises administering 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 (the pharmaceutical composition comprises a cyclic polypeptide of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier) to a patient in need of treatment for a disease or disorder mediated by PCSK9.

[0504] Another aspect of the present disclosure relates to a method 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. The method comprises administering to a patient in need of treatment 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 (the pharmaceutical composition comprises a cyclic polypeptide of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier).

[0505] In another aspect, the disclosure relates to a method for reducing Lp(a), reducing Lp(a) plasma levels, reducing Lp(a) serum levels, reducing serum TRL or LDL levels, reducing serum triglyceride levels, reducing LDL-C, reducing the total concentration of plasma apoB, reducing LDL apoB, reducing TRL apoB, or reducing non-HDL-C. The method comprises administering to a patient in need thereof an effective amount of a cyclic polypeptide having formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, or a pharmaceutical composition (the pharmaceutical composition comprising a cyclic polypeptide having formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier).

[0506] In another aspect, the present disclosure relates to a cyclic polypeptide having formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, or a pharmaceutical composition (the pharmaceutical composition comprising a cyclic polypeptide having 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 plays a role.

[0507] Another aspect of the present disclosure relates to a cyclic polypeptide having formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, or a pharmaceutical composition (the pharmaceutical composition comprising a cyclic polypeptide having 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 the inhibition of PCSK9.

[0508] Another aspect of the present disclosure relates to a cyclic polypeptide having formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition (the pharmaceutical composition comprises a cyclic polypeptide having 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 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.

[0509] In another aspect, the present disclosure relates to a cyclic polypeptide having formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, or a pharmaceutical composition (the pharmaceutical composition comprising a cyclic polypeptide having 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.

[0510] Another aspect of the present disclosure relates to a cyclic polypeptide having formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, or a pharmaceutical composition (the pharmaceutical composition comprising a cyclic polypeptide having 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 plays a role.

[0511] On the other hand, the present disclosure relates to a cyclic polypeptide having formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, or a pharmaceutical composition (the pharmaceutical composition comprising a cyclic polypeptide having 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 inhibiting PCSK9.

[0512] In another aspect, the present disclosure relates to a cyclic polypeptide having formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition (the pharmaceutical composition comprising a cyclic polypeptide having 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.

[0513] Another aspect of the present disclosure relates to the use of a cyclic polypeptide having formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, or a pharmaceutical composition (the pharmaceutical composition comprising a cyclic polypeptide having 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.

[0514] In another aspect, the present disclosure relates to a cyclic polypeptide having formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, or a pharmaceutical composition (the pharmaceutical composition comprising a cyclic polypeptide having 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 inhibition of PCSK9.

[0515] Another aspect of the present disclosure relates to a cyclic polypeptide having formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, or a pharmaceutical composition (the pharmaceutical composition comprising a cyclic polypeptide having 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 plays a role.

[0516] In another aspect, the present disclosure relates to a cyclic polypeptide having formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition (the pharmaceutical composition comprising a cyclic polypeptide having 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.

[0517] Another aspect of the present disclosure relates to a cyclic polypeptide having formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, or a pharmaceutical composition (the pharmaceutical composition comprising a cyclic polypeptide having 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.

[0518] In another aspect, the disclosure relates to the use of a PCSK9 inhibitor for the preparation of a medicament for treating, preventing, inhibiting or eliminating 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.

[0519] Another aspect of the present disclosure relates to a cyclic polypeptide having formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, or a pharmaceutical composition (the pharmaceutical composition comprising a cyclic polypeptide having 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.

[0520] Another aspect of the present disclosure relates to a cyclic polypeptide having formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, or a pharmaceutical composition (the pharmaceutical composition comprising a cyclic polypeptide having 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 the group consisting 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, and xanthomas.

[0521] In another aspect, the present disclosure relates to a cyclic polypeptide having formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, or a pharmaceutical composition (the pharmaceutical composition comprising a cyclic polypeptide having 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.

[0522] Another aspect of the present disclosure relates to a cyclic polypeptide having formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, or a pharmaceutical composition (the pharmaceutical composition comprising a cyclic polypeptide having 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.

[0523] In another aspect, the present disclosure relates to a cyclic polypeptide having formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, or a pharmaceutical composition (the pharmaceutical composition comprising a cyclic polypeptide having formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier), for use as a medicament.

[0524] The present disclosure also relates to the use of a PCSK9 inhibitor in the preparation of a medicament for treating, preventing, inhibiting or eliminating a disease or condition in which PCSK9 plays a role, wherein the medicament comprises a cyclic polypeptide having formula (I).

[0525] In another aspect, the disclosure relates to a method for manufacturing a medicament for treating, preventing, inhibiting or eliminating a disease or condition mediated by PCSK9, wherein the medicament comprises a cyclic polypeptide having formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer.

[0526] In some embodiments of the above methods, the PCSK9-mediated disease or disorder, the disease or disorder in which PCSK9 plays a role, the disease or disorder associated with inhibition of PCSK9 in a patient, and the disease associated with inhibition of PCSK9 are selected from the group consisting 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, and xanthomas.

[0527] The polypeptide of the present disclosure can be used to reduce or reduce the low-density lipoprotein cholesterol (LDL-C) of an individual in need. An individual may have a continuously elevated LDL-C level. In certain embodiments, the LDL-C plasma level of an individual is always higher than 70 mg / dL, for example, higher than 80 mg / dL, 90 mg / dL, 100 mg / dL, 110 mg / dL, 120 mg / dL, 130 mg / dL, 140 mg / dL, 150 mg / dL, 160 mg / dL, 170 mg / dL, 180 mg / dL, 190 mg / dL, or higher. The polypeptide of the present disclosure can also be used to reduce or reduce non-high-density lipoprotein cholesterol (non-HDL-C) or total cholesterol in an individual in need.

[0528] The 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 ideal, cholesterol of 200 mg / dL-239 mg / dL is considered borderline high, and cholesterol of 240 mg / dL and higher is considered high.

[0529] In additional aspects, the disclosure provides methods 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.

[0530] 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 (the pharmaceutical composition comprises a cyclic polypeptide of formula (I) of the present disclosure or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier) for treating a disease (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).

[0531] In one embodiment, a method of treating a disease or disorder in which PCSK9 plays a role is provided, the disease or disorder 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, the method comprising administering a cyclic polypeptide having formula (I) to a patient suffering from at least one of the diseases or disorders.

[0532] The disclosed polypeptides can be administered in an amount effective to treat or prevent a disorder and / or prevent its development in a subject.

[0533] The disclosed polypeptides can be administered in an amount effective to treat or prevent a disorder and / or prevent its development in a subject.

[0534] Administration, pharmaceutical compositions and dosages of disclosed polypeptides

[0535] Administration of the disclosed polypeptides can be accomplished via any mode of administration of therapeutic agents, including systemic or local administration, such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal or topical administration.

[0536] Depending on the intended mode of administration, the disclosed compositions can be in solid, semisolid or liquid dosage forms, such as, for example, injections, tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, etc., sometimes in unit doses, and consistent with conventional pharmaceutical practice. They can also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous or intramuscular forms, and all forms used are well known to those skilled in the art of pharmacy.

[0537] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a cyclic polypeptide having formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier. A pharmaceutically acceptable carrier may further include an excipient, a diluent, or a surfactant. In another embodiment, the composition comprises at least two pharmaceutically acceptable carriers (such as those described herein). The pharmaceutical composition can be formulated for a specific route of administration, such as oral administration, parenteral administration (such as by injection, infusion, percutaneous or topical administration) and rectal administration. Topical administration may also involve inhalation or intranasal application. The pharmaceutical composition of the present disclosure can be made 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 can be added with a film coating or an enteric coating according to methods known in the art. Typically, the pharmaceutical composition is a tablet or gelatin capsule comprising an active ingredient and one or more of the following:

[0538] a) diluents, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine;

[0539] b) lubricants, for example silicon dioxide, talc, stearic acid, its magnesium or calcium salts and / or polyethylene glycol; in the case of tablets, also

[0540] c) binders, for example, magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; if necessary

[0541] d) disintegrants, for example, starch, agar, alginic acid or its sodium salt or effervescent mixtures; and

[0542] e) Adsorbents, colorants, flavoring agents and sweeteners.

[0543] Liquid (particularly injectable) compositions can be prepared, for example, by dissolving, dispersing, etc. For example, the disclosed polypeptides are dissolved in or mixed with a pharmaceutically acceptable solvent (such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, etc.), thereby forming an injectable isotonic solution or suspension. Proteins (such as albumin, chylomicron particles, or serum proteins) can be used to dissolve the disclosed polypeptides.

[0544] The disclosed polypeptides may also be formulated as suppositories, which may be prepared from fatty emulsions or suspensions; using polyalkylene glycols (eg, propylene glycol) as carriers.

[0545] Parenteral injectable administration is generally for subcutaneous, intramuscular or intravenous injection and infusion. Injections can be prepared in conventional forms (either as liquid solutions or suspensions, or in solid forms suitable for dissolution in liquid prior to injection).

[0546] The compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the pharmaceutical compositions of the present invention can contain from about 0.1% to about 99%, from about 5% to about 90%, or from about 1% to about 20% of the disclosed polypeptides by weight or volume.

[0547] The dosage regimen for using the disclosed polypeptides is selected based on 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 liver function; and the specific disclosed polypeptide used. A physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.

[0548] When used for the indicated effects, the disclosed cyclic polypeptides, disclosed pharmaceutical compositions, or disclosed combinations have effective dosage ranges from about 0.5 mg to about 5000 mg of the disclosed polypeptides required to treat the condition. Compositions for in vivo or in vitro use may contain about 0.5, 5, 20, 50, 75, 100, 150, 250, 500, 750, 1000, 1250, 2500, 3500, or 5000 mg of the disclosed polypeptides, or a range from one amount to another in the dosage list. In one embodiment, the composition is in the form of a tablet that can be scored. The therapeutically effective dose of the cyclic peptide, pharmaceutical composition, or combination thereof depends on the species, weight, age, and individual condition, disorder, or disease being treated, or its severity, of the subject. A physician, clinician, or veterinarian with ordinary skills can easily determine the effective amount of each active ingredient necessary to prevent, treat, or inhibit the progression of a disorder or disease.

[0549] The above dosage characteristics are demonstrated in in vitro and in vivo tests using advantageous mammals (e.g., mice, rats, dogs, monkeys) or their isolated organs, tissues and products. The cyclic polypeptides disclosed herein can be applied in vitro in the form of a solution (e.g., an aqueous solution), and in vivo in the form of an enteral, parenteral (advantageously, intravenous), for example, suspension or aqueous solution. The in vitro dose may be between about 10-3 molar and 10-9 molar concentrations. Depending on the route of administration, the in vivo therapeutically effective amount may be between about 0.1-500 mg / kg, or within the range of about 1-100 mg / kg.

[0550] Combination therapy

[0551] The cyclic polypeptides of the present application can be administered in a therapeutically effective amount in a combination therapy with one or more therapeutic agents (drug combinations) or methods (e.g., non-drug therapies). For example, synergistic effects may occur with other cardiovascular agents, antihypertensive agents, coronary vasodilators, and diuretics. When the polypeptides of the present application are administered in combination with other therapies, the dosage of the co-administered polypeptides will of course vary depending on the type of combined drug used, the specific drug used, the condition being treated, etc.

[0552] The cyclic polypeptides of the present disclosure can be administered simultaneously with one or more other therapeutic agents or before or after the therapeutic agents. The cyclic polypeptides of the present disclosure can be administered separately by the same or different administration routes, or administered together with other agents in the same pharmaceutical composition. The therapeutic agent is, for example, a chemical compound, a peptide, an antibody, an antibody fragment, or a nucleic acid, which has therapeutic activity or enhances therapeutic activity when administered to a patient in combination with the cyclic polypeptides of the present disclosure.

[0553] In one embodiment, the disclosure provides a product comprising a cyclic polypeptide of the 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 the treatment of a disease or condition mediated by PCSK9. Products provided as combined preparations include compositions comprising a cyclic polypeptide of the disclosure and one or more other therapeutic agents together in the same pharmaceutical composition, or a cyclic polypeptide of the disclosure and one or more other therapeutic agents in separate form (e.g., in the form of a kit).

[0554] On the other hand, the present disclosure includes cyclic polypeptides of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), or any of embodiments 1 to 50, or any of the embodiments of formula (I), formula (II), formula (III), formula (IV), formula (V), and / or formula (VI) as described herein, or pharmaceutically acceptable salts thereof, for use in combination therapy. Compositions, drugs and polypeptides of formula (I), formula (II), formula (III), formula (IV), formula (V), and formula (VI), or polypeptides according to any of embodiments 1 to 50, or any of the embodiments of formula (I), formula (II), formula (III), formula (IV), formula (V), and / or formula (VI) as described herein, or pharmaceutically acceptable salts thereof, can also be advantageously used in combination with one or more other therapeutic agents.

[0555] Another aspect of the present disclosure relates 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 include an excipient, a diluent, or a surfactant.

[0556] Combination therapy includes further combination with other biologically active ingredients (such as but not limited to a second agent, such as but not limited to a cardiovascular agent, an adrenergic blocker, an antihypertensive agent, an angiotensin system inhibitor, angiotensin converting enzyme (ACE) inhibitor, a coronary vasodilator, a diuretic or an adrenergic stimulant or a second agent targeting PCSK9) and non-drug therapy (such as but not limited to surgery or radiotherapy) to administer the polypeptide to the subject. For example, the polypeptide of the present application can be used in combination with other pharmaceutically active compounds or polypeptides (preferably, compounds or polypeptides that can enhance the effect of the polypeptide of the present application). The polypeptide of the present application can be administered to other drug therapies or treatments simultaneously (as a single preparation or a separate preparation) or sequentially. In general, combination therapy envisions the administration of two or more drugs during a single cycle or course of treatment.

[0557] In some embodiments, the polypeptides of the present application can be used in combination with agents known to be beneficial for lowering cholesterol (including LDL-C, non-HDL-C, agents that lower triglycerides, and total cholesterol) and / or increasing HDL-C.

[0558] Exemplary therapeutic agents that can be used in combination with the polypeptides of the present disclosure include, but are not limited to, hypolipidemic 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 oils, anti-diabetic agents, anti-obesity agents, peroxisome proliferator-activated receptor agonists, ATP citrate lyase (ACL) inhibitors, and anti-hypertensive agents.

[0559] Examples of lipid-lowering agents that can 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, niacin and other GPR109 agonists, and aspirin.

[0560] HMG-CoA reductase inhibitors (i.e., statins) are a class of drugs used to reduce cholesterol levels by inhibiting HMG-CoA reductase, which plays an important role in the production of cholesterol in the liver. Elevated cholesterol levels are associated with cardiovascular diseases, so statins can be used to prevent these diseases. Exemplary statins include, but are not limited to, atorvastatin, cerivastatin, mevastatin, dalvastatin, dihydromevastatin, fluvastatin, fluvastatin, lovastatin, pitavastatin, mevastatin, pravastatin, rivastatin, simvastatin and its vetstatin, or a pharmaceutically acceptable salt thereof.

[0561] Fibrates or fibric acid derivatives reduce triglycerides and increase HDL cholesterol. They may have little effect on LDL cholesterol. For example, gemfibrozil or fenofibrate can be used for people with very high triglyceride levels or low HDL levels and high triglyceride levels. Gemfibrozil can be used to reduce the risk of heart attack in patients with coronary heart disease (CAD) with low HDL and high triglycerides. Examples of fibrates include but are not limited to clofibrate, gemfibrozil, fenofibrate, ciprofibrate and bezafibrate.

[0562] Cholesterol absorption inhibitors are a class of compounds that prevent cholesterol from being absorbed from the small intestine into the circulatory system and thereby reduce the concentration of plasma LDL-C. Elevated cholesterol levels are associated with an increased risk of CVD; therefore, cholesterol absorption inhibitors are used with the goal of reducing CVD risk. A non-limiting example of a cholesterol absorption inhibitor is ezetimibe, previously known as "Sch-58235". Another example is Sch-48461. Both compounds were developed by Schering-Plough.

[0563] Examples of bile acid sequestrants that can be used in combination with the polypeptides of the present disclosure include, but are not limited to, cholestyramine, colestipol, and colesvelam.

[0564] A non-limiting example of a thyroid hormone mimetic that can be used in combination with the polypeptides of the present disclosure is compound KB2115.

[0565] A non-limiting example of a thyroid hormone receptor (THR) β-selective agonist that can be used in combination with the polypeptides of the present disclosure is MGL-3196.

[0566] DGAT is an enzyme that catalyzes the last step of triacylglycerol biosynthesis. DGAT catalyzes the coupling of 1,2-diacylglycerol with fatty acyl-CoA to produce coenzyme A and triacylglycerol. Two enzymes showing DGAT activity have been identified: DGAT1 (acyl coA-diacylglycerol acyltransferase 1, see Cases et al., Proc. Natl. Acad. Sci [Proceedings of the National Academy of Sciences of the United States]. 95: 13018-13023, 1998) and DGAT2 (acyl coA-diacylglycerol acyltransferase 2, see Cases et al., J. Biol. Chem. [Journal of Biological Chemistry] 276: 38870-38876, 2001). DGAT1 and DGAT2 have no obvious 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 may be useful for treating obesity and obesity-related complications. Useful DGAT1 inhibitors in the combination are compounds and analogs disclosed generally and specifically in, for example, WO 2007 / 126957 and WO 2009 / 040410, particularly in the compound claims, and the final products of the working examples, the subject matter of the final products, the pharmaceutical preparations and the claims.

[0567] Examples of DGAT1 inhibitors suitable for use in combination with the polypeptides of the present disclosure include, but are not limited to, {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-trifluoromethyl-pyridin-3-ylamino)-pyridin-2-yl]-spirocyclohexylidene-1,1'-indanyl}-acetic acid, (4-{4-[5-(1-methyl-1H-pyrazol-3-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-acetic acid, -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-tetrazolyl-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)- 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-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-benzimidazole-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)-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]-phosphine Acid, 2-(2,6-dichloro-phenyl)-6-(4,5-diphenyl-oxazol-2-yl)-1H-benzimidazole, (4-{6-[5-(4-chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-1H-benzimidazole-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-benzimidazole-2-yl}-phenol.

[0568] A non-limiting example of a Niemann-Pick C1-like 1 (NPC1-L1) inhibitor that can be used in combination with the polypeptides of the present disclosure is ezetimibe.

[0569] Apolipoprotein AI is a protein encoded by the APOA1 gene in humans. It has a specific role in lipid metabolism. Apolipoprotein AI is the main protein component of high-density lipoprotein (HDL) in plasma. Chylomicrons secreted by enterocytes also contain ApoA-I, but are quickly transferred to HDL in the blood. This protein promotes the excretion of cholesterol from tissues to the liver for secretion. It is a cofactor of lecithin cholesterol acyltransferase (LCAT), which is responsible for the formation of most plasma cholesterol esters. As assessed by intravascular ultrasound, infusion of apoA-I variants in humans has been shown to regress atherosclerotic plaques; thus, apoA-I reduces CVD risk and has the ability to slow progression and induce regression of atherosclerosis. A non-limiting example of an apoA-I upregulator / inducer is RVX208.

[0570] ATP-binding cassette transporter ABCA1 (member 1 of human transporter subfamily ABCA), also known as cholesterol efflux regulatory protein (CERP), is a protein encoded by the ABCA1 gene in humans. This transporter is a major regulator of cellular cholesterol and phospholipid homeostasis. A non-limiting example of an ABCA1 regulator is probucol. Probucol lowers cholesterol levels in the blood by increasing the rate of LDL catabolism. In addition, probucol can inhibit cholesterol synthesis and delay cholesterol absorption. Probucol is a powerful antioxidant that inhibits the oxidation of cholesterol in LDL; this slows the formation of foam cells that contribute to atherosclerotic plaques.

[0571] Liver X receptors (LXRs) are members of the nuclear receptor family of transcription factors and are closely related to nuclear receptors such as PPAR, FXR and RXR. Liver X receptors (LXRs) are important regulators of cholesterol, fatty acid and glucose homeostasis. LXR agonists are effective in treating atherosclerosis, diabetes, anti-inflammatory and Alzheimer's disease mouse models. Treatment with LXR agonists (including but not limited to hypocholamide, T0901317, GW3965 or N, N-dimethyl-3-β-hydroxy-cholesterolamide (DMHCA)) reduces serum and liver cholesterol levels in mouse disease models and inhibits the development of atherosclerosis. Examples of LXR agonists include but are not limited to GW3965 (synthetic nonsteroidal liver X receptor (LXR) agonist / activator) and T0901317 (dual LXR, FXR agonist).

[0572] Farnesoid X receptor (FXR), also known as NR1H4 (nuclear receptor subfamily 1, group H, member 4) is a nuclear hormone receptor that is similar in activity to other steroid receptors such as estrogen or progesterone, but more similar in form to PPAR, LXR and RXR. Activation of the nuclear receptor FXR is known to improve 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).

[0573] Phospholipid transfer protein (PLTP) is a protein that is 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, CETP being the other. The encoded protein transfers phospholipids from triglyceride-rich lipoproteins to HDL. In addition to regulating the size of HDL particles, this protein may also be involved in cholesterol metabolism. At least two transcript variants encoding different isoforms have been found for this gene. Since PLTP affects the metabolism of both triglyceride-rich lipoproteins and HDL, modulation of this transfer protein has the potential to alter cardiovascular disease risk.

[0574] Fish oil is derived from the tissue of oily fish. Fish oil contains the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are precursors to eicosanoids known to have many health benefits. The use of fish oil and other omega-3 sources is strongly recommended in the following situations: hypertriglyceridemia, secondary cardiovascular disease, and prevention of hypertension. For example, Used with a low-fat and low-cholesterol diet, it can reduce very high triglycerides (fats) in the 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 and (icosapent ethyl).

[0575] Examples of antidiabetic agents that can be used in combination with the polypeptides of the present disclosure include, but are not limited to, insulin, insulin derivatives and mimetics; insulin secretagogues, such as sulfonylureas; insulinotropic sulfonylurea receptor ligands, such as meglitinides, such as 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 co-transporter inhibitors, including but not limited to T-1095; glycogen phosphorylase A inhibitors, including but not limited to BAY R3401; biguanides, including but not limited to metformin; α-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.

[0576] Examples of sulfonylureas include, but are not limited to, tolbutamide, chlorpropamide, tolsulfonyl cyclohexylurea, 4-chloro-N-[(1-pyrrolidinylamino)carbonyl]-benzenesulfonamide (glyburide), glibenclamide (glyburide), gliclazide, 1-butyl-3-aminobenzenesulfonyl urea, amosulfuronamide, glibornamide, glipizide, gliquidone, glipartide, glitazole, glibuzole, glihexamide, glipizide, glipindone, glipizide, glipitazole, glibuzole, glihexamide, glipizide, glipindamide, tolbutamide, amaryl and tolylcyclamide, or pharmaceutically acceptable salts thereof.

[0577] DPP-IV (Dipeptidyl peptidase IV) is responsible for inactivating GLP-1. More specifically, DPP-IV produces a GLP-1 receptor antagonist and thereby shortens the physiological response to GLP-1. GLP-1 is the primary stimulator of pancreatic insulin secretion and has a direct beneficial effect on glucose disposal.

[0578] The DPP-IV inhibitor can be a peptide or preferably a non-peptide. The example of the DPP-IV inhibitor also includes, but is not limited to, the DPP-IV inhibitor disclosed generally and specifically in WO 98 / 19998, DE 196 16 486A1, WO 00 / 34241 and WO 95 / 15309 (in each case, particularly in the compound claims), and the final products of the working examples, the subject matter of the final products, the pharmaceutical preparations and the claims are hereby incorporated into the present application by reference to these publications.

[0579] GLP-1 (glucagon-like peptide-1) is an insulinotropic protein, which is described, for example, by WE Schmidt et al., in Diabetologia [Diabetology], 28, 1985, 704-707 and in US 5,705,483. The term "GLP-1 agonist" includes variants and analogs of GLP-1 (7-36) NH2, which are disclosed in particular in US 5,120,712, US 5,118666, US 5,512,549, WO 91 / 11457 and in C. Orskov, et al., J. Biol. Chem. [Journal of Biological Chemistry], 264 (1989) 12826. Further examples include: GLP-1 (7-37), in which Arg is replaced by Gly at position 37 of the GLP-1 (7-36) NH2 molecule. 36 Compounds having a carboxyl terminal amide functional group, and variants and analogs thereof, including 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 4-imidazopropionyl-GLP-1. Also particularly preferred are the GLP agonist analogs: agonist peptide-4, described by Greig et al. (in Diabetologia 1999, 42, 45-50).

[0580] Also included in the definition of "antidiabetic agent" are insulin sensitivity enhancers, which restore impaired insulin receptor function to reduce insulin resistance and thus enhance insulin sensitivity. Examples include hypoglycemic thiazolidinedione derivatives (e.g., glitazone, (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 (DRF2 189), 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-dihydroindole-1-yl)ethoxy)phenyl]methyl}-thiazolidine-2,4-dione, 5-[3-(4-chloro-phenyl])-2-propynyl]-5-phenylsulfonyl)thiazolidine-2,4-dione, 5-[3-(4-chlorophenyl])-2-propynyl]-5-(4-fluorophenyl-sulfonyl)thiazolidine-2,4-dione, 5-{[4-(2-(methyl-2-pyridyl-amino)-ethoxy)phenyl]methyl}-thiazolidine-2,4-dione (rosiglitazone), 5-{[4-(2-(5-ethyl-2-pyridyl)ethoxy)phenyl]-methyl}thiazolidine-2,4-dione 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)).

[0581] Examples of peroxisome proliferator-activator receptor agonists that can 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, compounds specifically described in patent application WO 2004 / 103995 (i.e., compounds of Examples 1 to 35 or compounds specifically listed in claim 21), or compounds specifically described in patent application WO 03 / 043985 (i.e., compounds of Examples 1 to 7 or 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-carboxylic acid or a salt thereof.

[0582] Examples of lipid-lowering agents that can 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, niacin and other GPR109 agonists, and aspirin.

[0583] Examples of antihypertensive agents that can 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; neutral endopeptidase (NEP) inhibitors; ACE / NEP inhibitors; angiotensin II antagonists; renin inhibitors; β-adrenergic receptor blockers; inotropic agents; calcium channels; aldosterone receptor antagonists; and aldosterone synthase inhibitors.

[0584] Examples of loop diuretics that can be used in combination with the polypeptides of the present disclosure include, but are not limited to, ethacrynic acid, furosemide, and torsemide.

[0585] The term "ACE inhibitor" (also known as angiotensin converting enzyme inhibitor) includes molecules that interrupt the enzymatic degradation of angiotensin I to angiotensin II. Such compounds can be used to regulate blood pressure and treat congestive heart failure. Examples include, but are not limited to, alacepril, benazepril, benazeprilat, captopril, cilazapril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, imidapril, lisinopril, moexipril, moveltopril, perindopril, quinapril, ramipril, spirapril, temocapril and trandolapril, or a pharmaceutically acceptable salt thereof.

[0586] A non-limiting example of a Na-K-ATPase membrane pump inhibitor is digoxin.

[0587] The term "NEP inhibitor" refers to a compound that inhibits neutral endopeptidase (NEP). Examples include, but are not limited to, candoxatril, candoxatrilat, dexadotril, ecadotril, racecadotril, sampatrilat, fasidotril, olpatraz, gomotrilat, 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 phosphine / biaryl substituted dipeptide derivatives, such as disclosed in U.S. Pat. No. 5,155,100. NEP inhibitors also include N-mercaptoacylphenylalanine derivatives disclosed in PCT application WO 2003 / 104200. NEP inhibitors also include dual-acting antihypertensive agents, such as those disclosed in PCT applications WO 2008 / 133896, WO 2009 / 035543, or WO 2009 / 134741. Other examples include compounds disclosed in: U.S. applications 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 compounds disclosed in WO 2015116786, WO 2015116760, WO 2014138053, WO 2014025891, WO2013184934, WO 2013067163, WO 2012166389, WO 2012166387, WO 2012112742, and WO2012082853.

[0588] 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 can be used in combination with the polypeptides of the present disclosure include, but are not limited to, olapatrilat, sampatrilat, and fasidotril.

[0589] The class of angiotensin II antagonists or AT1 receptor antagonists includes compounds with different structural features, and non-peptide compounds are generally preferred. Examples of angiotensin II antagonists that can be used in combination with the polypeptides disclosed herein include, but are not limited to, valsartan, losartan, candesartan, eprosartan, irbesartan, saprisartan, tasosartan, telmisartan, compounds named E-1477 and ZD-8731 having the formula

[0590]

[0591] or in each case, a pharmaceutically acceptable salt thereof.

[0592] 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-pyridylmethyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-N-α-methyl-L-histidinamide); terlakiren (chemical name: [R-(R,S)]-N-(4-morpholinylcarbonyl)-L-phenylalanyl-N-[1-(cyclohexylmethyl)-2-hydroxy-3-(1-methylethoxy)-3-oxopropyl]-S-methyl-L-cysteineamide); en) (chemical name: (2S, 4s, 5S, 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 zankiren (chemical name: [1S- [1R [R (R)], 2S, 3r]] -N- [1- (cyclohexylmethyl) -2, 3-dihydroxy-5-methylhexyl] -α- [[2- [[(4-methyl-1-piperazinyl) sulfonyl] methyl] -1-oxo-3-phenylpropyl] -amino] -4-thiazole propionamide) or its hydrochloride, or SPP630, SPP635 and SPP800 developed by Speedel, or RO having formula (A) and (B) 66-1132 and RO 66-1168:

[0593]

[0594] If not explicitly defined, the term "aliskiren" is understood to mean the free base and its salts, especially its pharmaceutically acceptable salts, most preferably its hemifumarate salt.

[0595] Examples of beta-adrenergic receptor blockers that can 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.

[0596] Examples of inotropic agents that can be used in combination with the polypeptides of the present disclosure include, but are not limited to, digoxin, dobutamine, and milrinone; inotropic agents (Inotropes) as used herein include, for example, dobutamine, isoproterenol, milrinone, amrinone, levosimendan, epinephrine, norepinephrine, isoproterenol, and digoxin.

[0597] Examples of calcium channel blockers that can 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.

[0598] Aldosterone synthase inhibitors include steroidal and nonsteroidal aldosterone synthase inhibitors, the latter being most preferred. The class of aldosterone synthase inhibitors includes compounds having different structural features. Examples of aldosterone synthase inhibitors that can be used in combination with the polypeptides disclosed herein include, but are not limited to, the (+)-enantiomer of fadrozole hydrochloride having the formula (U.S. Pat. Nos. 4,617,307 and 4,889,861)

[0599]

[0600] or, if applicable, a pharmaceutically acceptable salt thereof; and compounds and analogs disclosed generally and specifically in, for example, US 2007 / 0049616 (particularly in the compound claims), and the final products of the working examples, the subject matter of the final products, the pharmaceutical preparations and the claims are hereby incorporated into the present application by reference to that publication. Examples of aldosterone synthase inhibitors that can be used in combination with the polypeptides disclosed herein include, but are not limited to: 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]azepine -5-yl)biphenyl-3-carbonitrile; butyl 5-(4-cyano-2-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylate; 4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-yl)-2-methoxybenzonitrile; 4-fluorobenzyl 5-(2-chloro-4-cyanophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylate; methyl 5-(4-cyano-2-trifluoromethoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylate; 2-isopropoxyethyl 5-(4-cyano-2-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylate esters; 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]azepine -5-yl)biphenyl-3-carbonitrile; 4'-fluoro-6-(9-methyl-6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepine -5-yl)biphenyl-3-carbonitrile, or in each case, the (R) or (S) enantiomer thereof; or, if applicable, a pharmaceutically acceptable salt thereof.

[0601] The term aldosterone synthase inhibitor also includes, but is not limited to, compounds disclosed in WO 2008 / 076860, WO 2008 / 076336, WO 2008 / 076862, WO 2008 / 027284, WO 2004 / 046145, WO 2004 / 014914 and WO 2001 / 076574 and analogs.

[0602] In addition, aldosterone synthase inhibitors also include, but are not limited to, compounds and analogs disclosed in U.S. patent applications US 2007 / 0225232, US2007 / 0208035, US2008 / 0318978, US2008 / 0076794, US2009 / 0012068, US20090048241, and PCT applications WO 2006 / 005726, WO 2006 / 128853, WO 2006128851, WO 2006 / 128852, WO2007065942, WO 2007 / 116099, WO 2007 / 116908, WO 2008 / 119744, and European patent application EP1886695. Preferred aldosterone synthase inhibitors suitable for use in the present disclosure include, but are not limited to, 8-(4-fluorophenyl)-5,6-dihydro-8H-imidazo[5,1-c1[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)-2,6-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]oxazin-8-yl)phthalonitrile; 4-(8-(4-cyanophenyl)-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, as developed by Speedel or in each case, its (R) or (S) enantiomer; or, if applicable, a pharmaceutically acceptable salt thereof.

[0603] Aldosterone synthase inhibitors useful in the combination include, but are not limited to, compounds and analogs disclosed generally and specifically in, for example, WO 2009 / 156462 and WO 2010 / 130796 (particularly in the compound claims), as well as the final products of the working examples, the subject matter of the final products, the pharmaceutical preparations and the claims.Preferred aldosterone synthase inhibitors suitable for use in the disclosed combinations include: 3-(6-fluoro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzonitrile hydrochloride, 1-(4-methylsulfonyl-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)-pyrrolidine-1-sulfonic acid ethyl ester, 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-4-cyanophenyl)pyridin-3-yl)(cyclopropyl)methyl)ethanesulfonamide, N-(cyclopropyl(5-(1H-indol-5-yl)pyridin-3-yl)methyl)ethanesulfonamide, N-(cyclopropyl(5-naphth-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.

[0604] Lipid-lowering agents 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., Thomson PDR, ed., 63rd ed. (2008).

[0605] "Combination therapy" is intended to include the administration of these therapeutic agents in a sequential manner, wherein each therapeutic agent is administered at different times and in any order, or in an alternating manner and in any order, and the administration of these therapeutic agents or at least two therapeutic agents in a substantially simultaneous manner. Substantially simultaneous administration can be achieved, for example, by administering a single capsule of each therapeutic agent with a fixed ratio or a plurality of single capsules for each therapeutic agent to the subject. The sequential or substantially simultaneous administration of each therapeutic agent can be carried out by any suitable route, including but not limited to oral routes, intravenous routes, intramuscular routes, and direct absorption by mucosal tissue. The therapeutic agent can be administered by the same route or by different routes. For example, the first therapeutic agent of the selected combination can be administered by intravenous injection, and the 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 agent is administered is not very strict.

[0606] In accordance with the foregoing, the present disclosure also provides a therapeutic combination (e.g., a kit, a set of kits), for example, for use in any of the methods defined herein, comprising a cyclic polypeptide having formula (I) or a pharmaceutically acceptable salt thereof, for simultaneous or sequential use with at least one pharmaceutical composition comprising at least another therapeutic agent or a pharmaceutically acceptable salt thereof, the at least another therapeutic agent or a pharmaceutically acceptable salt thereof being selected from 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) Inhibitors, acyl CoA: diacylglycerol acyltransferase (DGAT) 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 up-regulators / inducers, ABCA1 stabilizers or inducers, phospholipid transfer protein (PLTP) inhibitors, fish oils, antidiabetic agents, antiobesity agents, peroxisome proliferator activator receptor agonists, ATP citrate lyase (ACL) inhibitors and antihypertensive agents. The kit may include instructions for its administration. The combination may be a fixed combination (e.g., in the same pharmaceutical composition) or a free combination (e.g., in a separate pharmaceutical composition).

[0607] Similarly, the present disclosure provides a kit comprising: (i) a pharmaceutical composition of the present disclosure; and (ii) a pharmaceutical composition comprising a compound selected from the following or a pharmaceutically acceptable salt thereof: a lipid-lowering agent, niacin or its analogs, 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-CoA:diacylglycerol acyltransferase (DGAT) inhibitor, a Niemann-Pick C1-like 1 (NPC1-L1) inhibitor , 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 oils, antidiabetic agents, antiobesity agents, peroxisome proliferator-activated receptor agonists, ATP citrate lyase (ACL) inhibitors and antihypertensive agents, the kit being in the form of two separate units of components (i) to (ii).

[0608] Likewise, the present disclosure provides a method as defined above, which comprises, for example, co-administering simultaneously or sequentially a therapeutically effective amount of a cyclic polypeptide having formula (I) or a pharmaceutically acceptable salt thereof with a second drug substance, wherein the second drug substance is 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, an acyl-CoA: diacylglycerol acyltransferase (DGAT) inhibitor, a Niemanpik Inhibitors of NPC1-like 1 (NPC1-L1), 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 oils, anti-diabetic agents, anti-obesity agents, peroxisome proliferator-activated receptor agonists, ATP citrate lyase (ACL) inhibitors, and anti-hypertensive agents, such as those shown above.

[0609] Examples

[0610] The disclosure is further illustrated by the following examples and synthetic schemes, which should not be construed as limiting the scope or spirit of the disclosure to the specific procedures described herein. It should be understood that these examples are provided to illustrate certain embodiments, and are not intended to limit the scope of the disclosure thereto. It should be further understood that, without departing from the spirit of the disclosure and / or the scope of the appended claims, various other embodiments, modifications and equivalents thereof that may be proposed by those skilled in the art may be adopted.

[0611] Analytical methods, materials and instruments

[0612] Unless otherwise stated, reagents and solvents received from commercial suppliers are used. Proton nuclear magnetic resonance (NMR) spectra are obtained using a 400MHz Varian spectrometer, a 300MHz or 400MHz Bruker spectrometer. Spectra are given in ppm (δ), and coupling constants J are reported in Hertz. Tetramethylsilane (TMS) or solvent peaks are used as internal standards. If not otherwise stated, purity and low-resolution mass spectrometric data are measured using a ThermoFinnigan Surveyor HPLC system and a Thermo LCQ FleetTM ion trap mass spectrometer with a Surveyor photodiode array (PDA) detection. Column: Synergi 4 micron, hydro-RP80A, 30x2.0 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 at 3 min to 95% B at 3.3 min.

[0613] General preparative HPLC purification procedure and mass spectrometry

[0614] The crude peptide was purified by preparative reverse phase C18-HPLC using columns of different sizes and at different 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. The fractions containing the product were collected and lyophilized to obtain the purified product.

[0615] Condition AA-1 (HRMS) - Column: Acquity BEH C18, 1.7 μm 2.1 x 50 mm, 50°C; Flow rate: 1.0 mL / min; Mobile phase: (A) 0.1% formic acid + 3.75 mM ammonium acetate in water / (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 spectrometry (+), DAD-UV chromatogram 214, 254 nm.

[0616] Condition BB-1 (HRMS) - Column: Acquity BEH C18, 1.7μm2.1x50mm, 50℃; flow rate: 1.0mL / min; mobile phase: (A) 0.001% formic acid + 2% acetonitrile + 3.75mM ammonium acetate in water / (B) 5% water + 3.75mM ammonium acetate in acetonitrile; gradient: 2% to 99.9% in 4.4min; electrospray mass spectrometry (+), DAD-UV chromatogram 214, 254nm.

[0617] Condition CC-1 (HRMS) - Column: Acquity BEH C18, 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 spectrometry (+), DAD-UV chromatography 214 nm.

[0618] Condition A-1 (LCMS) - Column: Acquity BEH C18, 1.7 μm 2.1 x 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 spectrometry (+), DAD-UV chromatography 214 nm.

[0619] Condition B-1 (LCMS) - Column: Acquity HSS T3 1.8 μm 2.1 x 50 mm, 50 ° C; flow rate: 1.2 mL / min; mobile phase: (A) 0.05% formic acid + 3.75 mM ammonium acetate in water / (B) 0.04% formic acid in acetonitrile; gradient: 2% to 98% in 1.4 min; electrospray mass spectrometry (+), DAD-UV chromatography 214 nM

[0620] Condition C-1 (LCMS) - Column: Acquity BEH C18, 1.7μm2.1x50mm, 40℃; Flow rate: 0.7mL / min; Mobile phase: 5% to 95% in 2.8min, (A) 0.1% formic acid in water / (B) 0.1% formic acid in acetonitrile; Gradient: 5% to 95% in 2.8min; Electrospray mass spectrometry (+), DAD-UV chromatography 214nm.

[0621] Condition D-1 (LCMS) - Column: Acquity BEH C18, 1.7 μm 2.1 x 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: 5% B for 2 min, 5% to 100% B in 11 min; electrospray mass spectrometry (+), DAD-UV chromatogram 214 nm.

[0622] Condition E-1 (LCMS) - Column: Acquity BEH C18, 1.7 μm 2.1 x 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 spectrometry (+), DAD-UV chromatography 214 nm.

[0623] 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 spectrometry (+), DAD-UV chromatogram 212-216 nm.

[0624] Condition G-1 (LCMS) - Column: Acquity BEH C18, 1.7 μm, 2.1 x 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 spectrometry (+), DAD-UV chromatography 214 nm.

[0625] Condition H-1 (LCMS) - Column: Acquity BEH C18 1.7 μm 2.1 x 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 spectrometry (+), DAD-UV chromatogram 214 nm.

[0626] The abbreviations used in the following examples and elsewhere in this document are:

[0627]

[0628]

[0629] General procedure for cyclic peptide synthesis:

[0630] The polypeptides of the present disclosure can be synthesized in a similar manner by following the steps outlined in the general scheme shown below.

[0631]

[0632] Step 1: Peptide synthesis

[0633] In the Solid phase peptide synthesis was performed on a peptide synthesizer.

[0634] Synthesis cycle A-1

[0635] The resin was washed with DMF and then deprotected by treatment with 4-methylpiperidine / DMF (1:4) in two cycles, 30 seconds for the first cycle and 3 minutes for the second cycle. Coupling was completed by adding Fmoc-amino acid (4-5 equivalents; 0.2M solution in DMF), HATU (4-5 equivalents; 0.5M solution in DMF) and DIPEA (4-6 equivalents; 2M 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 min, except for the amino acids shown in Table 3 below. After the final coupling was completed, Fmoc was removed by repeated treatment with 4-methylpiperidine / DMA (1:4) to provide a deprotected peptide.

[0636] Table 3: AA coupling conditions for synthetic cycle A-1

[0637]

[0638] In the case of Gyros Protein Technologies AB Solid phase peptide synthesis .

[0639] Alternatively, as described in Synthesis Cycle B-1 or Synthesis Cycle B-2, Peptides were synthesized on a peptide synthesizer.

[0640] Synthesis cycle B-1

[0641] The resin is washed with DMA. Fmoc is then removed by repeatedly treating the resin with piperidine / DMA (1:4). Coupling is accomplished by adding Fmoc-amino acid (3 equivalents; 0.2M solution in NMP), HCTU (3 equivalents; 0.3M solution in NMP) and DIPEA (3-6 equivalents; 0.66-0.9M solution in NMP), and the suspension is then mixed with nitrogen at room temperature (rt), typically 15min to 4h (this depends on the specific requirements). After washing with DMA, the coupling step is repeated. After washing with DMA, end-capping is performed by adding a mixture of Ac2O / pyridine / DMA (1:1:8) and then mixing the suspension at room temperature. After completing the final coupling, Fmoc is removed as described above in synthesis cycle A-1 to provide a peptide.

[0642] Synthetic Cycle B-2

[0643] The resin is washed with DMA. Fmoc is removed by repeated treatment with 4-methylpiperidine / DMA (1:4). Coupling is completed by adding a mixture of Fmoc-amino acid (3 equivalents; 0.2M solution in NMP), Oxyma Pure (3 equivalents; 0.3M solution in NMP) and DIPEA (6-7 equivalents; 0.66M solution in NMP), and then the suspension is mixed with nitrogen at room temperature for 15min to 4h (depending on the specific requirements). After washing with DMA, the coupling step is repeated. After washing with DMA, end-capping is performed by adding a mixture of Ac2O / pyridine / DMA (1:1:8) and then mixing the suspension at room temperature. After completing the final coupling, Fmoc is removed as described above in synthesis cycle A-1 to provide a peptide.

[0644] Step 2: Peptide acylation

[0645] The resin product obtained 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 each with dimethylformamide and dichloromethane to provide the acylated peptide product.

[0646] Step 3: Cleavage from the resin with or without simultaneous removal of the protecting group (PG)

[0647] The resin product obtained from step 2 is vibrated together with one of the cleavage solutions listed below this article (1-5mL, 0.1mmol scale) for 1-2h. The resin is filtered and treated with fresh cleavage solution again for 0.5-1h. Repeat the cleavage cycle as required. The resin is then filtered, and the combined filtrate is slowly poured into a mixture of cold heptane / diethyl ether (1:1) to provide a precipitate. The suspension containing the precipitate is centrifuged, and the supernatant is poured out. The precipitate is suspended in cold ether, vortexed for a short time, and then centrifuged. The washing process is repeated twice more. The crude peptide product is dried in a high vacuum.

[0648] Use the following lysis solution:

[0649] Lysis method 1: TFA / H2O / TIS / DTT (92.5:2.5:2.5:2.5)

[0650] Cleavage method 2: 95% aqueous TFA / EDT / TIS (95:2.5:2.5)

[0651] Step 4: Peptide cyclization

[0652] The crude peptide product obtained from step 3 is dissolved in DMSO or DMA and treated with TEA or DIPEA. The reaction mixture is then shaken overnight at room temperature. The resulting reaction mixture containing the cyclized peptide is concentrated on a centrifugal evaporator to provide the desired cyclic polypeptide of formula (I).

[0653] Example 1: Synthesis of Ac*-FVDTTS-(N-Me)FB-(N-Me)ENSPC*-G-NH2(1-1)

[0654]

[0655] 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)

[0656] exist The peptide synthesizer was used to synthesize Fmoc-Gly-RAM TentaGel 100 following the 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)). TM Peptide sequence 1b was synthesized on resin (1a, 0.22 mmol / g loading, 0.25 mmol scale).The resin was then filtered and washed with DMF (2x) and DCM (3x) to afford the desired product 1b.

[0657] 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)

[0658] A solution of N-succinimidyl 2-chloroacetate (1c, 287 mg, 1.5 mmol) in NMP (8 mL) was added to the peptide resin 1b (0.25 mmol) from step 1, and the resulting mixture was shaken at room temperature overnight. The resin was then drained, washed with DMF (3x) and DCM (4x), and dried to provide the desired product 1d.

[0659] Step 3: ClCH2C(O)-FVDTTS-(N-Me)FB-(N-Me)ENSPCG (1e)

[0660] The peptide resin product 1d from step 2 was cleaved from the resin and simultaneously deprotected using cleavage method 1 described above to provide crude peptide 1e (266 mg). ESI-MS m / z: 866.6 [M+2H] 2+ .

[0661] 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)- 1-1)-24,39-bis(hydroxymethyl)-12-isopropyl-26,32-dimethyl-1,7,10,13,16,19,22,25,28,31,34,37,40-tridecaoxotetradecanoyl-6H-pyrrolo[2,1-f][1]thia[4,7,10,13,16,19,22,25,28,31,34,37,40]tridecaazacyclotetradecanoyl-33-yl)propanoic acid (1-1)

[0662] The crude peptide 1e (266 mg) obtained from step 3 was dissolved in DMSO (20.5 mL). A few drops of TEA were added to reach pH 8-9. The resulting mixture was stirred at room temperature overnight. The reaction mixture was then concentrated to a few milliliters of DMSO on a centrifugal evaporator. The crude cyclic peptide was purified by preparative HPLC (Sunfire TM Prep C18 column, 5 μm, 30×50 mm, 15%-40% in 6 min, 75 mL / min, ACN in water containing 0.1% TFA) and then lyophilized to afford the title polypeptide 1-1 as a white solid (58 mg, 22%).

[0663] use The following polypeptides in Table 4 were synthesized using a peptide synthesizer according to the procedure described for polypeptide (1-1) in Example 1.

[0664] Table 4:

[0665]

[0666]

[0667] use The following polypeptides in Table 5 were synthesized using a peptide synthesizer according to the procedure described for polypeptide (1-1) in Example 1.

[0668] Table 5:

[0669]

[0670]

[0671] The analytical data of the polypeptides of Examples 1-1 to 1-27 are summarized in Table 6 below, and were generated using the HRMS* or UPLC-MS** analytical methods described above.

[0672] Table 6:

[0673]

[0674]

[0675] Example 2: Synthesis of Ac*-FVPTTF-(N-Me)A-(p-Cl)F-(N-Me)APAPC*-NH2(2-1)

[0676]

[0677] Step 1: FVPT(tBu)-T(tBu)-F-(N-Me)A-(p-Cl)F-(N-Me)APAPC-(Trt)NH resin (2b)

[0678] exist The peptide synthesizer was used to synthesize Fmoc-NH TentaGel 100 following the 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)). TM The peptide sequence 2b was synthesized on RAM resin (2a, 0.23 mmol / g loading, 0.1 mmol scale). The resin was then filtered and washed with DMF (2x) and DCM (3x) to afford the desired product 2b.

[0679] Step 2: ClCH2C(O)-FVPT(tBu)-T(tBu)-F-(N-Me)A-(p-Cl)F-(N-Me)APAPC-(Trt)NH-resin (2c)

[0680] A solution of N-succinimidyl 2-chloroacetate (1c, 100 mg, 0.522 mmol) in NMP (6 mL) was added to the peptide resin 2b (0.1 mmol) from step 1, 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 provide the desired product 2c.

[0681] Step 3: ClCH2C(O)-FVPTTF-(N-Me)A-(p-Cl)F-(N-Me)APAPC-NH2(2d)

[0682] The resin product 2c from step 2 was cleaved from the resin and simultaneously deprotected using cleavage method 1 described above to provide crude peptide 2d (106 mg) as a white solid. ESI-MS m / z: 1503.7 [MH] - .

[0683] 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 ,19,22,25,28,31,36,39,42,48-Tridecanoyltetrahydro-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]tridecacyclotetradecane-46-carboxamide (2-1)

[0684] The 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 pH of the mixture to 8-9. The resulting mixture was stirred at room temperature for 18 h and then concentrated to a few milliliters of DMSO on a centrifugal evaporator. The crude cyclic peptide was purified by preparative HPLC (Sunfire TM Prep C18 column, 5 μm, 30x50 mm, 25%-50% in 6 min, 75 mL / min, ACN in water containing 0.1% TFA) and then lyophilized to afford the title polypeptide 2-1 as a white solid (10 mg, 9%). The following polypeptides in Table 7 were synthesized using a peptide synthesizer according to the procedure described for polypeptide (2-1) in Example 2.

[0685] Table 7:

[0686]

[0687] The analytical data of the polypeptides of Examples 2-1 to 2-6 are summarized in Table 8 below, and were generated using the HRMS analytical method described above.

[0688] Table 8:

[0689]

[0690] Example 3: Synthesis of Ac*-FVNTTF-(N-Me)AB-(N-Me)A-(N-Me)EAPC*-NHEt (3-1)

[0691]

[0692] Step 1: FVNT(tBu)-T(tBu)-F-(N-Me)AB-(N-Me)A-(N-Me)E(tBu)-APC(Trt)N(Et) resin (3b)

[0693] exist Peptide sequence 3b was synthesized on a peptide synthesizer following the general peptide synthesis described below on {3-[(ethyl-Fmoc-amino)methyl]-indol-1-yl}-acetyl AM resin (3a, 0.93 mmol / g loading, 0.1 mmol scale). The resin was then filtered and washed with DMA to provide the desired product 3b.

[0694] AA Synthesis Cycle Fmoc-C(Trt) B-2 Fmoc-(N-Me)AA B-2 Any Fmoc-AA coupled to N-methyl AA B-2 Other Fmoc-AA B-1

[0695] Synthesis cycle B-1 : Fmoc-AA (3 eq., 0.2 M solution in NMP), HCTU (3 eq., 0.3 M solution in NMP), and DIPEA (3.3 eq., 0.66 M solution in NMP).

[0696] Synthetic Cycle B-2 : Fmoc-AA (3 eq., 0.2 M solution in NMP), PyOxim (3 eq., 0.3 M solution in NMP), and DIPEA (6.3 eq., 0.66 M solution in NMP).

[0697] Step 2: ClCH2C(O)-FVNT(tBu)-T(tBu)-F-(N-Me)AB-(N-Me)A-(NMe)E(tBu)-APC(Trt)N(Et)-resin (3c)

[0698] A solution of N-succinimidyl 2-chloroacetate (1c, 96 mg, 0.5 mmol) in NMP (3 mL) was added to the peptide resin 3b (0.1 mmol) from step 1, 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 provide the desired product 3c.

[0699] Step 3: ClCH2C(O)-FVNTTF-(N-Me)AB-(N-Me)A-(N-Me)EAPCN(H)Et(3d)

[0700] The peptide resin product 3c from step 2 was cleaved from the resin and simultaneously deprotected using cleavage method 2 described above to provide crude peptide 3d. The crude peptide was then purified by preparative HPLC ( T3 OBD preparative column, 5 μm, 30x150 mm, 5%-35% in 2.5 min, 35%-55% in 12 min, ACN in water containing 0.1% TFA). The fractions containing the product were lyophilized to give the product 3d (36 mg, 22%) as a white fluffy solid. ESI-MS m / z: 1638.6 [M+H] + .

[0701] 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-tridecahydro-6H-pyrrolo[2,1-f][1]thia[4,7,10,13,16,19,22,25,28,31,34,37,40]tridecahydro-36-dodecane-1-yl)propanoic acid (3-1)

[0702] 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 room temperature for 18 h and then concentrated in vacuo. The crude cyclic peptide was purified by preparative HPLC (SunFire TM C18 preparative column, 5 μm, 30×100 mm, 30 mL / min, 20%-60% in 30 min, ACN in water containing 0.1% TFA) and fractions containing the desired product were lyophilized to afford the title polypeptide 3-1 (27 mg, 76%) as a white solid.

[0703] The following polypeptides in Table 9 were synthesized according to the procedure described in Example 3 for polypeptide (3-1).

[0704] Table 9:

[0705]

[0706] The analytical data of the polypeptides of Examples 3-1 to 3-4 are summarized in Table 10 below, and were generated using the UPLC-MS analytical method described above.

[0707] Table 10:

[0708]

[0709] Example 4: PCSK9 ligand binding assay.

[0710] The PCSK9 binding of the cyclic polypeptides of the present disclosure was measured using a time-resolved fluorescence resonance energy transfer (TR-FRET) assay. The TR-FRET assay measures the ability of the cyclic polypeptides of the present disclosure to interfere with the binding of human PCSK9 to human LDLR, providing potency (IC 50 ) and efficacy (A max )’s measured value.

[0711] Material

[0712] Human PCSK9

[0713] Human PCSK9 Alexa Fluor 647

[0714] Human LDLR extracellular domain-europium pyrophosphate

[0715] Proxi Plate Low Volume Assay Plate (PerkinElmer #6008280)

[0716] Greiner V-bottom (Greiner BioOne #781280)

[0717] Assay buffer

[0718] ο20 mM HEPES, pH 7.5

[0719] ο150 mM NaCl

[0720] ο1mM CaCl2

[0721] ο0.01% v / v Tween20

[0722] ο0.01% w / v BSA

[0723] Prepare a master compound plate in a Greiner V-bottom plate by diluting the cyclic polypeptide of the present disclosure in dimethyl sulfoxide to the correct concentration of the desired maximum concentration based on the desired final concentration: for a final concentration of 30uM, the master plate concentration is 1.5mM (68uL DMSO + 12uL 10mM cyclic polypeptide of the present disclosure); for a final concentration of 10uM, the master plate concentration is 0.5mM (76uL DMSO + 4uL 10mM cyclic polypeptide of the present disclosure); for a final concentration of 3uM, the master plate concentration is 150uM (69uL DMSO + 1uL 10mM cyclic polypeptide of the present disclosure). Pipette these solutions into columns 1 and 11 of the compound plate. Create three-fold serial dilutions in columns 2-10 and 12-20 of the compound plate by transferring 10uL into 20uL DMSO. Columns 21 and 22 of the compound plate are negative controls containing only DMSO.

[0724] An intermediate plate was generated in a Greiner V-bottom plate by transferring 8uL from each well of the master plate to the corresponding well containing 92uL of assay buffer and mixing well.

[0725] The assay was performed using a Proxi plate low volume assay plate. 10uL of 16nM human PCSK9 Alexa Fluor 647 was added to all wells of the plate, followed by 5uL from the intermediate plate. For the positive control wells in columns 23 and 24 of the plate, 5uL of unlabeled human PCSK9 was added at 4uM in assay buffer containing 8% DMSO. After incubation for 30 minutes, 5uL of 4nM human LDLR extracellular domain-europium pyrophosphate was added and the mixture was incubated for another 2 hours.

[0726] TR-FRET signals were measured on an EnVision or PheraStar instrument with 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.

[0727] Data analysis

[0728] In columns 21 and 22 of the compound plate, no inhibition (0%) was observed from wells containing DMSO (control). In columns 23 and 24 of the plate, complete inhibition (100%) was observed from wells containing 1 uM human PCSK9 (control). Data are expressed as percent inhibition: (value - 0%) / (100% - 0%).

[0729] Table 11: PCSK9 activity of cyclic polypeptides of the disclosure in the PCSK9 Fret assay.

[0730]

[0731]

[0732] Equivalent

[0733] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments explicitly described herein. Such equivalents are intended to be encompassed within the scope of the following claims.

Claims

1. A cyclic polypeptide selected from:

2. A pharmaceutical composition comprising a therapeutically effective amount of the cyclic polypeptide according to claim 1 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

3. A combination comprising a polypeptide as claimed in claim 1 or a pharmaceutically acceptable salt thereof, and one or more additional therapeutically active agents.

4. The combination of claim 3, wherein the additional therapeutically active agent is a statin.

5. Use of the polypeptide according to claim 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating, preventing, ameliorating or delaying the progression of a disease or disorder mediated by PCSK9 or for treating, preventing, ameliorating or delaying the progression of a disease or disorder requiring inhibition of PCSK9.

6. The use of a polypeptide as claimed in claim 5, wherein the PCSK9-mediated disease or disorder or the disease or disorder requiring inhibition of PCSK9 is selected from the group consisting 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, and xanthomas.

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