V1a receptor partial agonists and methods of use

Abstract

V1a RECEPTOR PARTIAL AGONISTS AND METHODS OF USE SOLUTION: The present invention provides novel partial V1a agonists for partial activation of V1a receptors. The partial V1a agonists have therapeutic indices of at least 20 (e.g., at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, at least 100). Also provided is a method of treating liver fibrosis, hepatocirrhosis, portal hypertension, peritoneal fluid, esophageal varices, fundic varices, hemorrhage, arterial hypotension, and / or hepatorenal syndrome, comprising administering to a subject in need thereof a therapeutically effective dose of a composition comprising one or more of the disclosed partial V1a agonists, optionally in combination with a V2 antagonist.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Patent Application No. 63 / 053,340, filed July 17, 2020, the disclosure of which is hereby incorporated by reference in its entirety.

[0002] Sequence Listing Description The Sequence Listing accompanying this application is provided in text format in lieu of a paper copy and is hereby incorporated by reference. The name of the text file containing the Sequence Listing is 3097_P27WO_Seq_List_Final.txt. This text file is 18.0 KB; was created on July 16, 2021; and is being submitted via EFS-Web with the application hereof.

[0003] Government license statement This invention was made with federal support under award DK103553 from the National Institutes of Health. The federal government has certain rights in this invention. [Background technology]

[0004] Ascites is a serious complication of liver cirrhosis, occurring in approximately 50% of patients within 10 years of cirrhosis diagnosis and associated with a 50% mortality rate within 2 years. Ascites is the result of portal hypertension due to obstruction of intrahepatic blood flow. This obstruction results in increased nitric oxide, which leads to splanchnic arterial dilation, thereby increasing the inflow blood supply and trapping more blood in the portal venous tract, resulting in portal hypertension. The resulting nitric oxide-induced vasodilation is interpreted by the kidneys as hypovolemia, which responds by conserving salt and water through the renin-angiotensin-aldosterone system (RAAS). The current standard treatment for ascites involves reducing fluid retention by counteracting RAAS activity with diuretics and draining the ascites via paracentesis. However, this treatment does not improve the underlying pathophysiology and is only effective when the disease is in its early stages and peripheral blood volume and total body salt content are still suitable for such treatment. Furthermore, this treatment becomes ineffective when the total salt content and blood volume are reduced to such low levels that the RAAS system becomes overactive and cuts off the arterial blood supply to the kidneys, leading to an increased likelihood of renal failure and hepatorenal syndrome.

[0005] Vasoconstrictors in general, and V1a agonists in particular, appear to have beneficial effects in decompensated cirrhosis without severe renal dysfunction and are considered potential treatments for cirrhotic complications, including ascites. See Krag et al., Hepatology 2007;46:1863-1871. Without wishing to be bound by theory, vasoconstrictors are thought to reverse arterial dilation by vasoconstriction, restoring arterial pressure, reducing splanchnic blood supply, and ultimately reducing portal vein pressure; vasoconstrictors can also increase renal perfusion and filtration pressure, thereby reversing the RAAS response.

[0006] Vasopressin, also known as antidiuretic hormone (ADH), is a hormone that acts on both V1 and V2 receptors and is therefore both a vasoconstrictor and an antidiuretic. Vasopressin is synthesized in the hypothalamus and then transported to the posterior pituitary gland, where it is released into the circulation in response to hypertonicity (hypertonicity) of extracellular fluid. In humans, vasopressin has an arginine residue at amino acid position 8 and is called arginine vasopressin (AVP) or argipressin. In pigs, vasopressin has a lysine residue instead of arginine at amino acid position 8 and is called lysine vasopressin (LVP). Terlipressin is a porcine vasopressin with three additional glycine residues at the N-terminus, called triglycyl[8-lys]vasopressin. Terlipressin is an inactive prodrug of LVP that is rapidly converted to active LVP after administration, resulting in its AVP-like effects. Vasopressin is not protein-bound; it is rapidly metabolized by vasopressinase in the liver and kidney (35%) and ultimately excreted renally (65%). It has a volume of distribution of 140 ml / kg and a plasma half-life of 10–35 minutes. LVP also has a short half-life of 50 minutes. See Keun Suk Park and Kyung Yeon Yoo, Korean J Anesthesiol. 2017 Jun;70(3):245–257 and Jayanta K. Mitra et al., Indian J Crit Care Med. 2011 Apr–Jun;15(2):71–77. Vasopressin's actions extend to V1 (also called V1a, primarily present in blood vessels), V2, V3 (also called V1b, primarily present in the central nervous system (CNS)), and oxytocin-type receptors (OTRs). See Continuing Education in Anaesthesia Critical Care & Pain 2008,8(4):134-137.

[0007] Vasopressin has two primary functions. First, it activates V1 receptors (also called V1a) in smooth muscle, resulting in vasoconstriction and attenuation of nitric oxide (NO) synthesis; this increases peripheral vascular resistance and leads to elevated arterial pressure. Second, activation of V2 receptors in the kidney by vasopressin increases the reabsorption of solute-free water, reversing hypertonicity (i.e., increased excretion of salt relative to water). However, excessive activation of V2 receptors can lead to low blood sodium levels, or hyponatremia. Sima,M.et al.,Prague Medical Report 2016,117(1):68-72;Sola E.et al.,Hepatology 2010 52(5):1783-90;Krag et al.,Hepatology 2011,53(1):367-369;Eriksen,PL,et al.,United European Gastroenterology Journal 2018,(8):1199-1205.

[0008] Because vasopressin can act on three distinct receptors (V1, V2, and V3), changes in the equilibrium of activity at these three receptors can have dramatic physiological effects. Even minor modifications to vasopressin's structure can result in dramatic and unpredictable changes in activity. For example, changing the L-arginine residue of AVP to D-arginine and deaminating the N-terminus provides desmopressin, which has a half-life of 2 hours and a more selective V2 agonist or antidiuretic effect compared with AVP and LVP. Desmopressin is therefore suitable for use in treating polyuria, such as diabetes insipidus, polyuria, and nocturnal enuresis. Counterintuitively, even though modified vasopressin is called antidiuretic hormone, not all of them have a diuretic effect; the diuretic effect depends on the details of the modification to the peptide structure.

[0009] For example, terlipressin has limited V2 or antidiuretic activity (only 3%, see www.medicines.org.uk / emc / product / 2115 / smpc / print), and its V1a blood pressure increasing effect makes it useful in treating bleeding esophageal varices and hepatorenal syndrome. See www.medsafe.govt.nz / profs / datasheet / g / Glypressin01mgmlFerringinj.pdf. However, its use is currently limited to emergency settings due to its short half-life. Furthermore, high bolus doses to compensate for terlipressin's short half-life result in extremely high C max Because terlipressin can cause severe hypertension and ischemia in many organs due to its high peak blood concentration, frequent intravenous (IV) bolus injections are required every 4 to 6 hours to avoid high blood concentrations of terlipressin that could induce ischemia. In addition, subcutaneous administration of terlipressin results in high local concentrations under the skin, which can cause necrosis at the injection site in addition to skin necrosis elsewhere in the body with sustained high-dose administration. Thus, although terlipressin has been available in Europe for the past 20 years, there are still many developments that have required improvements in its pharmacokinetic properties and an extended half-life (but not in the C form, which does not cause ischemia). max Attempts to increase V2 receptor activity have failed, often resulting in a loss of receptor specificity, and in some cases, antagonists or inhibitors of targeted and non-targeted receptors have been proposed instead. Rihakova, L. et al., VRQ397 (CRAVKY): a novel noncompetitive V2 receptor antagonist. Am J Physiol Regul Integr Comp Physiol, 2009. 297(4): p. R1009-18; Gupta, J. et al., Oxytocin-induced contractions within rat and rabbit ejaculatory tissues are mediated by vasopressin V1a receptors and not oxytocin receptors. Br J Pharmacol, 2008. 155(1): p. 118 - 26; Chan, W. Y. et al., Discovery and design of novel and selective vasopressin and oxytocin agonists and antagonists: the role of bioassays. Exp Physiol, 2000. 85 Spec No: p. 7S - 18S; Yea, C. M. et al., New benzylureas as a novel series of potent, nonpeptidic vasopressin V2 receptor agonists. J Med Chem, 2008. 51(24): p. 8124 - 34; Saito, M., A. Tahara, and T. Sugimoto, 1 - desamino - 8 - D - arginine vasopressin (DDAVP) as an agonist on V1b vasopressin receptor. Biochem Pharmacol, 1997. 53(11): p. 1711 - 7; Yazawa, H. et al., Oxytocin receptors expressed and coupled to Ca2+ signaling in a human vascular smooth muscle cell line. Br J Pharmacol, 1996. 117(5): p. 799 - 804; Tsukamoto, I., Recent patenting activities in the discovery and development of vasopressin V2 receptor agonists. Expert Opin Ther Pat, 2012. 22(6): p. 579 - 86; and Wisniewski, K., et al., Discovery of Potent, Selective, and Short - Acting Peptidic V2 Receptor Agonists. J Med Chem, 2019. 62(10): p. 4991 - 5005. See also

[0010] A V2 inhibitor (tolvaptan) that acts as an aquaretic (i.e., a diuretic without natriuresis) has been approved for the treatment of hypervolemic and euvolemic hyponatremia (i.e., hyponatremia characterized by a serum sodium of 125 mEq / L or less), including in patients with heart failure and the syndrome of inappropriate antidiuretic hormone (SIADH). Tolvaptan is a hepatotoxic drug and is therefore contraindicated in patients with cirrhosis, hepatonephropathy, and portal hypertension-related ascites. See the drug warning label for tolvaptan, available at www.accessdata.fda.gov / drugsatfda_docs / label / 2018 / 204441lbl.pdf. Therefore, any innovation that would improve the efficacy of this medication while reducing its dosage to avoid hepatotoxicity would significantly contribute to the long-felt need for improved treatment of patients with ascites and varices caused by cirrhosis, hepatonephropathy, and portal hypertension. Summary of the Invention [Problem to be solved by the invention]

[0011] There is a need for a V1a receptor agonist that avoids or minimizes the drawbacks or limitations of terlipressin. This V1a receptor agonist would target common vascular hydrodynamic imbalances, such as those seen in cirrhosis, portal hypertension, hemorrhage, ascites, sepsis, and hepatorenal syndrome. This therapeutic agent could be: 1) a V1a agonist that can be administered repeatedly subcutaneously without causing injection site necrosis; 2) a V1a agonist that has limited activity even at high doses, such as by not activating the receptor to its full potential, thereby limiting organ ischemia side effects (and thus providing a very high therapeutic index) (i.e., a V1a partial agonist); and / or 3) a V1a agonist that lacks significant V2 activity or antidiuretic activity in vivo. The present disclosure seeks to meet these needs and provides additional advantages. [Means for solving the problem]

[0012] This Summary is provided to introduce a selection of concepts in a simplified form that are further described below in the Detailed Description. This Summary is not intended to identify key features of the claimed subject matter, nor is it intended to be used as an aid in determining the scope of the claimed subject matter.

[0013] In one aspect, the present disclosure provides a V1a partial agonist peptide of formula (A): [Mpa-Tyr-Phe-Z-Asn-Cys-Pro-B(X) a -Gly-NH2][SEQ ID NOs: 1-2] (A) or a pharmaceutically effective salt thereof, (In the formula: The Mpa and Cys residues are covalently linked by a disulfide bond, Z is Hgn or Gln; Where Z is Hgn [SEQ ID NO: 1]: B is any one of L-Lys, D-Lys, L-Orn, D-Orn, L-Dab, D-Dab, L-Dap, or D-Dap; and X is an amino acid residue, where each occurrence of the amino acid residue is independently selected from Gly, L-Ala, D-Ala, L-Lys, D-Lys, L-Orn, D-Orn, L-Glu, D-Glu, L-Asp, and D-Asp, and a is an integer from 0 to 10 (e.g., 0 to 1, 1 to 2, 1 to 3, 1 to 10, 1 to 6, 4 to 10, or 6 to 10); or X is a non-α primary amino group-containing C 3~12 Fatty acids (e.g., C 3~6 , C 3~10 , C 4~12 , C 4~6 , C 4~10 , C 6~10 , C 8~10 , or C 10~12 a moiety derived from a fatty acid, and a is an integer of 1 to 3; Where Z is Gln [SEQ ID NO: 2]: B is any one of L-Lys, D-Lys, L-Orn, D-Orn, L-Dab, D-Dab, L-Dap, or D-Dap; and X is an amino acid residue, wherein each occurrence of the amino acid residue is independently selected from Gly, L-Ala, D-Ala, L-Lys, D-Lys, L-Orn, D-Orn, L-Glu, D-Glu, L-Asp, and D-Asp, and a is an integer from 6 to 10; or X is a non-α primary amino group-containing C 3~12 Fatty acids (e.g., C 3~6 , C 3~10 , C 4~12 , C 4~6 , C 4~10 , C 6~10 , C 8~10 , or C 10~12 a is a moiety derived from a fatty acid, and a is an integer of 1 to 3 A composition comprising: Compositions are characterized as having a therapeutic index of at least 20 (e.g., at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100).

[0014] In another aspect, the disclosure features a method of treating a subject, the method including administering to a subject in need thereof a therapeutically effective dose of a pharmaceutical composition of Formula (A), optionally in combination with a V2 antagonist, the pharmaceutical composition being administered before or after administration of a therapeutically effective dose of the V2 antagonist, preferably within 1 to 8 hours, preferably 1 to 3 hours, before administration of the therapeutically effective dose of the V2 antagonist.

[0015] In another aspect, the present disclosure provides a method of treating a subject comprising administering to a subject in need thereof a therapeutically effective dose of a pharmaceutical composition comprising a peptide of formula (B), administered before or after administration of a therapeutically effective dose of a V2 antagonist, preferably within 1 to 8 hours, preferably 1 to 3 hours after administration of a therapeutically effective dose of a V2 antagonist, wherein the peptide of formula (B) is V1a agonist peptide of formula (B) [X'-Tyr-Phe-Gln-Asn-Cys-Pro-Lys(Z) d -Gly-NH2][SEQ ID NOs: 3-4] (B) or a pharmaceutically acceptable salt thereof, (In the formula: X' is (U) c -Cys or Mpa, Here, X' is (U) c -Cys [SEQ ID NO: 3], The two Cys residues are covalently linked by a disulfide bond; U is an amino acid residue, each occurrence independently selected from Gly, L-Ala, D-Ala, L-Lys, D-Lys, L-Orn, D-Orn, L-Glu, D-Glu, L-Asp, and D-Asp; and c is an integer from 0 to 10; Z is absent; and d is the number of Z and is 0; and where X' is Mpa [SEQ ID NO: 4] The Mpa and Cys residues are covalently linked by a disulfide bond, Z is an amino acid residue, each occurrence independently selected from Gly, D-Ala, L-Ala, D-Lys, L-Lys, D-Orn, L-Orn, D-Glu, L-Glu, D-Asp, and L-Asp; and and d is an integer of 0 to 5.

[0016] In some embodiments, the subject has a condition selected from hepatic fibrosis, cirrhosis, portal hypertension, ascites, esophageal varices, gastric fundal varices, bleeding, arterial hypotension, hepatorenal syndrome, and any combination thereof; or wherein the subject has hepatic fibrosis; or wherein the subject has cirrhosis; or wherein the subject has portal hypertension; or wherein the subject has esophageal varices; or wherein the subject has gastric fundal varices; or wherein the subject has bleeding varices; or wherein the subject has arterial hypotension; or wherein the subject has hepatorenal syndrome.

[0017] DESCRIPTION OF THE DRAWINGS The foregoing aspects and many of the attendant advantages of this invention will become more readily appreciated as the same becomes better understood by reference to the following detailed description when considered in conjunction with the accompanying drawings.

[0018] The foregoing aspects and many of the attendant advantages of the present disclosure will become more readily appreciated as the same becomes better understood by reference to the following detailed description, when considered in conjunction with the accompanying drawings. [Brief explanation of the drawings]

[0019] [Figure 1] 1 is an illustration of the stages of liver fibrosis and cirrhosis. [Figure 2] 1 is a graph showing the results of EC50 determination of the peptide of formula (I) [Mpa-Tyr-Phe-Hgn-Asn-Cys-Pro-Lys(X)a-Gly [SEQ ID NO: 5]; disulfide bond between Mpa and Cys] at the V1a receptor. The peptide of formula (I) (wherein "(X)a" has X = Lys and a = 0, 3, 6, or 9) has an EC50 of 5.2, 53.5, 45.9, or 104.8 nM at the V1a receptor (n=2). This is a partial V1a agonist, with the highest agonist effect of 42.8, 32.9, 28.2, or 28.1% compared to the 100% control, arginine vasopressin (AVP) (n=2). [Figure 3] 1 is a graph showing the EC50 of peptide of formula (II) [Mpa-Tyr-Phe-Gln-Asn-Cys-Pro-Lys(X)a-Gly [SEQ ID NO: 6]; disulfide bond between Mpa and Cys] at the V1a receptor. The peptide of formula (II) (wherein "(X)a" has X = Gly and a = 6 or 9) has an EC50 of 27.3 nM or 12.6 nM at the V1a receptor (n = 2). It is a partial V1a agonist, with a maximum agonist effect of 60.9% or 55.9% compared to the 100% control, arginine vasopressin (AVP) (n = 2). DETAILED DESCRIPTION OF THE INVENTION

[0020] The present disclosure provides a V1a partial agonist peptide of formula (A): [Mpa-Tyr-Phe-Z-Asn-Cys-Pro-B(X) a -Gly-NH2][SEQ ID NOs: 1-2] (A) or a pharmaceutically effective salt thereof, (In the formula: The Mpa and Cys residues are covalently linked by a disulfide bond, Z is Hgn or Gln; Where Z is Hgn [SEQ ID NO: 1]: B is any one of L-Lys, D-Lys, L-Orn, D-Orn, L-Dab, D-Dab, L-Dap, or D-Dap; and X is an amino acid residue, where each occurrence of the amino acid residue is independently selected from Gly, L-Ala, D-Ala, L-Lys, D-Lys, L-Orn, D-Orn, L-Glu, D-Glu, L-Asp, and D-Asp, and a is the number of X and is an integer from 0 to 10 (e.g., 0 to 1, 1 to 2, 1 to 3, 1 to 10, 1 to 6, 4 to 10, or 6 to 10); or X, at each occurrence, is a non-alpha primary amino group-containing C 3~12 Fatty acids (e.g., C 3~6 , C 3~10 , C 4~12 , C 4~6 , C 4~10 , C 6~10 , C 8~10 , or C 10~12 a is the number of X's and is an integer of 1 to 3; Where Z is Gln [SEQ ID NO: 2]: B is any one of L-Lys, D-Lys, L-Orn, D-Orn, L-Dab, D-Dab, L-Dap, or D-Dap; and X is an amino acid residue, where each occurrence of the amino acid residue is independently selected from Gly, L-Ala, D-Ala, L-Lys, D-Lys, L-Orn, D-Orn, L-Glu, D-Glu, L-Asp, and D-Asp, and a is the number of X and is an integer from 6 to 10; or X, at each occurrence, is a non-alpha primary amino group-containing C 3~12 Fatty acids (e.g., C 3~6 , C 3~10 , C 4~12 , C 4~6 , C 4~10 , C 6~10 , C 8~10 , or C 10~12 a is the number of X's, which is an integer of 1 to 3. A composition comprising: Compositions are described that have a therapeutic index of at least 20 (eg, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100).

[0021] A V2 antagonist can be administered before or after administration of one or more V1a partial agonist peptides of the present disclosure, preferably within 1 to 8 hours, preferably 1 to 3 hours, before administration of one or more V1a partial agonist peptides.

[0022] In some embodiments, the present disclosure provides a method of treating a subject comprising administering to a subject in need thereof a therapeutically effective dose of a pharmaceutical composition of (i) or (ii), administered before or after administration of a therapeutically effective dose of a V2 antagonist, preferably within 1 to 8 hours, preferably 1 to 3 hours after administration of a therapeutically effective dose of a V2 antagonist, wherein (i) and (ii) are as defined below: (i) a therapeutically effective dose of a pharmaceutical composition comprising a V1a agonist peptide of formula (III) [(U) c -Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Lys-Gly-NH2] [SEQ ID NO: 7] (III) or a pharmaceutically effective salt thereof, (In the formula: The two Cys residues are covalently linked by a disulfide bond, U is an amino acid residue, each occurrence independently selected from Gly, L-Ala, D-Ala, L-Lys, D-Lys, L-Orn, D-Orn, L-Glu, D-Glu, L-Asp, and D-Asp; and c is the number of U and is an integer from 0 to 10; (ii) a therapeutically effective dose of a pharmaceutical composition comprising a V1a agonist peptide of formula (IV): [Mpa-Tyr-Phe-Gln-Asn-Cys-Pro-Lys(Z) d -Gly-NH2][SEQ ID NO: 4] (IV) or a pharmaceutically effective salt thereof, (In the formula: The Mpa and Cys residues are covalently linked by a disulfide bond, Z is an amino acid residue, each occurrence independently selected from Gly, D-Ala, L-Ala, D-Lys, L-Lys, D-Orn, L-Orn, D-Glu, L-Glu, D-Asp, and L-Asp; and d is the number of Z and is an integer from 0 to 5; the subject has a condition selected from hepatic fibrosis, cirrhosis, portal hypertension, ascites, esophageal varices, gastric fundal varices, hemorrhage, arterial hypotension, hepatorenal syndrome, and any combination thereof; or The subject has liver fibrosis; or The subject has cirrhosis; or The subject has portal hypertension; or The subject has esophageal varices; or The subject has gastric fundus varices; or The subject has bleeding varices; or The subject has arterial hypotension; or The method is characterized in that the subject has hepatorenal syndrome.

[0023] definition At various places in the present specification, substituents of compounds of the present disclosure are disclosed in groups or in ranges. Specifically, the present disclosure is intended to include any and all individual subcombinations of the members of such groups and ranges. For example, the term "C 1~6 "Alkyl" is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0024] As used herein, the term "polymer" refers to a macromolecule formed primarily or entirely of many similar repeating units covalently linked together. The term polymer includes cellulose derivatives, poly(ethylene glycol) (PEG), methoxypoly(ethylene glycol) (MPEG), poly(lactic-co-glycolic acid), and poly(N-vinylpyrrolidone) and its derivatives. These polymers may be branched or linear. As used herein, a polymer can be attached to a peptide, protein, or linker group by an amide, ester, ether, thioether, thioester, or carbamate bond, or by a linker bearing one of these bonds. Polymers can also be grafted to each other to create protected graft copolymer excipients, which, when mixed with an active pharmaceutical ingredient, can enhance the pharmacokinetic and pharmacodynamic performance of the active pharmaceutical ingredient by prolonging its presence in the blood or plasma after in vivo administration.

[0025] The term "amino acid," as used herein, refers to an organic compound with a molecular weight of less than 500 Da, containing amino (-NH) and carboxyl (-COOH) functional groups, along with a side chain (R group) specific to each amino acid. The primary elements of amino acids are carbon (C), hydrogen (H), oxygen (O), and nitrogen (N), although other elements are also found in the side chains of certain amino acids. As of 1983, approximately 500 naturally occurring amino acids were known (although only 20 appear in the mammalian genetic code; these 20 amino acids are also referred to herein as "natural amino acids"). An amino acid may be an alpha amino acid, in which the amino group is directly attached to the alpha carbon. An amino acid may be a non-alpha amino acid, in which the primary amino group is linked to a carbon other than the alpha position. The alpha carbon is the carbon immediately adjacent to the carboxyl group. Amino acids can form the building blocks of proteins and can have chiral carbons, such that amino acids can be D or L optical isomers.

[0026] Three-letter codes are used herein for amino acids and / or peptide residues, with the exception of non-alpha primary amino group-containing fatty acid moieties, as described below: alanine is Ala, arginine is Arg, asparagine is Asn, aspartic acid is Asp, cysteine ​​is Cys, diaminobutyric acid is Dab, diaminopimelic acid is Dap, glutamic acid is Glu, glutamine is Gln, glycine is Gly, histidine is His, homoglutamine is Hgn, isoleucine is Ile, leucine is Leu, lysine is Lys, mercaptopropionic acid is Mpa, methionine is Met, ornithine is Orn, phenylalanine is Phe, proline is Pro, serine is Ser, threonine is Thr, tryptophan is Trp, tyrosine is Tyr, and valine is Val. As used herein, the amino acid designations refer to L-amino acids unless otherwise indicated by a "D-" preceding the designation (e.g., D-Arg, etc.).

[0027] When single letter amino acids are used herein, alanine is A, arginine is R, asparagine is N, aspartic acid is D, cysteine ​​is C, glutamic acid is E, glutamine is Q, homoglutamine is homoQ, glycine is G, histidine is H, isoleucine is I, leucine is L, lysine is K, methionine is M, phenylalanine is F, proline is P, serine is S, threonine is T, tryptophan is W, tyrosine is Y, and valine is V. For purposes of this application, the single letter amino acid designations include L and / or D amino acid stereoisomers.

[0028] It is understood that when amino acids combine to form a peptide, the amino acids are referred to as amino acid residues with the water element removed. Furthermore, when this disclosure refers to an amino acid in a peptide sequence, it is understood to be an amino acid residue.

[0029] As used herein, the term "residue" refers to the divalent moiety obtained upon removal of the hydrogen from the alpha amino group and the hydroxyl group from the carboxyl group of an alpha-amino acid.

[0030] The term "derivative" or "analog," as used herein, includes a compound whose core structure is the same as or closely resembles that of the parent compound but has chemical or physical modifications, such as different or additional groups; the term includes copolymers of the parent compound, which may be linked to other atoms or molecules. The term also includes peptides or proteins having at least 80% (e.g., at least 85%, at least 90%, at least 95%, or at least 98%) sequence identity with the parent peptide or protein. The term also includes peptides that have additional groups attached thereto, such as additional labels or tags, compared to the parent peptide. The term also includes polymers that have additional groups attached thereto, such as alkoxy or methoxy groups, compared to the parent polymer.

[0031] As used herein, "addition derivative" or "extension derivative" refers to a peptide derivative in which the backbone amino acid sequence of the peptide remains the same, but the addition of extra functional groups and / or amino acid residues to the backbone amino acid sequence using one or more reactive moieties present in the backbone amino acid sequence results in the addition or extension derivative. Addition or extension derivatives are distinct from truncation and / or substitution peptide derivatives in which one or more amino acid residues in the backbone amino acid sequence of the peptide are removed and / or replaced with different functional groups and / or amino acids, respectively.

[0032] As used herein, the term "fatty acid" refers to a molecule having a carboxyl group covalently attached to an alkyl chain, and fatty acids have 3 to 16 carbon units or more. In some embodiments, fatty acids have a C 3~12 Carbon units (e.g., C 3~6 , C 3~10 , C 4~12 , C 4~6 , C 4~10 , C 6~10 , C 8~10 , or C 10~12 The fatty acids may be functionalized with a non-alpha primary amino group, and the functionalized fatty acid may be obtained from a fatty acid or a carboxylamine. The fatty acids may be saturated or unsaturated. Examples of fatty acids include caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, and / or lignoceric acid.

[0033] As used herein, a "non-alpha primary amino group-containing fatty acid" is a fatty acid that contains a primary amino group attached to a carbon atom that is not alpha to a carboxyl group, and the amino group is not acylated. For example, β-aminopropanoic acid (propionic acid) is a non-α-primary amino group-containing fatty acid having 3 carbon units, 4-aminobutanoic acid (butyric acid) is a non-α-primary amino group-containing fatty acid having 4 carbon units, 5-aminopentanoic acid (valeric acid) is a non-α-primary amino group-containing fatty acid having 5 carbon units, 6-aminohexanoic acid (caproic acid) is a non-α-primary amino group-containing fatty acid having 6 carbon units, 7-aminoheptanoic acid (enanthic acid) is a non-α-primary amino group-containing fatty acid having 7 carbon units, 8-aminooctanoic acid (caprylic acid) is a non-α-primary amino group-containing fatty acid having 8 carbon units, 9-aminononanoic acid (pelargonic acid) is a non-α-primary amino group-containing fatty acid having 9 carbon units, and 10-aminodecanoic acid ( capric acid) is a non-alpha primary amino group-containing fatty acid having 10 carbon units, 11-aminoundecanoic acid (undecylic acid) is a non-alpha primary amino group-containing fatty acid having 11 carbon units, 12-aminododecanoic acid (lauric acid) is a non-alpha primary amino group-containing fatty acid having 12 carbon units, 13-aminotridecanoic acid (tridecylic acid) is a non-alpha primary amino group-containing fatty acid having 13 carbon units, 14-aminotetradecanoic acid (myristic acid) is a non-alpha primary amino group-containing fatty acid having 14 carbon units, 15-aminopentadecanoic acid (pentadecylic acid) is a non-alpha primary amino group-containing fatty acid having 15 carbon units, and 16-aminopalmitic acid is a non-alpha primary amino group-containing fatty acid having 16 carbon units, etc. The non-alpha primary amino fatty acid may be covalently attached to the peptide sequence through a carboxyl group at its N-terminus or through an amino group at its C-terminus. When the non-alpha primary amino fatty acid residue is covalently attached to a peptide sequence or to another molecule, it is referred to as a "moiety derived from a non-alpha primary amino fatty acid."

[0034] As used herein, the term "fatty acid ester" refers to a long aliphatic chain (saturated or unsaturated) with a -C(=O)O- moiety at the end of the chain.

[0035] As used herein, the term "fatty acid amide" refers to a long aliphatic chain (saturated or unsaturated) with a -C(=O)NR- moiety at the end of the chain.

[0036] As used herein, the term "alkyl" refers to a straight-chain (e.g., linear) or branched saturated hydrocarbon group. Exemplary alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like. The alkyl group can contain 1 to about 30, 1 to about 24, 2 to about 24, 1 to about 20, 2 to about 20, 1 to about 10, 1 to about 8, 1 to about 6, 1 to about 4, or 1 to about 3 carbon atoms.

[0037] As used herein, the term "fibrosis" or "liver fibrosis" refers to scarring of the liver, and the term "liver cirrhosis" refers to widespread scarring or fibrosis of the liver in which multiple lobules are surrounded by fibrous collagen scar tissue due to the integrated bridging of several portal and central areas. Referring to Figure 1, liver fibrosis in chronic hepatitis is graded on a 5-point scale (0-4) according to the METAVIR scoring system (1994). According to this score, F0 corresponds to no fibrosis; F1 (mild fibrosis), with fibrotic expansion of portal tracts but no septa; F2 (moderate fibrosis), where fibrous septa are extensive and occasionally form bridges between adjacent vascular structures, including portal tract to portal tract and / or portal tract to central tract; F3 (severe fibrosis), with numerous bridges or septa but no cirrhosis (thickened collagen scars bridging portal and central tracts); and F4 (cirrhosis), where the tissue has nodules completely surrounded by fibrosis (e.g., numerous lobules become nodular surrounded by fibrous collagen scarring). See, Lipid Peroxidation in Hepatic Fibrosis, Ichiro Shimizu et al., Lipid Peroxidation in Hepatic Fibrosis, Published August 29, 2012; DOI: 10.5772 / 46180, www.intechopen.com / books / lipid-peroxidation / lipid-peroxidation-in-hepatic-fibrosis (incorporated herein by reference in its entirety). Without wishing to be bound by theory, cirrhosis of the liver is thought to be caused by many factors, including chronic heavy alcohol consumption, chronic hepatitis B or C, hepatic fat accumulation, iron accumulation, cystic fibrosis, copper accumulation, bile duct hypoplasia, autoimmune liver disease, bile duct injury, liver infection, and / or the use of certain medications, such as methotrexate.

[0038] As used herein, the term "compensated cirrhosis" refers to cirrhosis in which the liver is still functioning properly, without clinical symptoms such as varices and / or ascites.

[0039] As used herein, the term "decompensated cirrhosis" refers to an advanced stage of cirrhosis, when liver scarring becomes so severe that the liver cannot function properly. Clinically, this is characterized by one or more of the following: ascites, varicose veins with or without bleeding, jaundice, fatigue, weight loss, easy bleeding and bruising, ascites, leg swelling, confusion, slurred speech, drowsiness, hepatic encephalopathy, nausea and loss of appetite, spider veins, redness of the palms, testicular atrophy in men, and breast development. Serum bilirubin, creatinine, and the international normalized ratio (INR) of prothrombin time are used to model end-stage liver disease (MELD) scores, which range from 6 to 40 and are the most commonly used diagnostic tool for advanced liver disease. MELD score = 3.78 × ln[serum bilirubin (mg / dL)] + 11.2 × ln[INR] + 9.57 × ln[serum creatinine (mg / dL)] + 6.43.

[0040] As used herein, the term "mean arterial pressure" or "MAP" refers to one-third of the difference between the systolic blood pressure (SBP) and the diastolic blood pressure (DBP) + DBP (i.e., MAP = 1 / 3 (SBP - DBP) + DBP).

[0041] As used herein, the term "hypotension" refers to low blood pressure, e.g., when the pressure of blood pushing against the walls of arteries is low, or when the systolic pressure is less than 90 mmHg and / or the diastolic pressure is less than 60 mmHg. Hypotension can be caused by the relaxation of smooth muscles surrounding blood vessels, increasing the diameter of the blood vessels.

[0042] As used herein, the term "portal vein" refers to a blood vessel that carries blood from the esophagus, stomach, spleen, pancreas, small intestine, and / or colon to the liver.

[0043] As used herein, the term "portal hypertension" or "portal hypertension" refers to high portal vein pressure, for example, when blood pressure increases against the walls of the portal vein due to resistance or blockage of blood flow through the liver (e.g., blockage may be due to cirrhosis). Portal hypertension or portal hypertension can occur simultaneously with a decrease in mean arterial pressure or MAP. Portal hypertension can be characterized by a hepatic venous pressure gradient (HVPG) greater than 5 mmHg (e.g., greater than 7 mmHg, greater than 10 mmHg, or greater than 15 mmHg). Clinically significant portal hypertension (CSPH) is defined as an HVPG of 10 mmHg or greater.

[0044] As used herein, the term "hepatic venous pressure gradient" or HVPG corresponds to the clinical measurement of the pressure gradient between obstructed hepatic venous pressure (WHVP) and open hepatic venous pressure (FHVP), which is an estimate of the pressure gradient between the portal vein and the inferior vena cava. HVPG is determined by inserting an inflatable catheter into a hepatic vein (through the antecubital, femoral, or right jugular vein) and measuring the pressure before inflation (this is the FHVP). WHVP is measured by inflating a balloon catheter in the right hepatic vein to occlude flow and then measuring the proximal resting blood pressure (which reflects the pressure in the sinusoids). HVPG is then determined by subtracting FHVP from WHVP (i.e., HVPG = WHVP - FHVP). WHVP actually slightly underestimates portal vein pressure due to sinusoidal equilibration in patients without cirrhosis, but the difference between these two is clinically negligible. In patients with cirrhotic livers, sinusoidal pressure equilibrium cannot be maintained due to the disruption of intersinusoidal communication; therefore, WHVP is a much more accurate measurement of portal venous pressure catheters and has become the standard method for estimating portal venous pressure. A HVPG of 5 mmHg or greater is defined as portal hypertension, and a measurement greater than 10 mmHg is called clinically significant portal hypertension. Above 12 mmHg, variceal bleeding can occur at any time, potentially leading to a life-threatening emergency.

[0045] As used herein, the term "ascites" refers to an abnormal accumulation of fluid in the abdomen (e.g., 25 ml or more), often caused by cirrhosis of the liver. Fluid is an ideal medium for bacterial growth, leading to spontaneous bacterial peritonitis.

[0046] As used herein, the term "refractory ascites" refers to ascites that does not subside despite salt restriction and diuretic therapy, or that recurs shortly after therapeutic paracentesis. To date, there are no medical therapies approved specifically for refractory ascites. As used herein, the term "paracentesis" refers to the removal of fluid (or gas) from the body's (peritoneal) cavity by puncturing it with a hollow needle.

[0047] As used herein, the term "varices" refers to enlarged, swollen, or dilated blood vessels caused by portal hypertension, which can be life-threatening when present in the esophagus or stomach fundus. Varices do not cause symptoms, but if they rupture and bleed, it represents a life-threatening event and requires emergency medical attention. As used herein, "esophageal varices" refers to abnormally enlarged veins in the esophagus that occur when normal venous blood flow to the liver is blocked by a blood clot or cirrhosis. Such varices can become life-threatening if they rupture open and bleed. The esophagus is the tube connecting the pharynx to the stomach. When enlarged veins occur in the lining of the esophagus, they are called esophageal varices.

[0048] As used herein, the term "gastric varices" refers to the dilation of the submucosal veins of the stomach, which can be a life-threatening source of bleeding in the upper gastrointestinal tract. This is most commonly seen in patients with portal hypertension, i.e., elevated pressure in the portal venous system, which can be a complication of liver cirrhosis. As used herein, the term "gastric fundus varices" refers to gastric varices located at the base of the stomach.

[0049] As used herein, the term "hepatorenal syndrome" or "HRS" refers to a type of progressive kidney failure seen in people with severe liver damage, most often caused by cirrhosis. This is an extremely serious and almost always fatal condition. As the kidneys stop functioning, toxins begin to accumulate in the body. This ultimately leads to liver failure. There are two forms of HRS: Type 1 HRS (median survival of 2 weeks, 100% mortality within 8-10 weeks without liver transplant) is associated with rapid kidney failure and creatinine accumulation; Type 2 HRS (median survival of 6 months) is associated with more gradual kidney damage. Type 2 HRS generally progresses more slowly. Symptoms are generally subtle and are accompanied by portal hypertension and the development or onset of ascites. Type 2 HRS is treated with diuretics and salt restriction, but these patients eventually develop diuretic-resistant ascites, in which the kidneys are unable to excrete enough sodium for fluid clearance, even with diuretic medication. Most patients with type 2 HRS have diuretic-resistant ascites before developing renal function decline.

[0050] As used herein, the term "V1a partial agonist" refers to a therapeutic agent (e.g., a peptide) that binds to the V1a receptor but is only partially effective at that receptor compared to a full agonist. For purposes of this disclosure, arginine vasopressin is a full agonist and is known as such in the art. Partial agonists exhibit both agonist and antagonist effects; in the presence of a full agonist, the partial agonist acts as an antagonist, competing with the full agonist for the same receptor and thus reducing the full agonist's ability to produce its full effect. V1a partial agonists cause partial vasoconstriction by acting on the smooth muscle intima of peripheral arterial vessels, resulting in an increase in blood pressure. Partial vasoconstriction minimizes the risk of ischemia while increasing blood pressure; partial vasoconstriction also reduces blood supply to visceral regions, which contributes to portal hypertension in addition to liver cirrhosis. In vivo, high doses of full agonists increase the risk of complete vascular occlusion, resulting in decreased tissue oxygenation or tissue ischemia. Partial agonism can be demonstrated by measuring the maximal activity (e.g., calcium influx) of a saturating concentration of the test agonist in cell culture and comparing it to the maximal activity of arginine vasopressin under the same conditions. To ensure that a saturating concentration is reached during measurement, multiple concentrations of the test agonist are used until saturation is demonstrated (as evidenced by an approximately sigmoidal saturation curve). Saturating concentrations of full agonists can be performed in parallel and / or in a similar manner. Full agonists may have a reference 100% signal at saturation, while partial agonists have a signal less than 100% at saturation (e.g., 80%, 60%, 50%, 40%, 20%, or 10%). This determination also provides the effective concentration at 50% saturation, i.e., the EC50, the concentration required for half-maximal receptor binding. This procedure is well known in the art and is described in several examples herein.

[0051] As used herein, the term "therapeutic index" (TI; also referred to as therapeutic ratio) is a quantitative measure of the relative safety of a drug. For purposes of this disclosure, TI is a ratio in which the numerator is the highest dose that does not cause lethargy or adverse effects compared to a control (the no-observed-adverse-effect level, or NOAEL); and the denominator is the highest dose that does not cause observable peripheral vasoconstriction compared to an untreated control (the no-observed-effect level, or NOEL) (i.e., TI is the ratio NOAEL / NOEL). For purposes of this application, lethargy is a lack of energy and / or drowsiness visually observed as immobility, such as lack of movement in rats in the presence of human activity. For purposes of this specification, peripheral vasoconstriction is visually observed by paleness of the extremities (e.g., the skin of the hands, feet, ears, and lips). In rats, peripheral vasoconstriction is determined by a side-by-side comparison of ear pallor between treated subjects (e.g., Sprague-Dawley rats, albino rats with easily visible redness / pallor changes) and untreated control subjects. V1a agonists (or partial agonists) with a high therapeutic index have a better safety profile than those with a low therapeutic index by providing a wider margin of safety during disease treatment. This NOAEL / NOEL ratio, a quantitative measure of relative safety, compares the amount of a therapeutic agent that produces a therapeutic effect (a beneficial effect, for purposes of this specification, vasoconstriction) with the amount that causes toxicity. V1a agonists that produce severe vasoconstriction will affect not only peripheral blood vessels with several layers of smooth muscle, but also other blood vessels in other organs (e.g., the heart, lungs, kidneys, and brain), resulting in lethargy and ultimately ataxia. Partial agonists are less likely to produce such extreme levels of vasoconstriction and are therefore considered to have a higher therapeutic index.

[0052] As used herein, the term "V2 antagonist" refers to a therapeutic agent that binds to and inhibits the function of the V2 receptor. Because V2 receptor inhibition increases the production of low-salt urine, V2 antagonists are also called aquaretics. One example of a V2 antagonist is tolvaptan, which competitively and selectively binds to the V2 receptor without activating it, thereby reducing the likelihood that natural V2 receptor agonists will bind to and activate the receptor, thereby causing water reabsorption from the glomerular filtrate into the blood. Therefore, V2 antagonists cause a decrease in the water content of the blood and, therefore, blood volume.

[0053] As used herein, the terms "individual," "subject," or "patient" are used interchangeably and refer to any animal, including a mammal, preferably a mouse, rat, other rodent, rabbit, dog, cat, pig, cow, sheep, horse, or primate, and most preferably a human.

[0054] As used herein, the phrases "therapeutically effective amount" or "therapeutically effective dose" are used interchangeably and refer to the following: (1) Preventing disease; e.g., preventing a disease, condition, or disorder in an individual who may be predisposed to the disease, condition, or disorder but who has not yet shown or exhibited lesions or symptoms of the disease; (2) inhibiting a disease; e.g., inhibiting a disease, condition, or disorder in an individual exhibiting or displaying a lesion or symptom of the disease, condition, or disorder; and (3) Ameliorating a disease; e.g., reducing the severity of the disease, extending survival, or preventing death, to ameliorate a disease, condition, or disorder in an individual who exhibits or displays the lesions or symptoms of the disease, condition, or disorder (i.e., reversing the lesions and / or symptoms). "Amount of therapeutic agent (i.e., drug, or therapeutic agent composition) that elicits the biological or medical response sought by a researcher, veterinarian, physician, or other clinician in a tissue, system, animal, individual, or human, including one or more of:

[0055] As used herein, the term "treatment" refers to procedures performed after diagnosis of a condition.

[0056] As used herein, the term "mitigation" refers to a procedure undertaken to prevent anticipated injury or illness or to reduce the likelihood of it occurring.

[0057] As used herein, the term "healthy subject" refers to an individual (human and / or mammalian animal) who is a participant in a research study and who has no significant health-related problems.

[0058] As used herein, "bolus," "bolus dose," or "bolus administration" refers to a single dose of a drug or other substance given or administered within a short period of time, e.g., in less than 10 minutes (e.g., less than 8 minutes, less than 5 minutes, less than 3 minutes, or less than 1 minute). Administration includes one of the following: injection at any site in the body (including, but not limited to, intravenous, subcutaneous, intrathecal, or intradermal); enteral (e.g., orally, as a dosage form); inhalation (e.g., by intratracheal inhalation administration, where the subject is exposed to high aerosol concentrations, resulting in direct deposition of the active pharmaceutical ingredient in the lower respiratory tract); or intranasal (e.g., as an aerosol, liquid, or powder). For purposes of this disclosure, bolus administration is distinguished from infusion administration, which typically takes 30 minutes or more to complete.

[0059] As used herein, "administration," also referred to as "route of administration," refers to the location in the body where a pharmacological agent is given or applied to a subject. Examples: enteral / gastrointestinal, which refers to delivery through the gastrointestinal tract, including the entire digestive system from the mouth to the rectum, including oral, rectal, sublingual, and buccal. Parenteral, which refers to delivery through routes other than the gastrointestinal tract, such as intravenous, subcutaneous, subdermal, intramuscular, intraperitoneal, intrapleural, intranasal, etc.

[0060] As used herein, the terms "subcutaneous administration," "sc," "sc administration," "SC," or "SC administration" refer to the delivery of a drug, usually in liquid form, directly into the fatty tissue just below the skin. Delivery is usually by direct injection. Such injections are shallower than those injected into muscle tissue. Providers often use subcutaneous injections for drugs that are suitable for slow and steady absorption into the bloodstream.

[0061] As used herein, the terms "intravenous administration," "IV administration," or "IV injection" refer to the delivery of a drug, typically in liquid form, directly into the veins of an animal or human. This method of delivery is usually by direct injection. The intravenous administration route can be used for both injection at higher pressure using a syringe; and infusion using pressure provided, for example, by gravity.

[0062] As used herein, the terms "intramuscular administration," "IM administration," or "IM injection" refer to the intramuscular delivery of a drug, usually in liquid form, directly into the muscle of an animal or human. Delivery is usually by direct injection, which allows the drug to be rapidly absorbed into the bloodstream. In some cases, a person may self-administer an IM injection. In some embodiments, for example, when certain therapeutic agents are irritating to veins or when a suitable vein cannot be found, an IM injection can be used instead of an intravenous injection.

[0063] As used herein, the term "nasal administration" refers to the delivery of a therapeutic agent (e.g., in the form of a gel, liquid, aerosol, gas, or powder) into the nose of an animal or human by topical application, instillation as a liquid, or insufflation (or blown or sprayed). Depending on the formulation, this form of administration can be used to deliver a therapeutic agent to the nasal cavity or lungs (depending on the device used), and / or may not be absorbed systemically (purely local administration), and / or may be completely absorbed systemically (purely systemic), and / or more frequently, may be partially absorbed (both local and systemic). Nasal sprays can contain locally acting agents whose systemic effects are typically minimal, such as decongestants for treating colds and allergies. Examples of systemically active drugs available as nasal sprays include, for example, migraine medications, nicotine replacement medications, and hormone therapies.

[0064] As used herein, the term "parenteral" or "non-gastrointestinal" administration refers to a route of administration that does not go through the enteral or gastrointestinal pathway. Examples of parenteral administration include subcutaneous (under the skin), intravenous (into a vein), intraarterial (into an artery), intramuscular (into a muscle), intraperitoneal (infusion or injection into the peritoneum), inhalation (e.g., by intratracheal inhalation administration, where the subject is exposed to a high aerosol concentration of the active pharmaceutical ingredient, so that the active pharmaceutical ingredient directly deposits in the lower respiratory tract), intranasal administration (through the nose), sublingual and buccal medication, intrathecal (into the spinal canal), intracerebral (into the cerebrum), intraventricular (into the ventricles of the brain), intradermal (into the skin itself), or any other route of administration that does not involve the gastrointestinal tract. As used herein, the term "enteral" means administration into any area of ​​the digestive tract, including the mouth (oral), pharynx (throat), esophagus, stomach, small intestine, large intestine, rectum, and anus, or through an artificial opening in any of these areas.

[0065] As used herein, the term "enteral" refers to administration into any region of the digestive tract, including the mouth (oral), pharynx (throat), esophagus, stomach, small intestine, large intestine, rectum, anus, and / or through an artificial opening in any of these regions.

[0066] As used herein, the term "oral administration," also abbreviated as "PO," refers to a route of administration in which a substance is taken by mouth, and includes drank, swallowed, sublingual (dissolved / absorbed under the tongue), buccal (dissolved / absorbed inside the cheek), and sublabial (dissolved / absorbed under the lip) routes of administration.

[0067] As used herein, the term "therapeutic agent," "drug," or "active pharmaceutical ingredient" refers to a substance or molecule capable of producing a therapeutic effect in a disease state.

[0068] As used herein, the terms "formulation" and "pharmaceutical formulation" are used interchangeably and refer to a finished pharmaceutical product that contains one or more active drugs along with various inert chemicals, excipients, and / or buffers. In some embodiments, the formulation may take the form of a tablet, lozenge, ointment, or injectable solution for administration to a subject.

[0069] As used herein, the term "excipient" refers to a substance or ingredient mixed with one or more active drugs or active pharmaceutical ingredients to, for example, provide long-term stability; increase the formulation's volume (hence, often referred to as a "bulking agent," "filler," or "diluent"); and / or impart a therapeutic enhancement to the active pharmaceutical ingredient in the final dosage form, such as facilitating drug absorption and / or efficacy / dosing, reducing viscosity, enhancing solubility, and / or prolonging the action or presence of the active pharmaceutical ingredient in the blood. The selection of a suitable excipient may depend on the route of administration and dosage form, the active pharmaceutical ingredient, and other factors. Excipients can include, for example, sugars, amino acids, buffers, antioxidants, chelating agents, solvents, or vehicles, and / or conjugated polymers that bind to and stabilize the active pharmaceutical ingredient in vitro and / or in vivo. For examples of such and other additives, see "Handbook of Pharmaceutical Excipients"; Ed. A.H. Kibbe, 3rd Ed., American Pharmaceutical Association, USA and Pharmaceutical Press UK, 2000 (hereby incorporated by reference in its entirety).

[0070] As used herein, a "liquid" is a substance that flows freely at room temperature, such that its shape changes but its volume remains constant, such as does water or oil.

[0071] As used herein, "room temperature" means a typical ambient room temperature of about 25°C.

[0072] Unless otherwise specified, any feature within any aspect or embodiment of the present disclosure may be combined with any feature within any other aspect or embodiment of the present disclosure, and such combinations are encompassed by the present disclosure. This also applies, but is not limited to, the endpoints of ranges disclosed herein. For example, if a given substance is disclosed as being present in a composition in a concentration range of X-Y% or A-B%, the disclosure is to be understood to explicitly disclose not only the ranges X-Y% and A-B%, but also the ranges X-B%, A-Y%, and, to the extent numerically feasible, Y-A% and B-X%. Each of these ranges and combinations of ranges is contemplated and is to be understood to be directly and explicitly disclosed herein.

[0073] Unless otherwise specified, range expressions herein using a hyphen ("-") separating two grouped values ​​X and Y, or two grouped ratios, shall be understood to mean and disclose both endpoints X and Y of the specified range. The same applies to ranges expressed as "from X to Y." Thus, the range expressions "X to Y," "of X to Y," "from X to Y," "of X to Y," and "from X to Y" shall be understood to equally mean and disclose ranges that include the endpoint X, all values ​​(including decimals) between X and Y, and the endpoint Y.

[0074] As used herein, the term "about," when referring to a particular value, e.g., one or more endpoints of a range, encompasses and discloses, in addition to the specifically recited value itself, certain variations around that specifically recited value. Such variations may occur, for example, from normal measurement variability, such as that which occurs when weighing or dispensing various substances using methods known to those of ordinary skill in the art. The term "about" shall be understood to encompass and disclose a range of variation above and below the specific value indicated, and the percentage values ​​are relative to the specifically recited value itself, as follows: the term "about" encompasses and discloses a variation of ±5.0%; the term "about" encompasses and discloses a variation of ±4.5%; the term "about" encompasses and discloses a variation of ±4.0%; the term "about" encompasses and discloses a variation of ±3.5%. The term "about" can encompass and disclose a variation of ±3.0%. The term "about" can encompass and disclose a variation of ±2.5%. The term "about" can encompass and disclose a variation of ±2.0%. The term "about" can encompass and disclose a variation of ±1.5%. The term "about" can encompass and disclose a variation of ±1.0%. The term "about" can encompass and disclose a variation of ±0.5%. When referring to a particular stated value, the term "about" can encompass and disclose the exact particular value itself, regardless of whether there is an explicit mention that the exact particular value is included; even if there is no explicit indication that the term "about" includes the particular exact stated value, the exact particular value is still included in the range of variation created by the term "about" and is therefore disclosed herein. Unless otherwise specified, when the term "about" is used before the first endpoint of a numerical range but not before the second endpoint of that range, the term, and the variation it implies within the range and disclosure, refers to both the first endpoint of that range and the second endpoint of that range. For example, a range described as "about X to Y" should be read as "about X to about Y." The same applies to describing ratio ranges. For example, a weight ratio range described as "about X:Y to A:B" should be read as a weight ratio of "(about X):(about Y) to (about A):(about B)."

[0075] Unless otherwise defined, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Although methods and materials similar or equivalent to those described herein can be used in the practice or 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 in their entirety. In case of conflict, the present specification, including definitions, will control. Additionally, the materials, methods, and examples are illustrative only and are not intended to be limiting.

[0076] It will be readily understood that the aspects of the present disclosure as generally described herein and illustrated in the Figures can be arranged, substituted, combined, separated, and designed in a wide variety of different configurations, all of which are expressly contemplated herein.

[0077] Furthermore, the particular arrangements shown in the figures should not be considered limiting. It should be understood that other embodiments may include more or fewer of each element shown in a given figure. Furthermore, some of the illustrated elements may be combined or omitted. Still further, example embodiments may include elements not shown in the figures.

[0078] composition The present disclosure provides: V1a partial agonist peptide of formula (A) [Mpa-Tyr-Phe-Z-Asn-Cys-Pro-B(X) a -Gly-NH2][SEQ ID NOs: 1-2] (A) or a pharmaceutically effective salt thereof, [In formula: The Mpa and Cys residues are covalently linked by a disulfide bond, Z is Hgn or Gln; wherein when Z is Hgn [SEQ ID NO: 1], the peptide of formula (A) is a peptide of formula (I): [Mpa-Tyr-Phe-Hgn-Asn-Cys-Pro-B(X) a -Gly-NH2][SEQ ID NO: 1] (I) (In the formula: B is any one of L-Lys, D-Lys, L-Orn, D-Orn, L-Dab, D-Dab, L-Dap, or D-Dap; and X is an amino acid residue, where each occurrence of the amino acid residue is independently selected from Gly, L-Ala, D-Ala, L-Lys, D-Lys, L-Orn, D-Orn, L-Glu, D-Glu, L-Asp, and D-Asp, and a is an integer from 0 to 10 (e.g., 0 to 1, 1 to 2, 1 to 3, 1 to 10, 1 to 6, 4 to 10, or 6 to 10); or X, at each occurrence, is a non-alpha primary amino group-containing C 3~12 Fatty acids (e.g., C 3~6 , C 3~10 , C 4~12 , C 4~6 , C 4~10 , C 6~10 , C 8~10 , or C 10~12 a) is a moiety derived from a fatty acid; and a is an integer from 1 to 3; wherein when Z is Gln [SEQ ID NO: 2], the peptide of formula (A) is a peptide of formula (II): [Mpa-Tyr-Phe-Gln-Asn-Cys-Pro-B(X) a -Gly-NH2][SEQ ID NO: 2] (II) (In the formula: B is any one of L-Lys, D-Lys, L-Orn, D-Orn, L-Dab, D-Dab, L-Dap, or D-Dap; and X is an amino acid residue, wherein each occurrence of the amino acid residue is independently selected from Gly, L-Ala, D-Ala, L-Lys, D-Lys, L-Orn, D-Orn, L-Glu, D-Glu, L-Asp, and D-Asp, and a is an integer from 6 to 10; or X, at each occurrence, is a non-alpha primary amino group-containing C 3~12 Fatty acids (e.g., C 3~6, C 3~10 , C 4~12 , C 4~6 , C 4~10 , C 6~10 , C 8~10 , or C 10~12 a is a moiety derived from a fatty acid, and a is an integer of 1 to 3. A composition comprising: Compositions are characterized as having a therapeutic index of at least 20 (e.g., at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100).

[0079] In some embodiments, Z is Hgn and B is Lys, X is optionally GIy, and a is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, Z is Hgn, X is GIy, and a is 6, 7, 8, 9, or 10. In some embodiments, Z is Gln, X is GIy, and a is 6, 7, 8, 9, or 10.

[0080] In some embodiments, the present disclosure provides a peptide of formula (I) [Mpa-Tyr-Phe-Hgn-Asn-Cys-Pro-B(X) a -Gly-NH2][SEQ ID NO: 1] (I) or a pharmaceutically effective salt thereof, wherein: The Mpa and Cys residues are covalently linked by a disulfide bond; B is any one of L-Lys, D-Lys, L-Orn, D-Orn, L-Dab, D-Dab, L-Dap, or D-Dap; X is an amino acid residue, and at each occurrence is independently selected from Gly, L-Ala, D-Ala, L-Lys, D-Lys, L-Orn, D-Orn, L-Glu, D-Glu, L-Asp, and D-Asp, and a is an integer from 0 to 10; or X is a non-α primary amino group-containing C 3~12a is a moiety derived from a fatty acid, and a is an integer of 1 to 3.

[0081] In some embodiments, in Formula (A) or Formula (I), each occurrence of X is independently selected from Gly, Ala, Lys, Orn, Glu, and Asp.

[0082] In some embodiments, in Formula (A) or Formula (I), each occurrence of X is independently selected from Gly, Ala, and Lys.

[0083] In some embodiments, in formula (I), when X is an amino acid residue as defined in any of the above embodiments, a can be an integer from 0 to 10, 0 to 1, 1 to 2, 2 to 3, 3 to 4, 4 to 5, 1 to 4, 1 to 6, 1 to 10, 2 to 3, 3 to 4, 4 to 5, 4 to 10, 5 to 6, 6 to 8, 6 to 10, or 8 to 10.

[0084] In some embodiments, in Formula (A) or Formula (I), when X, at each occurrence, is a moiety derived from a non-alpha primary amino group-containing fatty acid, the fatty acid is C 3~12 fatty acids, C 3~6 fatty acids, C 3~10 fatty acids, C 4~12 fatty acids, C 4~6 fatty acids, C 4~10 fatty acids, C 6~10 fatty acids, C 8~10 Fatty acids, or C 10~12 It is a fatty acid.

[0085] In some embodiments, each occurrence of X is a non-alpha primary amino group-containing C 3~12 When the moiety is derived from a fatty acid, a is 1, 2, or 3 (eg, 1 or 2, 2 or 3, or 1 or 3).

[0086] In some embodiments, in formula (I), B is L-Lys. In some embodiments, in formula (I), B is D-Lys. In some embodiments, in formula (I), B is L-Orn. In some embodiments, in formula (I), B is D-Orn. In some embodiments, in formula (I), B is L-Dab. In some embodiments, in formula (I), B is D-Dab. In some embodiments, in formula (I), B is L-Dap. In some embodiments, in formula (I), B is D-Dap.

[0087] In some embodiments, in the compound of Formula (A) or Formula (I), B is Lys and X comprises Lys.

[0088] In some embodiments, in the peptide of formula (I), B is L-Lys, X is Gly, and a is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0089] In some embodiments, in the peptide of formula (I), B is D-Lys, X is Gly, and a is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0090] In some embodiments, in the peptide of formula (I), B is L-Dap, X is Gly, and a is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0091] In some embodiments, in the peptide of formula (I), B is D-Dap, X is Gly, and a is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0092] In some embodiments, in the peptide of formula (I), B is L-Orn, X is Gly, and a is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0093] In some embodiments, in the peptide of formula (I), B is D-Orn, X is Gly, and a is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0094] In some embodiments, in the peptide of formula (I), B is L-Dab, X is Gly, and a is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0095] In some embodiments, in the peptide of formula (I), B is D-Dab, X is Gly, and a is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0096] In some embodiments, in the peptide of Formula (I), B is Lys and a is 0.

[0097] In some embodiments, in the peptide of formula (I), B is Lys, X is Gly, and a is 1.

[0098] In some embodiments, in the peptide of formula (I), B is Lys, X is Gly, and a is 2.

[0099] In some embodiments, in the peptide of formula (I), B is Lys, X is Gly, and a is 3.

[0100] In some embodiments, in the peptide of formula (I), B is Lys, X is Gly, and a is 4.

[0101] In some embodiments, in the peptide of formula (I), B is Lys, X is Gly, and a is 5.

[0102] In some embodiments, in the peptide of Formula (A) or Formula (I), B is Lys, X is Gly, and a is 6.

[0103] In some embodiments, in a peptide of Formula (A) or Formula (I), B is Lys, X is Gly, and a is 7.

[0104] In some embodiments, in the peptide of Formula (A) or Formula (I), B is Lys, X is Gly, and a is 8.

[0105] In some embodiments, in the peptide of Formula (A) or Formula (I), B is Lys, X is Gly, and a is 9.

[0106] In some embodiments, in a peptide of Formula (A) or Formula (I), B is Lys, X is Gly, and a is 10.

[0107] In some embodiments, in the peptide of Formula (I), B is D-Lys and a is 0.

[0108] In some embodiments, in the peptide of formula (I), B is D-Lys, X is Gly, and a is 1.

[0109] In some embodiments, in the peptide of formula (I), B is D-Lys, X is Gly, and a is 2.

[0110] In some embodiments, in the peptide of formula (I), D-Lys, X is Gly, and a is 3.

[0111] In some embodiments, in the peptide of formula (I), B is D-Lys, X is Gly, and a is 4.

[0112] In some embodiments, in the peptide of formula (I), B is D-Lys, X is Gly, and a is 5.

[0113] In some embodiments, in a peptide of Formula (A) or Formula (I), B is D-Lys, X is Gly, and a is 6.

[0114] In some embodiments, in a peptide of Formula (A) or Formula (I), B is D-Lys, X is Gly, and a is 7.

[0115] In some embodiments, in a peptide of Formula (A) or Formula (I), B is D-Lys, X is Gly, and a is 8.

[0116] In some embodiments, in the peptide of Formula (A) or Formula (I), B is D-Lys, X is Gly, and a is 9.

[0117] In some embodiments, in a peptide of Formula (A) or Formula (I), B is D-Lys, X is Gly, and a is 10.

[0118] In some embodiments, in the peptide of Formula (I), B is Orn and a is 0.

[0119] In some embodiments, in the peptide of formula (I), B is Orn, X is Gly, and a is 1.

[0120] In some embodiments, in the peptide of formula (I), B is Orn, X is Gly, and a is 2.

[0121] In some embodiments, in the peptide of formula (I), B is Orn, X is Gly, and a is 3.

[0122] In some embodiments, in the peptide of formula (I), B is Orn, X is Gly, and a is 4.

[0123] In some embodiments, in the peptide of formula (I), B is Orn, X is Gly, and a is 5.

[0124] In some embodiments, in the peptide of Formula (A) or Formula (I), B is Orn, X is Gly, and a is 6.

[0125] In some embodiments, in a peptide of Formula (A) or Formula (I), B is Orn, X is Gly, and a is 7.

[0126] In some embodiments, in the peptide of Formula (A) or Formula (I), B is Orn, X is Gly, and a is 8.

[0127] In some embodiments, in the peptide of Formula (A) or Formula (I), B is Orn, X is Gly, and a is 9.

[0128] In some embodiments, in a peptide of Formula (A) or Formula (I), B is Orn, X is Gly, and a is 10.

[0129] In some embodiments, in the peptide of formula (I), B is D-Orn and a is 0.

[0130] In some embodiments, in the peptide of formula (I), B is D-Orn, X is Gly, and a is 1.

[0131] In some embodiments, in the peptide of formula (I), B is D-Orn, X is Gly, and a is 2.

[0132] In some embodiments, in the peptide of formula (I), B is D-Orn, X is Gly, and a is 3.

[0133] In some embodiments, in the peptide of formula (I), B is D-Orn, X is Gly, and a is 4.

[0134] In some embodiments, in the peptide of formula (I), B is D-Orn, X is Gly, and a is 5.

[0135] In some embodiments, in the peptide of Formula (A) or Formula (I), B is D-Orn, X is Gly, and a is 6.

[0136] In some embodiments, in the peptide of Formula (A) or Formula (I), B is D-Orn, X is Gly, and a is 7.

[0137] In some embodiments, in the peptide of Formula (A) or Formula (I), B is D-Orn, X is Gly, and a is 8.

[0138] In some embodiments, in the peptide of Formula (A) or Formula (I), B is D-Orn, X is Gly, and a is 9.

[0139] In some embodiments, in a peptide of Formula (A) or Formula (I), B is D-Orn, X is Gly, and a is 10.

[0140] In some embodiments, in the peptide of formula (I), B is Dap and a is 0.

[0141] In some embodiments, in the peptide of formula (I), B is Dap, X is Gly, and a is 1.

[0142] In some embodiments, in the peptide of formula (I), B is Dap, X is Gly, and a is 2.

[0143] In some embodiments, in the peptide of formula (I), B is Dap, X is Gly, and a is 3.

[0144] In some embodiments, in the peptide of formula (I), B is Dap, X is Gly, and a is 4.

[0145] In some embodiments, in the peptide of formula (I), B is Dap, X is Gly, and a is 5.

[0146] In some embodiments, in the peptide of Formula (A) or Formula (I), B is Dap, X is Gly, and a is 6.

[0147] In some embodiments, in the peptide of Formula (A) or Formula (I), B is Dap, X is Gly, and a is 7.

[0148] In some embodiments, in the peptide of Formula (A) or Formula (I), B is Dap, X is Gly, and a is 8.

[0149] In some embodiments, in the peptide of Formula (A) or Formula (I), B is Dap, X is Gly, and a is 9.

[0150] In some embodiments, in the peptide of Formula (A) or Formula (I), B is Dap, X is Gly, and a is 10.

[0151] In some embodiments, in the peptide of formula (I), B is D-Dap and a is 0.

[0152] In some embodiments, in the peptide of formula (I), B is D-Dap, X is Gly, and a is 1.

[0153] In some embodiments, in the peptide of formula (I), B is D-Dap, X is Gly, and a is 2.

[0154] In some embodiments, in the peptide of formula (I), B is D-Dap, X is Gly, and a is 3.

[0155] In some embodiments, in the peptide of formula (I), B is D-Dap, X is Gly, and a is 4.

[0156] In some embodiments, in the peptide of formula (I), B is D-Dap, X is Gly, and a is 5.

[0157] In some embodiments, in the peptide of Formula (A) or Formula (I), B is D-Dap, X is Gly, and a is 6.

[0158] In some embodiments, in the peptide of Formula (A) or Formula (I), B is D-Dap, X is Gly, and a is 7.

[0159] In some embodiments, in the peptide of Formula (A) or Formula (I), B is D-Dap, X is Gly, and a is 8.

[0160] In some embodiments, in the peptide of Formula (A) or Formula (I), B is D-Dap, X is Gly, and a is 9.

[0161] In some embodiments, in the peptide of Formula (A) or Formula (I), B is D-Dap, X is Gly, and a is 10.

[0162] In some embodiments, in the peptide of formula (I), B is Dab and a is 0.

[0163] In some embodiments, in the peptide of formula (I), B is Dab, X is Gly, and a is 1.

[0164] In some embodiments, in the peptide of formula (I), B is Dab, X is Gly, and a is 2.

[0165] In some embodiments, in the peptide of formula (I), B is Dab, X is Gly, and a is 3.

[0166] In some embodiments, in the peptide of formula (I), B is Dab, X is Gly, and a is 4.

[0167] In some embodiments, in the peptide of formula (I), B is Dab, X is Gly, and a is 5.

[0168] In some embodiments, in the peptide of Formula (A) or Formula (I), B is Dab, X is Gly, and a is 6.

[0169] In some embodiments, in the peptide of Formula (A) or Formula (I), B is Dab, X is Gly, and a is 7.

[0170] In some embodiments, in the peptide of Formula (A) or Formula (I), B is Dab, X is Gly, and a is 8.

[0171] In some embodiments, in the peptide of Formula (A) or Formula (I), B is Dab, X is Gly, and a is 9.

[0172] In some embodiments, in a peptide of Formula (A) or Formula (I), B is Dab, X is Gly, and a is 10.

[0173] In some embodiments, in the peptide of formula (I), B is D-Dab and a is 0.

[0174] In some embodiments, in the peptide of formula (I), B is D-Dab, X is Gly, and a is 1.

[0175] In some embodiments, in the peptide of formula (I), B is D-Dab, X is Gly, and a is 2.

[0176] In some embodiments, in the peptide of formula (I), B is D-Dab, X is Gly, and a is 3.

[0177] In some embodiments, in the peptide of formula (I), B is D-Dab, X is Gly, and a is 4.

[0178] In some embodiments, in the peptide of formula (I), B is D-Dab, X is Gly, and a is 5.

[0179] In some embodiments, in the peptide of Formula (A) or Formula (I), B is D-Dab, X is Gly, and a is 6.

[0180] In some embodiments, in the peptide of Formula (A) or Formula (I), B is D-Dab, X is Gly, and a is 7.

[0181] In some embodiments, in the peptide of Formula (A) or Formula (I), B is D-Dab, X is Gly, and a is 8.

[0182] In some embodiments, in the peptide of Formula (A) or Formula (I), B is D-Dab, X is Gly, and a is 9.

[0183] In some embodiments, in the peptide of Formula (A) or Formula (I), B is D-Dab, X is Gly, and a is 10.

[0184] In some embodiments, in the peptide of Formula (A) or Formula (I), a is not 0.

[0185] In some embodiments, in a peptide of Formula (A) or Formula (I), B is Lys and X, at each occurrence, is a non-alpha primary amino group-containing C3-C 12 Fatty acids (e.g., C3-C6, C4-C 10 , C6~C 10 , C8~C 10 , or C 10 ~C 12 a is a moiety derived from a fatty acid, and a is 1.

[0186] In some embodiments, in a peptide of Formula (A) or Formula (I), B is Lys and X is a non-alpha primary amino group-containing C 12 is a moiety derived from a fatty acid, and a is 1.

[0187] In some embodiments, in a peptide of Formula (A) or Formula (I), B is Lys and X is a non-alpha primary amino group-containing C 10 is a moiety derived from a fatty acid, and a is 1.

[0188] In some embodiments, in the peptide of Formula (A) or Formula (I), B is Lys, X is a moiety derived from a non-alpha primary amino group-containing C8 fatty acid, and a is 1.

[0189] In some embodiments, in the peptide of Formula (A) or Formula (I), B is Lys, X is a moiety derived from a non-alpha primary amino group-containing C6 fatty acid, and a is 1.

[0190] In some embodiments, in the peptide of Formula (A) or Formula (I), B is Lys, X is a moiety derived from a non-alpha primary amino group-containing C6 fatty acid, and a is 2.

[0191] In some embodiments, in the peptide of Formula (A) or Formula (I), B is Lys, X is a moiety derived from a non-alpha primary amino group-containing C4 fatty acid, and a is 1.

[0192] In some embodiments, in the peptide of Formula (A) or Formula (I), B is Lys, X is a moiety derived from a non-alpha primary amino group-containing C4 fatty acid, and a is 2.

[0193] In some embodiments, in the peptide of Formula (A) or Formula (I), B is Lys, X is a moiety derived from a non-alpha primary amino group-containing C4 fatty acid, and a is 3.

[0194] In some embodiments, in the peptide of Formula (A) or Formula (I), B is Lys, X is a moiety derived from a non-alpha primary amino group-containing C3 fatty acid, and a is 1.

[0195] In some embodiments, in the peptide of Formula (A) or Formula (I), B is Lys, X is a moiety derived from a non-alpha primary amino group-containing C3 fatty acid, and a is 2.

[0196] In some embodiments, in the peptide of Formula (A) or Formula (I), B is Lys, X is a moiety derived from a non-alpha primary amino group-containing C3 fatty acid, and a is 3.

[0197] In some embodiments, in a peptide of Formula (A) or Formula (I), B is Lys and X is a moiety derived from a non-alpha primary amino group-containing fatty acid selected from β-aminopropanoic acid (propionic acid), 4-aminobutanoic acid (butyric acid), 5-aminopentanoic acid (valeric acid), 6-aminohexanoic acid (caproic acid), 7-aminoheptanoic acid (enanthic acid), 8-aminooctanoic acid (caprylic acid), 9-aminononanoic acid (pelargonic acid), 10-aminodecanoic acid (capric acid), 11-aminoundecanoic acid (undecylic acid), and 12-aminododecanoic acid (lauric acid).

[0198] In some embodiments, unless B is otherwise defined in the above embodiments of Formula (A) or Formula (I), B is Lys.

[0199] The peptide of formula (A) or formula (I) may be a V1a partial agonist. A V1a partial agonist partially activates the V1a receptor.

[0200] In any of the above-described embodiments, a composition comprising a peptide of Formula (A) or Formula (I) can have a therapeutic index of at least 20 (e.g., at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100). The peptide of Formula (A) or Formula (I) has specificity for the V1a receptor.

[0201] Amino acid sequence (X) a can provide the ability to tailor the solubility and / or stability properties of the peptides of Formula (A) and / or Formula (I), so that the peptides can be tailored to suit the intended route of administration and desired solubility while maintaining a therapeutic index of at least 20 (e.g., at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, at least 100) without altering the partial V1a agonist properties. Therapeutic index is defined herein as the ratio of NOAEL / NOEL. Stability of a formulation can be measured, for example, by one of skill in the art using established chromatographic protocols. Solubility can be readily measured by one of skill in the art by centrifugation or filtration of a given formulation followed by chromatographic analysis of the supernatant solution or filtrate. To confirm partial V1a agonist properties, partial agonist activity can be measured both in vitro and in vivo as described in the Examples below. Furthermore, (X) a It is believed that the amino acid sequence of may provide a therapeutic agent that degrades slowly in vivo over time, releasing similarly active degradation intermediates with partial agonist activity. Thus, the compositions of the present disclosure may provide a prolonged presence of a partial V1a agonist in the blood over a sustained period of time.

[0202] The present disclosure also provides a peptide of formula (II): [Mpa-Tyr-Phe-Gln-Asn-Cys-Pro-B(X) a -Gly-NH2][SEQ ID NO: 2] (II) or a pharmaceutically effective salt thereof, wherein: The Mpa and Cys residues are covalently linked by a disulfide bond, B is any one of L-Lys, D-Lys, L-Orn, D-Orn, L-Dab, D-Dab, L-Dap, and D-Dap; X is an amino acid residue, and at each occurrence is independently selected from Gly, L-Ala, D-Ala, L-Lys, D-Lys, L-Orn, D-Orn, L-Glu, D-Glu, L-Asp, and D-Asp, and a is an integer from 6 to 10; or X, at each occurrence, is a non-alpha primary amino group-containing C 3~12 a is a moiety derived from a fatty acid, and a is an integer of 1 to 3).

[0203] The peptide of formula (II) can have a therapeutic index of at least 20 (e.g., at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100). The peptide can be a V1a partial agonist.

[0204] In some embodiments, in the peptide of formula (II), when X is an amino acid residue, a can be an integer of 3 to 4, 4 to 6, 4 to 8, 4 to 10, 4 to 12, 6 to 10, 8 to 10, or 10 to 12.

[0205] In some embodiments, in the peptide of formula (II), X is Gly and a is 6, 7, 8, 9, and / or 10.

[0206] In some embodiments, in the peptide of formula (II), X, at each occurrence, is a non-alpha primary amino group-containing C3-C 12 Fatty acids (e.g., C4 to C 12 , C4~C6, C4~C 10 , C3~C6, C6~C 10 , C8~C 10 , or C 10 ~C 12 This is the part that comes from fatty acids.

[0207] In some embodiments, in the peptide of formula (II), X is a non-alpha primary amine-containing 12-carbon fatty acid and a is 1.

[0208] In some embodiments, in the peptide of formula (II), X is a non-alpha primary amino group-containing C 10 is a moiety derived from a fatty acid, and a is 1.

[0209] In some embodiments, in the peptide of formula (II), X is a moiety derived from a non-alpha primary amino group-containing C8 fatty acid, and a is 1.

[0210] In some embodiments, in the peptide of formula (II), X is a moiety derived from a non-alpha primary amino group-containing C6 fatty acid, and a is 1.

[0211] In some embodiments, in the peptide of formula (II), X is a moiety derived from a non-alpha primary amino group-containing C6 fatty acid, and a is 2.

[0212] In some embodiments, in the peptide of formula (II), Z is a moiety derived from a non-alpha primary amino group-containing C4 fatty acid, and a is 1.

[0213] In some embodiments, in the peptide of formula (II), X is a moiety derived from a non-alpha primary amino group-containing C4 fatty acid, and a is 2.

[0214] In some embodiments, in the peptide of formula (II), X is a moiety derived from a non-alpha primary amino group-containing C4 fatty acid, and a is 3.

[0215] In some embodiments, in the peptide of formula (II), X is a moiety derived from a non-alpha primary amino group-containing C3 fatty acid, and a is 1.

[0216] In some embodiments, in the peptide of formula (II), X is a moiety derived from a non-alpha primary amino group-containing C3 fatty acid, and a is 2.

[0217] In some embodiments, in the peptide of formula (II), X is a moiety derived from a non-alpha primary amino group-containing C3 fatty acid, and a is 3.

[0218] In some embodiments, in the peptide of Formula (II), X is a moiety derived from a non-alpha primary amino group-containing fatty acid selected from β-aminopropanoic acid (propionic acid), 4-aminobutanoic acid (butyric acid), 5-aminopentanoic acid (valeric acid), 6-aminohexanoic acid (caproic acid), 7-aminoheptanoic acid (enanthic acid), 8-aminooctanoic acid (caprylic acid), 9-aminononanoic acid (pelargonic acid), 10-aminodecanoic acid (capric acid), 11-aminoundecanoic acid (undecylic acid), and 12-aminododecanoic acid (lauric acid); and a is 1-3.

[0219] In some embodiments, the peptide of formula (II) is (X) a In some embodiments, the peptide of formula (II) does not include the moiety (X) a In some embodiments, the peptide of formula (II) does not include the moiety (X) a In some embodiments, the peptide of formula (II) does not include the moiety (X) a In some embodiments, the peptide of formula (II) does not include a moiety (X) wherein X is Gly, L-Ala, L-Val, L-Leu, L-Pro, L-Trp, L-Tyr, and / or L-Phe, and a is 1, 2, or 3. In some embodiments, the peptide of formula (II) does not include a moiety (X) aIn some embodiments, the peptide of formula (II) does not include the moiety (X) a The amino acid sequence does not include the moiety (wherein X is Gly, L-Ala, L-Val, L-Leu, L-Pro, L-Trp, L-Tyr, and / or L-Phe, and a is 1, 2, 3, 4, or 5).

[0220] In some embodiments, unless B is otherwise defined in the embodiments of Formula (II) above, B is Lys.

[0221] The peptide of formula (II) may be a V1a partial agonist, which partially activates the V1a receptor.

[0222] (X) a The amino acid sequence of (X) can provide the ability to tailor the solubility and / or stability properties of the peptide of formula (II), so that the peptide can be tailored to suit the intended route of administration and desired solubility while maintaining a therapeutic index of at least 20 (e.g., at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, at least 100) without altering the partial V1a agonist properties. The therapeutic index is defined herein as the ratio of NOAEL / NOEL. Measurement of formulation stability and solubility is as described above. To confirm partial V1a agonist properties, partial agonist activity can be measured both in vitro and in vivo as described in the Examples below. Additionally, (X) a It is believed that the amino acid sequence of Formula II (X) where a is 6-10 may provide a therapeutic agent that degrades slowly in vivo over time while releasing similarly active degradation intermediates with partial agonist activity. aThus, the compositions of the present disclosure can provide prolonged partial V1a agonist presence in the blood over a sustained period of time.

[0223] In some embodiments, the V1a partial agonist of the disclosed composition comprises a peptide of Formula (I), wherein X is Gly; and / or a peptide of Formula (II), wherein B is Lys and X is Gly, and / or a pharmaceutically acceptable salt thereof.

[0224] In some embodiments, the V1a partial agonist of the composition of the present disclosure comprises a peptide of formula (I) wherein X is GIy and a is 6; and / or a peptide of formula (II) wherein B is Lys, X is GIy and a is 6, and / or a pharmaceutically acceptable salt thereof.

[0225] In some embodiments, the V1a partial agonist of the composition of the present disclosure comprises a peptide of formula (I) wherein X is GIy and a is 7; and / or a peptide of formula (II) wherein B is Lys, X is GIy and a is 7, and / or a pharmaceutically acceptable salt thereof.

[0226] In some embodiments, the V1a partial agonist of the composition of the present disclosure comprises a peptide of formula (I) wherein X is GIy and a is 8; and / or a peptide of formula (II) wherein B is Lys, X is GIy and a is 8, and / or a pharmaceutically acceptable salt thereof.

[0227] In some embodiments, the V1a partial agonist of the composition of the present disclosure comprises a peptide of formula (I) wherein X is GIy and a is 9; and / or a peptide of formula (II) wherein B is Lys, X is GIy and a is 9, and / or a pharmaceutically acceptable salt thereof.

[0228] In some embodiments, the V1a partial agonist of the composition of the present disclosure comprises a peptide of formula (I) wherein X is GIy and a is 10; and / or a peptide of formula (II) wherein B is Lys, X is GIy and a is 10, and / or a pharmaceutically acceptable salt thereof.

[0229] In some embodiments, a pharmaceutical composition for partially activating the V1a receptor comprises a peptide of Formula (I) or Formula (II) and / or a pharmaceutically acceptable salt thereof; and one or more pharmaceutically acceptable excipients and / or buffers. The buffer may have an optimal buffer pH between 3.5 and 6.5, such as a citrate buffer, an acetate buffer, a succinate buffer, and / or a histidine buffer. The buffer concentration may be less than 100 mM (e.g., less than 90 mM, less than 75 mM, less than 60 mM, less than 45 mM, less than 30 mM, less than 15 mM, less than 10 mM, or less than 5 mM).

[0230] The present disclosure further provides a peptide of formula (B): [X'-Tyr-Phe-Gln-Asn-Cys-Pro-Lys(Z) d -Gly-NH2] [SEQ ID NOs: 7 and 4] (B) or a pharmaceutically acceptable salt thereof, [In formula: X' is (U) c -Cys or Mpa, Here, X' is (U) c -Cys, and (Z) d is absent [SEQ ID NO: 7], the peptide of formula (B) is a peptide of formula (III) [(U) c -Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Lys-Gly-NH2] [SEQ ID NO: 7] (III) (In the formula, The two Cys residues are covalently linked by a disulfide bond, U is an amino acid residue, each occurrence independently selected from Gly, L-Ala, D-Ala, L-Lys, D-Lys, L-Orn, D-Orn, L-Glu, D-Glu, L-Asp, and D-Asp, and c is the number of Us and is an integer from 0 to 10; and When X' is Mpa [SEQ ID NO: 4], the peptide of formula (B) is a peptide of formula (IV) [Mpa-Tyr-Phe-Gln-Asn-Cys-Pro-Lys(Z) d -Gly-NH2][SEQ ID NO: 4] (IV) (In the formula, The Mpa and Cys residues are covalently linked by a disulfide bond, Z is an amino acid residue, each occurrence of which is independently selected from Gly, D-Ala, L-Ala, D-Lys, L-Lys, D-Orn, L-Orn, D-Glu, L-Glu, D-Asp, and L-Asp, and d is the number of Z and is an integer from 0 to 5.

[0231] In some embodiments, the peptides of formula (III) or (IV) may be full or partial V1a agonists, although their activity may be modulated when used in conjunction with a V2 antagonist.

[0232] In some embodiments, the peptide of formula (B) is a peptide of formula (III): [(U) c -Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Lys-Gly-NH2] [SEQ ID NO: 7] (III) or a pharmaceutically effective salt thereof, (In the formula: The two Cys residues are covalently linked by a disulfide bond, U is an amino acid residue, each occurrence independently selected from Gly, L-Ala, D-Ala, L-Lys, D-Lys, L-Orn, D-Orn, L-Glu, D-Glu, L-Asp, and D-Asp; and c is the number of one or more amino acid residues U and is an integer of 0 to 10 (for example, 1 to 10, 4 to 10, or 6 to 10). The peptide may be a V1a agonist.

[0233] In some embodiments, the peptide of formula (III) can behave as a full or partial V1a agonist when used in conjunction with a V2 antagonist.

[0234] In some embodiments, for a peptide of formula (III), c is not 0. In some embodiments, one or both of the termini of a peptide of formula (III) does not contain an alkyl group (e.g., an alkyl group having 3 to 36 carbon units). In some embodiments, one or both of the termini of a peptide of formula (III) does not contain an alkyl group having 3 to 36 carbon units, nitrilotriacetic acid, imidodiacetic acid, or one or more histidine residues. In some embodiments, a peptide of formula (III) does not contain a peptide in which U is Gly and / or His and c is an integer from 1 to 6, optionally containing a terminal alkyl group. In some embodiments, (U) in a peptide of formula (III) does not contain an alkyl group having 3 to 36 carbon units, nitrilotriacetic acid, imidodiacetic acid, or one or more histidine residues. c does not include Leu, Phe, Tyr, Trp, Pro, Gly-Gly, Leu-Leu, Gly-Pro, sarkosyl-Gly, and / or Gly-Gly-Gly.

[0235] In some embodiments, the peptide of formula (B) is a peptide of formula (IV): [Mpa-Tyr-Phe-Gln-Asn-Cys-Pro-Lys(Z) d -Gly-NH2][SEQ ID NO: 4] (IV) or a pharmaceutically effective salt thereof, (In the formula: The Mpa and Cys residues are covalently linked by a disulfide bond, Z is an amino acid residue, each occurrence independently selected from Gly, D-Ala, L-Ala, D-Lys, L-Lys, D-Orn, L-Orn, D-Glu, L-Glu, D-Asp, and L-Asp; and and d is the number of one or more amino acid residues Z, which is an integer of 0 to 5. The peptide may be a V1a agonist.

[0236] In some embodiments, the peptide of formula (IV) can behave as a full or partial V1a agonist when used in conjunction with a V2 antagonist. In some embodiments, the compositions of the present disclosure include a pharmaceutically acceptable salt of a peptide of formula (I), formula (II), formula (III), or formula (IV).

[0237] In some embodiments, any one of the aforementioned compositions may be in the form of a pharmaceutical formulation, which comprises a peptide of Formula (I), Formula (II), Formula (III), or Formula (IV), and / or a pharmaceutically acceptable salt thereof, and may optionally further comprise one or more pharmaceutically acceptable excipients and / or buffers. By way of example, the composition may optionally comprise a buffer having an optimal buffer pH of 3.5 to 6.5, such as a citrate buffer, an acetate buffer, a succinate buffer, and / or a histidine buffer. The buffer salt concentration may be less than 100 mM (e.g., less than 90 mM, less than 75 mM, less than 60 mM, less than 45 mM, less than 30 mM, less than 15 mM, less than 10 mM, or less than 5 mM).

[0238] Treatment method In some embodiments, the present disclosure provides methods of treating a subject having one or more of the following conditions: liver fibrosis, cirrhosis, portal hypertension, ascites, varices (e.g., esophageal varices, gastric varices), bleeding (e.g., variceal bleeding), arterial hypotension, and / or hepatorenal syndrome, by administering a therapeutically effective dose of a pharmaceutical composition comprising a peptide of any embodiment of Formula (I) or Formula (II), as described above in the section entitled "Compositions," and / or a pharmaceutically acceptable salt thereof. For example, the subject may have hypotension, with a mean arterial pressure below 95 mmHg (e.g., below 90 mmHg, below 85 mmHg, below 80 mmHg, below 75 mmHg, or below 70 mmHg). As another example, the subject may have cirrhosis and a mean arterial pressure below 95 mmHg (e.g., below 90 mmHg, below 85 mmHg, below 80 mmHg, below 75 mmHg, below 70 mmHg). In some embodiments, the subject has liver fibrosis. In certain embodiments, the subject has cirrhosis. In some embodiments, the subject has portal hypertension. In certain embodiments, the subject has ascites. In some embodiments, the subject has esophageal varices. In certain embodiments, the subject has gastric varices. In some embodiments, the subject has variceal bleeding. In some embodiments, the subject has a mean arterial pressure below 95 mmHg (e.g., below 90 mmHg, below 85 mmHg, below 80 mmHg, below 75 mmHg, or below 70 mmHg).

[0239] As discussed above, the pharmaceutical composition can further comprise one or more pharmaceutically acceptable excipients and / or a buffer having an optimal buffer pH of 3.5 to 6.5, such as a citrate buffer, an acetate buffer, a succinate buffer, and / or a histidine buffer. The buffer salt concentration can be less than 100 mM (e.g., less than 90 mM, less than 75 mM, less than 60 mM, less than 45 mM, less than 30 mM, less than 15 mM, less than 10 mM, or less than 5 mM).

[0240] In some embodiments, the disclosure features a method of treating a subject having one or more of the following conditions: liver fibrosis, cirrhosis, portal hypertension, ascites, esophageal varices, gastric varices, hemorrhage, arterial hypotension, and / or hepatorenal syndrome, the method comprising administering a therapeutically effective dose of a pharmaceutical composition comprising any of the preceding embodiments of a peptide of Formula (I), where B is Lys, and / or a pharmaceutically acceptable salt thereof, and optionally further comprising a pharmaceutically acceptable excipient and / or buffer.

[0241] In some embodiments, the present disclosure provides methods of treating a subject having one or more of the following conditions: liver fibrosis, cirrhosis, portal hypertension, ascites, esophageal varices, gastric varices, hemorrhage, arterial hypotension, and hepatorenal syndrome, comprising administering a therapeutically effective dose of a pharmaceutical composition comprising the foregoing embodiments of a peptide of Formula (I), wherein B is Lys and X is Gly, and / or a pharmaceutically acceptable salt thereof, and optionally further comprising a pharmaceutically acceptable excipient and / or buffer.

[0242] In some embodiments, the present disclosure provides a method of treating a subject having one or more of the following conditions: liver fibrosis, cirrhosis, portal hypertension, ascites, esophageal varices, gastric varices, hemorrhage, arterial hypotension, and hepatorenal syndrome, comprising administering a therapeutically effective dose of a pharmaceutical composition comprising the peptide of formula (I) as described above, wherein B is Lys, X is Gly, and a is 6, and / or a pharmaceutically acceptable salt thereof, and optionally further comprising a pharmaceutically acceptable excipient and / or buffer.

[0243] In some embodiments, the present disclosure provides a method of treating a subject having one or more of the following conditions: liver fibrosis, liver cirrhosis, portal hypertension, ascites, esophageal varices, gastric varices, bleeding, arterial hypotension, and hepatorenal syndrome, comprising administering to a subject a peptide of formula (I) as described above, wherein B is Lys and X is a non-alpha primary amino group-containing C 12and a is a moiety derived from a fatty acid, and a is 1), and / or a pharmaceutically acceptable salt thereof, and optionally further comprising a pharmaceutically acceptable excipient and / or buffer.

[0244] For example, a method of treating a subject having one or more of the following conditions: liver fibrosis, liver cirrhosis, portal hypertension, ascites, esophageal varices, gastric varices, bleeding, arterial hypotension, and hepatorenal syndrome may involve administering any of the embodiments of the peptides of formula (I) above, e.g., wherein B is Lys, X is a non-alpha primary amine-containing fatty acid having 10 carbon units, and a is 1, and / or a pharmaceutically acceptable salt thereof; wherein B is Lys, X is a non-alpha primary amine-containing fatty acid having 8 carbon units, and a is 1, and / or a pharmaceutically acceptable salt thereof; wherein B is Lys, X is a non-alpha primary amine-containing fatty acid having 6 carbon units, and a is 1, and / or a pharmaceutically acceptable salt thereof; wherein B is Lys, X is a non-alpha primary amine-containing fatty acid having 6 carbon units, and a is 2, and / or a pharmaceutically acceptable salt thereof; wherein B is Lys, X is a non-alpha primary amine-containing fatty acid having 4 carbon units, and a is 1, and / or a pharmaceutically acceptable salt thereof; wherein B is Lys, X is a non-alpha primary amine-containing fatty acid having 4 carbon units, and a is 2, and / or a pharmaceutically acceptable salt thereof; wherein B is Lys, X is a non-alpha primary amine-containing fatty acid having 4 carbon units, and a is 3, and / or a pharmaceutically acceptable salt thereof; wherein B is Lys, X is a non-alpha primary amine-containing fatty acid having 3 carbon units, and a is 1, and / or a pharmaceutically acceptable salt thereof; wherein B is Lys, X is a non-alpha primary amine-containing fatty acid having 3 carbon units, and a is 2, and / or a pharmaceutically acceptable salt thereof; and / or wherein B is Lys, X is a non-alpha primary amine-containing fatty acid having 3 carbon units, and a is 3, and / or a pharmaceutically acceptable salt thereof. and each optionally further comprising a pharmaceutically acceptable excipient and / or buffer.

[0245] In some embodiments, the methods of treating a subject having a mean arterial pressure below 95 mmHg (e.g., below 90 mmHg, below 85 mmHg, below 80 mmHg, below 75 mmHg, or below 70 mmHg); the methods of treating a subject having cirrhosis and a mean arterial pressure below 95 mmHg (e.g., below 90 mmHg, below 85 mmHg, below 80 mmHg, below 75 mmHg, or below 70 mmHg); the methods of treating a subject having cirrhosis; the methods of treating a subject having portal hypertension; the methods of treating a subject having ascites; the methods of treating a subject having esophageal varices; the methods of treating a subject having gastric varices; the methods of treating a subject having variceal bleeding; or the methods of treating a subject having hepatorenal syndrome each independently comprise: a peptide of formula (I) as described above, for example, wherein B is Lys and a is 0, or wherein X is Gly and a is an integer from 1 to 10 (e.g., preferably a is 6), and / or a pharmaceutically acceptable salt thereof; or Peptides of formula (II) as described above, for example, wherein: B is Lys, X is Gly, and a is 6, 7, 8, 9, or 10, and / or a pharmaceutically acceptable salt thereof; or A peptide of formula (A) as described above, for example, wherein B is Lys, and X is a non-α primary amino group-containing C 12 a moiety derived from a fatty acid and a is 1; or X is a non-α primary amino group-containing C 10a moiety derived from a fatty acid and a is 1; or X is a moiety derived from a non-alpha primary amino group-containing C8 fatty acid and a is 1; or X is a moiety derived from a non-alpha primary amino group-containing C6 fatty acid, and a is 1; or X is a moiety derived from a non-alpha primary amino group-containing C6 fatty acid, and a is 2; or X is a moiety derived from a non-alpha primary amino group-containing C4 fatty acid, and a is 1; or X is a moiety derived from a non-alpha primary amino group-containing C4 fatty acid, and a is 2; or X is a moiety derived from a non-alpha primary amino group-containing C4 fatty acid and a is 3; or X is a moiety derived from a non-alpha primary amino group-containing C3 fatty acid and a is 1; or X is a moiety derived from a non-alpha primary amino group-containing C3 fatty acid, and a is 2; or X is a moiety derived from a non-alpha primary amino group-containing C3 fatty acid and a is 3; and / or pharmaceutically acceptable salts thereof and each optionally further comprising a pharmaceutically acceptable excipient and / or buffer.

[0246] In some embodiments, a method for treating a subject with hepatorenal syndrome comprises administering a therapeutically effective dose of a pharmaceutical composition comprising the peptide formula (A) above, where X is a moiety derived from 12-aminododecanoic acid (lauric acid), and a is 1; and / or a pharmaceutically acceptable salt thereof, and optionally, a pharmaceutically acceptable excipient and / or buffer. In some embodiments, when the peptide of formula (A) is a peptide of formula (II), additionally, B is Lys.

[0247] In some embodiments, a method for treating a subject with hepatorenal syndrome comprises administering a therapeutically effective dose of a pharmaceutical composition comprising a peptide of the foregoing formula (A), wherein X is a moiety derived from 8-aminooctanoic acid (caprylic acid), and a is 1; and / or a pharmaceutically acceptable salt thereof, and optionally, further comprising a pharmaceutically acceptable excipient and / or buffer. In some embodiments, when the peptide of formula (A) is a peptide of formula (II), additionally, B is Lys.

[0248] In some embodiments, a method for treating a subject with hepatorenal syndrome comprises administering a therapeutically effective dose of a pharmaceutical composition comprising a peptide of the aforementioned formula (A), wherein X is a moiety derived from 6-aminohexanoic acid (caproic acid), and a is 1; and / or a pharmaceutically acceptable salt thereof, and optionally, further comprising a pharmaceutically acceptable excipient and / or buffer. In some embodiments, when the peptide of formula (A) is a peptide of formula (II), additionally, B is Lys.

[0249] In some embodiments, a method for treating a subject with hepatorenal syndrome comprises administering a therapeutically effective dose of a pharmaceutical composition comprising a peptide of the aforementioned formula (A), wherein X is a moiety derived from 4-aminobutanoic acid (butyric acid), and a is 1; and / or a pharmaceutically acceptable salt thereof, and optionally, further comprising a pharmaceutically acceptable excipient and / or buffer. In some embodiments, when the peptide of formula (A) is a peptide of formula (II), additionally, B is Lys.

[0250] In some embodiments, a method for treating a subject with hepatorenal syndrome comprises administering a therapeutically effective dose of a pharmaceutical composition comprising a peptide of the aforementioned formula (A), wherein X is a moiety derived from β-aminopropanoic acid (propionic acid), and a is 1; and / or a pharmaceutically acceptable salt thereof, and optionally further comprising a pharmaceutically acceptable excipient and / or buffer. In some embodiments, when the peptide of formula (A) is a peptide of formula (II), additionally, B is Lys.

[0251] In some embodiments, in any of the aforementioned methods of treating a subject, the pharmaceutical composition is administered by an enteral route (e.g., orally, including drank, swallowed, sublingually, bucally, and / or sublabially; and / or rectally / anally).

[0252] In some embodiments, in any of the aforementioned methods of treating a subject, the pharmaceutical composition is administered by a parenteral route (e.g., intravenous, subcutaneous, subdermal, intramuscular, intraperitoneal, intrapleural, and / or intranasal routes).

[0253] In some embodiments, in any of the above-mentioned methods for treating a subject, the pharmaceutical composition is administered as a bolus dose.For example, the pharmaceutical composition may be administered as an intravenous bolus dose and / or a subcutaneous bolus dose.In certain embodiments, the pharmaceutical composition is administered as an intravenous bolus dose.

[0254] In some embodiments, in any of the aforementioned methods of treating a subject, the pharmaceutical composition is administered by intravenous infusion. For example, the pharmaceutical composition may be administered intravenously as a subcutaneous bolus.

[0255] In some embodiments, for any of the aforementioned methods of treating a subject, the dose is less than 500 nmol / Kg / day (e.g., less than 450 nmol / Kg / day, less than 300 nmol / Kg / day, less than 250 nmol / Kg / day, less than 200 nmol / Kg / day, less than 175 nmol / Kg / day, less than 150 nmol / Kg / day, less than 125 nmol / Kg / day, or less than 100 nmol / Kg / day); preferably less than 200 nmol / Kg / day (e.g., less than 175 nmol / Kg / day, less than 150 nmol / Kg / day, more preferably less than 100 nmol / Kg / day (e.g., less than 90 nmol / Kg / day, less than 80 nmol / Kg / day, less than 60 nmol / Kg / day, less than 50 nmol / Kg / day, less than 40 nmol / Kg / day, less than 30 nmol / Kg / day, less than 20 nmol / Kg / day, or less than 10 nmol / Kg / day). In some embodiments, dose limits may depend on whether the subject is also receiving other drug treatments for the same or a different indication, mean arterial pressure, one or more drugs affecting vascular capacitance, global organ perfusion, and / or the presence or absence of ischemia.

[0256] In some embodiments, for any of the aforementioned methods of treating a subject, the dose may be less than 150 nmol / Kg / day (e.g., less than 140 nmol / Kg / day, less than 130 nmol / Kg / day, less than 120 nmol / Kg / day, less than 110 nmol / Kg / day, less than 100 nmol / Kg / day, less than 90 nmol / Kg / day, less than 80 nmol / Kg / day, less than 70 nmol / Kg / day, or less than 50 nmol / Kg / day).

[0257] In certain embodiments, for any of the aforementioned methods of treating a subject, the dosage is less than 100 nmol / Kg / day (e.g., less than 90 nmol / Kg / day, less than 80 nmol / Kg / day, less than 70 nmol / Kg / day, less than 60 nmol / Kg / day, less than 50 nmol / Kg / day, less than 40 nmol / Kg / day, less than 30 nmol / Kg / day, less than 20 nmol / Kg / day, or less than 10 nmol / Kg / day).

[0258] In some embodiments, for any of the aforementioned methods of treating a subject, the administration frequency is three times per day or less (e.g., once every 8 hours, once every 12 hours, or once every 24 hours).

[0259] In some embodiments, for any of the aforementioned methods of treating a subject, administration occurs only during the daytime from 6:00 to 18:00, once every 4 to 6 hours, and administration does not occur during the nighttime from 18:00 to 6:00.

[0260] In some embodiments, for any of the aforementioned methods of treating a subject, the method can further include administering a V2 antagonist / inhibitor. The V2 antagonist can be administered between 1 and 8 hours (preferably within 1 to 3 hours) before or after (preferably before) administration of the V1a partial agonist. In some embodiments, V2 antagonists include, for example, mozavaptan, tolvaptan, tolvaptan phosphate, satavaptan, lixivaptan, conivaptan, RWJ-351647, VP-343, VP-393, [PmP1, D-Ile2, Ile4, Arg8, Ala9]vasopressin, [PmP1, D-Ile2, Ile4, Arg8, Ala9]vasopressin, and / or [PmP1, D-Ile2, Ile4, Arg8, Ala9]vasopressin-(1-8)-OH. The V1a partial agonist may be administered at a dose of 1 nmol / kg to 250 nmol / kg (e.g., 1 nmol / kg to 150 nmol / kg, or 1 nmol / kg to 75 nmol / kg). In a specific embodiment, when the V2 antagonist is tolvaptan, tolvaptan is parenterally administered at a dose of 1 μg / kg to 300 μg / kg (e.g., 1 μg / kg to 200 μg / kg, or 1 μg / kg to 100 μg / kg).

[0261] In some embodiments, for any of the aforementioned methods of treating a subject, the subject is suffering from ascites (eg, refractory ascites).

[0262] In some embodiments, the present disclosure provides a method of treating a subject with liver fibrosis, cirrhosis, portal hypertension, ascites, esophageal varices, gastric fundal varices, bleeding, mean arterial pressure less than 95 mmHg, hepatorenal syndrome, or any combination thereof, or a subject with liver fibrosis; or a subject with cirrhosis; or a subject with portal hypertension; or a subject with esophageal varices; or a subject with gastric fundal varices; or a subject with bleeding varices; or a subject with cirrhosis with mean arterial pressure less than 95 mmHg; or a subject with hepatorenal syndrome, comprising the steps of: Step (i) comprises reacting a peptide of formula (III) [(U) c -Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Lys-Gly-NH2] [SEQ ID NO: 7] (III) or a pharmaceutically effective salt thereof, wherein the two Cys residues are covalently linked by a disulfide bond, U is an amino acid residue, each occurrence independently selected from Gly, L-Ala, D-Ala, L-Lys, D-Lys, L-Orn, D-Orn, L-Glu, D-Glu, L-Asp, and D-Asp; and c is the number of one or more amino acid residues U and is an integer of 0 to 10. administering to a subject a therapeutically effective dose of a pharmaceutical composition comprising: Step (ii) comprises reacting a peptide of formula (IV) [Mpa-Tyr-Phe-Gln-Asn-Cys-Pro-Lys(Z) d -Gly-NH2][SEQ ID NO: 4] (IV) or a pharmaceutically effective salt thereof, wherein the Mpa and Cys residues are covalently linked by a disulfide bond; Z is an amino acid residue, each occurrence independently selected from Gly, D-Ala, L-Ala, D-Lys, L-Lys, D-Orn, L-Orn, D-Glu, L-Glu, D-Asp, and L-Asp; and d is the number of one or more amino acid residues Z, and is an integer of 0 to 5. administering to a subject a therapeutically effective dose of a pharmaceutical composition comprising:

[0263] In some embodiments, when a V2 antagonist is administered, the V2 antagonist is mozavaptan, tolvaptan, tolvaptan phosphate, satavaptan, lixivaptan, conivaptan, RWJ-351647, VP-343, VP-393, [PmP1, D-Ile2, Ile4, Arg8, Ala9]vasopressin, [PmP1, D-Ile2, Ile4, Arg8]vasopressin, and / or [PmP1, D-Ile2, Ile4, Arg8, Ala9]vasopressin-(1-8)-OH.

[0264] In some embodiments, the V2 antagonist is tolvaptan, which may be administered at a dose of 1 to 300 μg / Kg (e.g., 1 μg / Kg to 200 μg / Kg, or 1 μg / Kg to 100 μg / Kg).

[0265] Embodiments of the peptide of formula (III) are as discussed above. For example, in some embodiments, for a peptide of formula (III), c is not 0. In some embodiments, one or both of the termini of the peptide of formula (III) do not contain an alkyl group (e.g., an alkyl group having 3 to 36 carbon units). In some embodiments, one or both of the termini of the peptide of formula (III) do not contain an alkyl group having 3 to 36 carbon units, nitrilotriacetic acid, imidodiacetic acid, or one or more histidine residues. In some embodiments, the peptide of formula (III) does not contain a peptide in which U is Gly and / or His and c is an integer from 1 to 6, optionally containing a terminal alkyl group. In some embodiments, (U) in a peptide of formula (III) cdoes not include Leu, Phe, Tyr, Trp, Pro, Gly-Gly, Leu-Leu, Gly-Pro, sarkosyl-Gly, and / or Gly-Gly-Gly.

[0266] In some embodiments, a method of treating a subject having liver fibrosis, cirrhosis, portal hypertension, ascites, esophageal varices, gastric fundal varices, bleeding, mean arterial pressure less than 95 mmHg, hepatorenal syndrome, or any combination thereof, comprises administering a therapeutically effective dose of a pharmaceutical composition comprising a V1a agonist administered within 1 to 8 hours (e.g., preferably within 1 to 3 hours) either before or after (e.g., preferably after) administration of a therapeutically effective dose of a V2 antagonist; wherein the V1a agonist is a peptide of formula (IV): [Mpa-Tyr-Phe-Gln-Asn-Cys-Pro-Lys(Z) d -Gly-NH2][SEQ ID NO: 4] (IV) or a pharmaceutically effective salt thereof, wherein the Mpa and Cys residues are covalently linked by a disulfide bond; Z is an amino acid residue, each occurrence independently selected from Gly, D-Ala, L-Ala, D-Lys, L-Lys, D-Orn, L-Orn, D-Glu, L-Glu, D-Asp, and L-Asp; and d is the number of one or more amino acid residues Z, and is an integer of 0 to 5. and wherein the V2 antagonist is mozavaptan, tolvaptan, tolvaptan phosphate, satavaptan, lixivaptan, conivaptan, RWJ-351647, VP-343, VP-393, [PmP1, D-Ile2, Ile4, Arg8, Ala9]vasopressin, [PmP1, D-Ile2, Ile4, Arg8]vasopressin, and / or [PmP1, D-Ile2, Ile4, Arg8, Ala9]vasopressin-(1-8)-OH.

[0267] In some embodiments, a method of treating a subject having liver fibrosis, cirrhosis, portal hypertension, ascites, esophageal varices, gastric fundal varices, bleeding, mean arterial pressure less than 95 mmHg, hepatorenal syndrome, or any combination thereof, comprises administering a therapeutically effective dose of a pharmaceutical composition comprising a V1a agonist, followed 2 to 8 hours later by administering a therapeutically effective dose of a V2 antagonist; wherein the V1a agonist is a peptide of formula (III): [(U) c -Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Lys-Gly-NH2] [SEQ ID NO: 7] (III) or a pharmaceutically effective salt thereof, wherein the two Cys residues are covalently linked by a disulfide bond, U is an amino acid residue, each occurrence independently selected from Gly, L-Ala, D-Ala, L-Lys, D-Lys, L-Orn, D-Orn, L-Glu, D-Glu, L-Asp, and D-Asp; and c is the number of one or more amino acid residues U and is an integer of 0 to 10. and wherein the V2 antagonist is mozavaptan, tolvaptan, tolvaptan phosphate, satavaptan, lixivaptan, conivaptan, RWJ-351647, VP-343, VP-393, [PmP1, D-Ile2, Ile4, Arg8, Ala9]vasopressin, [PmP1, D-Ile2, Ile4, Arg8]vasopressin, and / or [PmP1, D-Ile2, Ile4, Arg8, Ala9]vasopressin-(1-8)-OH.

[0268] In some embodiments, a method for treating a subject having liver fibrosis, cirrhosis, portal hypertension, ascites, esophageal varices, gastric fundal varices, bleeding, mean arterial pressure less than 95 mmHg, hepatorenal syndrome, or any combination thereof, comprises administering a therapeutically effective dose of a pharmaceutical composition comprising a V1a agonist, followed 2 to 8 hours later by parenteral administration of tolvaptan at a dose of 1 to 300 μg / Kg (e.g., 1 μg / Kg to 200 μg / Kg, or 1 μg / Kg to 100 μg / Kg); wherein the V1a agonist is a peptide of formula (IV): [Mpa-Tyr-Phe-Gln-Asn-Cys-Pro-Lys(Z) d -Gly-NH2][SEQ ID NO: 4] (IV) or a pharmaceutically effective salt thereof, wherein the Mpa and Cys residues are covalently linked by a disulfide bond; Z is an amino acid residue, each occurrence independently selected from Gly, D-Ala, L-Ala, D-Lys, L-Lys, D-Orn, L-Orn, D-Glu, L-Glu, D-Asp, and L-Asp; and and d is the number of one or more amino acid residues Z, which is an integer of 0 to 5.

[0269] In some embodiments, the present disclosure provides a method for treating a subject having liver fibrosis, cirrhosis, portal hypertension, ascites, esophageal varices, gastric fundal varices, bleeding, mean arterial pressure less than 95 mmHg, hepatorenal syndrome, or any combination thereof, comprising administering a therapeutically effective dose of a pharmaceutical composition comprising a V1a agonist, followed 2 to 8 hours later by parenteral administration of tolvaptan at a dose of 1 to 300 μg / Kg (e.g., 1 μg / Kg to 200 μg / Kg, or 1 μg / Kg to 100 μg / Kg), The V1a agonist is a peptide of formula (III): [(U) c -Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Lys-Gly-NH2] [SEQ ID NO: 7] (III) or a pharmaceutically effective salt thereof, wherein the two Cys residues are covalently linked by a disulfide bond, U is an amino acid residue, each occurrence independently selected from Gly, L-Ala, D-Ala, L-Lys, D-Lys, L-Orn, D-Orn, L-Glu, D-Glu, L-Asp, and D-Asp; and and c is the number of one or more amino acid residues U and is an integer from 0 to 10.

[0270] In any of the foregoing methods, administration can be oral and / or parenteral. In certain embodiments, administration is parenteral, such as subcutaneous or intravenous administration. In certain embodiments, parenteral administration is subcutaneous administration. [Example]

[0271] Example 1: Peptide synthesis for peptides of formula (I). The formula (I) peptide was synthesized by solid phase peptide synthesis (SPPS) using Rink amide resin-ProTide (0.59 mmol / g) as the starting solid support (CEM, Matthews, NC) in an automated microwave peptide synthesizer (LibertyBlue HT12, CEM, Matthews, NC). Fmoc-protected amino acids were prepared as follows: Fmoc-Gly-OH (Combi-Blocks, San Diego, CA), Fmoc-Lys(dde)-OH (Combi-Blocks, San Diego, CA), Fmoc-Pro-OH (Combi-Blocks, San Diego, CA), Fmoc-Cys(Mmt)-OH, Fmoc-Asn(Trt)-OH (Combi-Blocks, San Diego, CA), Fmoc-Homogln(Trt)-OH (BLDPharm, Shanghai, China), Fmoc-Phe-OH (Combi-Blocks, San Diego, CA), Fmoc-Tyr(tBu)-OH (Combi-Blocks, San Diego, CA), Fmoc-12-Ado-OH (Combi-Blocks, San Diego, CA), MPA(Mmt)-OH (GLBiochem, Shanghai, China), Fmoc-L-Dab(Dde)-OH (BLDPharm, Shanghai, China), Fmoc-D-Dab(Dde)-OH (BLDPharm, Shanghai, China), Fmoc-L-Dap(Dde)-OH (BLDPharm, Shanghai, China), Fmoc-D-Dap(Dde)-OH (BLDPharm, Shanghai, China), Fmoc-L -Orn(Dde)-OH (BLDPharm, Shanghai, China), Fmoc-D-Orn(Dde)-OH (BLDPharm, Shanghai, China), Fmoc-D-Lys(Dde)-OH (BLDPharm, Shanghai, China), Fmoc-L-Ala-OH (BLDPharm, Shanghai, China), Fmoc-D-Ala-OH (BLDPharm, Shanghai, China), Fmo c-L-Glu(OtBu)-OH (BLDPharm, Shanghai, China), Fmoc-D-Glu(OtBu)-OH (BLDPharm, Shanghai, China), Fmoc-L-Asp(OtBu)-OH (BLDPharm, Shanghai, China), Fmoc-D-Asp(OtBu)-OH (BLDPharm, Shanghai, China), Fmoc-L-Lys(Boc)-OH(B Fmoc-D-Lys(Boc)-OH (BLDPharm, Shanghai, China), Fmoc-L-Orn(Boc)-OH (BLDPharm, Shanghai, China), Fmoc-D-Orn(Boc)-OH (BLDPharm, Shanghai, China), and Fmoc-Gly-Gly-OH (BLDPharm, Shanghai, China) were used. Each amino acid was sequentially anchored to the peptide resin using Fmoc chemistry, resulting in a linear, protected peptide on the resin. The Dde-protected side chain of Lys (or B) was then selectively deprotected with 2% hydrazine in DMF, followed by another Fmoc chemistry to form the protected branched peptide on the resin. The Mmt-protected side chains of cysteine ​​and 3-mercaptopropionic acid were then selectively deprotected with 2% TFA in DCM, followed by on-resin disulfide bond formation using N-chlorosuccinimide. Acidolysis with trifluoroacetic acid in the presence of a carbocation scavenger and ether precipitation afforded the cyclized crude peptide. Finally, the peptide was purified and analyzed by reverse-phase HPLC (1260 Infinity II).The compounds were characterized by Preparative LC Systems (Santa Clara, CA) using the following method:

[0272] [Table 1]

[0273] Fractions were then collected and lyophilized to a white powder. The mass of the peptide was determined using an Agilent LCMS system (6100 Series Single Quadrupole LC / MS, Santa Clara, CA) with the following gradient conditions:

[0274] [Table 2A]

[0275] [Table 2B]

[0276] Using the general method described in this example, the sequence [Mpa-Tyr-Phe-Hgn-Asn-Cys-Pro-B(X) a The TFA salt of a peptide having the structure: -Gly [SEQ ID NO: 8]; with a disulfide bond between Mpa and Cys, where B is Lys, X is a Gly residue, and a is 1, was synthesized and purified. HPLC analysis of this peptide showed a retention time of 21.615 min and a purity of 92%. The empirical formula is C 49 H 69 N 13 O 13 S2, and the theoretical monoisotopic mass was 1111.5. The actual mass measured by LCMS ([M+H] + was found to be 1112.5 using the method described herein.

[0277] Using the general method described in this example, the sequence [Mpa-Tyr-Phe-Hgn-Asn-Cys-Pro-B(X) aThe TFA salt of a peptide having the formula: β-Gly [SEQ ID NO: 9]; with a disulfide bond between Mpa and Cys, where B is Lys, where X is Gly, and a is 2, was synthesized and purified. HPLC analysis of this peptide shows a 94% pure peak with a retention time of 21.515 minutes. The empirical formula is C 51 H 72 N 14 O 14 S2, and the theoretical monoisotopic mass was 1168.5. Measured mass by LCMS [M+H] + was 1169.5 using the method described herein.

[0278] Using the general method described in this example, the sequence [Mpa-Tyr-Phe-Hgn-Asn-Cys-Pro-B(X) a The TFA salt of a peptide having the formula: [B-Gly [SEQ ID NO: 10]; with a disulfide bond between Mpa and Cys] (wherein B is Lys, X is Gly, and a is 3) was synthesized and purified. HPLC analysis of this peptide shows a 95% pure peak with a retention time of 21.355 min. The empirical formula is C 53 H 75 N 15 O 15 S2, and the theoretical monoisotopic mass was 1226.4. Measured mass by LCMS [M+H] + was 1227.5 using the method described herein.

[0279] Using the general method described in this example, the sequence [Mpa-Tyr-Phe-Hgn-Asn-Cys-Pro-B(X) a The TFA salt of a peptide having the formula: [B-Gly [SEQ ID NO: 11]; with a disulfide bond between Mpa and Cys] (where B is Lys, X is Gly, and a is 4) was synthesized and purified. HPLC analysis of this peptide shows a retention time of 21.281 min with 91% purity. The empirical formula is C 55 H 78 N 16 O 16S2, and the theoretical monoisotopic mass was 1282.5. Measured mass by LCMS [M+H] + was 1283.5 using the method described herein.

[0280] Using the general method described in this example, the sequence [Mpa-Tyr-Phe-Hgn-Asn-Cys-Pro-B(X) a The TFA salt of a peptide having the formula: [B-Gly [SEQ ID NO: 12]; with a disulfide bond between Mpa and Cys] (wherein B is Lys, X is Gly, and a is 5) was synthesized and purified. HPLC analysis of the above peptide shows a retention time of 20.959 min with 93% purity. The empirical formula is C 57 H 81 N 17 O 17 S2, and the theoretical monoisotopic mass was 1339.5. Measured mass by LCMS [M+H] + was 1340.5 using the method described herein.

[0281] Using the general method described in this example, the sequence [Mpa-Tyr-Phe-Hgn-Asn-Cys-Pro-B(X) a The TFA salt of a peptide having the structure: [B-Gly [SEQ ID NO: 13]; with a disulfide bond between Mpa and Cys] (wherein B is Lys, X is Gly, and a is 6) was synthesized and purified. HPLC analysis of the above peptide shows a retention time of 20.73 min with 90% purity. The empirical formula is C 59 H 84 N 18 O 18 S2 with a theoretical monoisotopic mass of 1396.5. Using the methods described herein, the observed mass by LCMS was: [M+H] + =1397.5.

[0282] Using the general method described in this example, the sequence [Mpa-Tyr-Phe-Hgn-Asn-Cys-Pro-B(X) aThe TFA salt of a peptide having the formula: [B - Gly [SEQ ID NO: 14]; with a disulfide bond between Mpa and Cys] (where B is Lys, X is Gly, and a is 7) was synthesized and purified. HPLC analysis of the above peptide shows a retention time of 20.988 min with 89% purity. The empirical formula is C 61 H 87 N 19 O 19 S2, and the theoretical monoisotopic mass was 1453.5. Measured mass by LCMS [M+H] + was 1454.5 using the method described herein.

[0283] Using the general method described in this example, the sequence [Mpa-Tyr-Phe-Hgn-Asn-Cys-Pro-B(X) a The TFA salt of a peptide having the formula: [B-Gly [SEQ ID NO: 15]; with a disulfide bond between Mpa and Cys] (wherein B is Lys, X is Gly, and a is 8) was synthesized and purified. HPLC analysis of the above peptide shows a retention time of 20.836 min with 87% purity. The empirical formula is C 63 H 90 N 20 O 20 S2, and the theoretical monoisotopic mass was 1510.6. Measured mass by LCMS [M+H] + was 1511.6 using the method described herein.

[0284] Using the general method described in this example, the sequence [Mpa-Tyr-Phe-Hgn-Asn-Cys-Pro-B(X) a The TFA salt of a peptide having the formula: [B - Gly [SEQ ID NO: 16]; with a disulfide bond between Mpa and Cys] (wherein B is Lys, X is Gly, and "a" is 9) was synthesized and purified. HPLC analysis of the above peptide shows a retention time of 20.729 min with 86% purity. The empirical formula is C 65 H 93 N 21 O 21S2, and the theoretical monoisotopic mass was 1567.6. Measured mass by LCMS [M+H] + was 1568.6 using the method described herein.

[0285] Using the general method described in this example, the sequence [Mpa-Tyr-Phe-Hgn-Asn-Cys-Pro-B(X) a The TFA salt of a peptide having the formula: α-Gly [SEQ ID NO: 17]; with a disulfide bond between Mpa and Cys (where B is Dap; where "a" is 0) was synthesized and purified. HPLC analysis of the above peptide shows a retention time of 20.981 min with 86% purity. The empirical formula is C 44 H 60 N 12 O 12 S2, and the theoretical monoisotopic mass was 1012.4. Measured mass by LCMS [M+H] + was 1013.4 using the method described herein.

[0286] Using the general method described in this example, the sequence [Mpa-Tyr-Phe-Hgn-Asn-Cys-Pro-B(X) a The TFA salt of a peptide having the formula: d-Gly [SEQ ID NO: 18]; with a disulfide bond between Mpa and Cys (where B is d-Lys; where "a" is 0) was synthesized and purified. HPLC analysis of the above peptide shows a retention time of 21.382 min with 91% purity. The empirical formula is C 47 H 66 N 12 O 12 S2, and the theoretical monoisotopic mass was 1054.4. Measured mass by LCMS [M+H] + was 1055.5 using the method described herein.

[0287] Using the general method described in this example, the sequence [Mpa-Tyr-Phe-Hgn-Asn-Cys-Pro-B(X) aThe TFA salt of a peptide having the formula: [(B)-Gly [SEQ ID NO: 19]; with a disulfide bond between Mpa and Cys] (where B is Lys; where "(X)" is 12-aminododecanoic acid, and "a" is 1) was synthesized and purified. HPLC analysis of the above peptide shows a retention time of 31.354 minutes with 91% purity. The empirical formula is C 59 H 89 N 13 O 13 S2, and the theoretical monoisotopic mass was 1251.6. Measured mass by LCMS [M+H] + was 1252.5 using the method described herein.

[0288] Example 2: Peptide synthesis for peptides of formula (II) and formula (IV). Peptides of formula (II) and formula (IV) were synthesized by solid phase peptide synthesis (SPPS) using Rink amide resin-ProTide (0.59 mmol / g) as the starting solid support (CEM, Matthews, NC) in an automated microwave peptide synthesizer (LibertyBlue HT12, CEM, Matthews, NC).Fmoc-protected amino acids were prepared as follows: Fmoc-Gly-OH (Combi-Blocks, San Diego, CA), Fmoc-Lys(dde)-OH (Combi-Blocks, San Diego, CA), Fmoc-Pro-OH (Combi-Blocks, San Diego, CA), Fmoc-Cys(Mmt)-OH (Combi-Blocks, San Diego, CA), Fmoc-Asn(Trt)-OH (Combi-Blocks, San Diego, CA), Fmoc-Gln(Trt)-OH (Combi-Blocks, San Diego, CA), Fmoc-Phe-OH (Combi-Blocks, San Diego, CA), Fmoc-Tyr(tBu)-OH (Combi-Blocks, San Diego, CA), MPA(Mmt)-OH (Combi-Blocks, San Diego, CA), and methylparaben-1-phosphate dehydrogenase (MPA)-OH (Combi-Blocks, San Diego, CA). Biochem, Shanghai, China), Fmoc-Gly-Gly-OH (BLDPharm, Shanghai, China), Fmoc-L-Orn(Dde)-OH (BLDPharm, Shanghai, China), Fmoc-D-Orn(Dde)-OH (BLDPharm, Shanghai, China), Fmoc-D-Ly s(Dde)-OH (BLDPharm, Shanghai, China), Fmoc-L-Ala-OH (BLDPharm, Shanghai, China), Fmoc-D-Ala-OH (BLDPharm, Shanghai, China), Fmoc-L-Glu(OtBu)-OH (BLDPharm, Shanghai, China), Fmoc- The amino acids used included D-Glu(OtBu)-OH (BLDPharm, Shanghai, China), Fmoc-L-Asp(OtBu)-OH (BLDPharm, Shanghai, China), Fmoc-D-Asp(OtBu)-OH (BLDPharm, Shanghai, China), Fmoc-L-Lys(Boc)-OH (BLDPharm, Shanghai, China), Fmoc-D-Lys(Boc)-OH (BLDPharm, Shanghai, China), Fmoc-L-Orn(Boc)-OH (BLDPharm, Shanghai, China), and Fmoc-D-Orn(Boc)-OH (BLDPharm, Shanghai, China). Each amino acid was sequentially anchored to the peptide resin using Fmoc chemistry, resulting in a linear protected peptide on the resin.Next, the Lys side chain was selectively deprotected with 2% hydrazine in DMF, followed by another Fmoc chemistry to provide the protected branched peptide on the resin. Next, the cysteine ​​and 3-mercaptopropionic acid side chains were selectively deprotected with 2% TFA in DCM, followed by on-resin disulfide bond formation using N-chlorosuccinimide. Acidolysis with trifluoroacetic acid in the presence of a carbocation scavenger and ether precipitation afforded the crude cyclized peptide. Finally, the peptide was purified and characterized by reverse-phase HPLC using the method described in Example 1, followed by lyophilization as a white powder. The mass of the peptide was determined using an Agilent LCMS system using the same LCMS method as in Example 1.

[0289] Using the general method described in this example, the sequence [Mpa-Tyr-Phe-Gln-Asn-Cys-Pro-Lys(X) a The TFA salt of a peptide having the formula: α-Gly [SEQ ID NO: 20]; with a disulfide bond between Mpa and Cys, where X is Gly and a is 6, was synthesized and purified. HPLC analysis of this peptide shows a retention time of 20.624 min with 96% purity. The empirical formula is C 58 H 82 N 18 O 18 S2, and the theoretical monoisotopic mass was 1382.5. Measured mass by LCMS [M+H] + was 1383.5 using the method described in Example 1.

[0290] Using the general method described in this example, the sequence [Mpa-Tyr-Phe-Gln-Asn-Cys-Pro-Lys(X) a The TFA salt of a peptide having the formula: [Cys-Gly [SEQ ID NO: 21]; disulfide bond between Mpa and Cys] (wherein X is Gly and a is 7) was synthesized and purified. HPLC analysis of the above peptide shows a retention time of 20.495 min with 95% purity. The empirical formula is C 60 H 85 N 19 O 19S2, the theoretical monoisotopic mass was 1439.6. Measured mass by LCMS: [M+H] + was 1440.5 using the method described in Example 1.

[0291] Using the general method described in this example, the sequence [Mpa-Tyr-Phe-Gln-Asn-Cys-Pro-Lys(X) a The TFA salt of a peptide having the formula: X-Gly [SEQ ID NO: 22]; with a disulfide bond between Mpa and Cys, where X is Gly and a is 8, was synthesized and purified. HPLC analysis of the above peptide shows a retention time of 21.121 min with 90% purity. The empirical formula is C 62 H 88 N 20 O 20 S2, and the theoretical monoisotopic mass was 1496.6. Measured mass by LCMS [M+H] + was 1497.6 using the method described in Example 1.

[0292] Using the general method described in this example, the sequence [Mpa-Tyr-Phe-Gln-Asn-Cys-Pro-Lys(X) a The TFA salt of a peptide having the formula: [Cys-Gly [SEQ ID NO: 23]; disulfide bond between Mpa and Cys] (wherein X is Gly and a is 9) was synthesized and purified. HPLC analysis of the above peptide shows a retention time of 20.409 min with 93% purity. The empirical formula is C 64 H 91 N 21 O 21 S2, and the theoretical monoisotopic mass was 1553.6. Measured mass by LCMS [M+H] + was 1554.6 using the method described in Example 1.

[0293] Example 3: (X) a (Gly) 0~9 A peptide partial agonist of formula (I) which is The peptide of formula (I) is Mpa-Tyr-Phe-Hg-Asn-Cys-Pro-Lys(X) a -Gly-NH2 [SEQ ID NO: 24] (wherein (X) a is a peptide with "a" residues, where each residue X is independently selected from Gly and the D- or L-amino acid versions of Ala, Lys, Orn, Glu, and Asp, where "a" is 0 to 10. V1a human vasopressin GPCR cell-based agonist calcium flux assays were performed at Eurofins Cerep SA (France) on a fee-for-service basis. Human recombinant CHO cells expressing the human V1 receptor were dispensed into microplates. Intracellular calcium signals were detected fluorimetrically, and signals were acquired before and after the addition of known agonist concentrations. The following agonist concentrations were tested (nM): 0.0128, 0.064, 0.32, 1.6, 8, 40, 200, and 1,000. Results are expressed as a percentage of the 1,000 nM AVP agonist response. All assays were performed in duplicate. Changes in fluorescence intensity reflected changes in the concentration of free cytosolic calcium. The standard reference agonist was AVP, and the maximal activity of other agonists is expressed as a percentage of the maximal AVP activity. The half-maximal effective concentration (EC50) was determined by nonlinear regression analysis of concentration-response curves generated using Hill equation curve fitting with replicate means (Cerep, I'Evescault, France). Figure 2 shows exemplary graphical data and an overview of representative species of Formula (I), which are also summarized in Table 3. All species are partial agonists.

[0294] [Table 3-1]

[0295] [Table 3-2]

[0296] Example 4: (X) aPeptides of formula (II) when is (Gly)6 or (Gly)9: partial agonists (Table 4). V1a human vasopressin GPCR cell-based agonist calcium flux assays were performed using human recombinant CHO cells expressing the human V1 receptor. Briefly, 4.5 x 10 human recombinant CHO cells expressing the human V1 receptor were plated in a microplate. 4 The assay plate was then placed in a microplate reader (CellLux, PerkinElmer) using test compounds, reference agonists, or HBSS buffer (basal control) to measure free cytosolic Ca. A fluorescent probe (Fluo4 Direct, Invitrogen) mixed with probenecid in HBSS buffer (Invitrogen) supplemented with 20 mM HEPES (Invitrogen), pH 7.4, was then added to each well and allowed to equilibrate with the cells for 60 minutes at 37°C, followed by 15 minutes at 22°C. The assay plate was then placed in a microplate reader (CellLux, PerkinElmer) using test compounds, reference agonists, or HBSS buffer (basal control) to measure free cytosolic Ca. 2+ The change in fluorescence intensity, which varies proportionally with ion concentration, is measured. The following agonist concentrations (nM) were tested: 0.0128, 0.064, 0.32, 1.6, 8, 40, 200, and 1,000. Results were expressed as a percentage of the 1,000 nM AVP agonist response. All assays were performed in duplicate. The change in fluorescence intensity reflected changes in the concentration of free cytosolic calcium. The standard reference agonist was AVP, and the maximal activity of other agonists was expressed as a percentage of the maximal AVP activity. Referring to Figure 3 and Table 4, the half-maximal effective concentration (EC50) was determined by nonlinear regression analysis of concentration-response curves generated using Hill equation curve fitting with replicate means (Cerep, I'Evescault, France).

[0297] [Table 4]

[0298] Example 5: Combination therapy with tolvaptan and terlipressin on acute diuretic activity in Wistar rats (Table 5) In this study, male Wistar rats (approximately 8 weeks old; Envigo; Somerset, NJ) were fasted overnight (18 hours; water ad libitum) and then treated with 20 ml / kg saline by oral gavage to ensure uniform hydration in all animals. Animals were then treated with various concentrations of terlipressin (Bachem, Torrance, CA), tolvaptan (Fisher Scientific, Waltham, MA), and a combination of these two compounds, administered subcutaneously (n=4). The test articles were terlipressin 0.05 mg / kg and 0.15 mg / kg, tolvaptan 0.3 mg / kg and 1.0 mg / kg, terlipressin 0.05 mg / kg + tolvaptan 0.3 mg / kg, terlipressin 0.05 mg / kg + tolvaptan 1.0 mg / kg, terlipressin 0.15 mg / kg + tolvaptan 0.3 mg / kg, and terlipressin 0.15 mg / kg + 1.0 mg / kg. Furosemide (Fisher Scientific, Waltham, MA) was used as a positive control and administered at a dose of 20 mg / kg by oral gavage. A subcutaneous vehicle control (9% Tween 80; Fisher Scientific, Waltham, MA) was included, and the resulting data were subtracted from the individual test article data. After dosing, animals were placed in metabolic cages (Tecniplast; Province of Varese, Italy), and urine was collected and measured at 2, 4, and 8 hours after test substance administration. Urine volume was expressed as ml / 100 g body weight by dividing by body weight (pre-dose) × 100. Table 4 shows that at low doses of subcutaneous tolvaptan (0.3 mg / kg), combinations of terlipressin to tolvaptan weight ratios of 1:2 to 1:6 were preferred, resulting in additive effects on total urine volume, equivalent to the sum of the individual doses. Higher doses of tolvaptan and ratios of 1:7 to 1:20 had subtractive effects on total urine volume, resulting in less than the sum of the individual doses.However, regardless of the ratio, a tolvaptan dose of approximately 0.3 mg / kg (i.e., 0.3±0.05 mg / kg) administered in rats (allometrically equivalent to approximately 2-5 mg / human, depending on body weight) is an ideal dose that, when combined with the compositions of the present disclosure, provides more than 50% of the total diuretic effect of the individual doses administered alone. A low dose of 0.3 mg / kg of subcutaneous tolvaptan is considered to be 1 / 13th the effective and safe human dose, thus providing an additional benefit to patients with liver disease. This allows for the V1a effect (elevation of mean arterial pressure (MAP)) induced by the compositions of the present disclosure to be significant (at least 50% of the total diuretic effect of the individual doses administered alone) while maintaining both significant effects.

[0299] [Table 5]

[0300] Example 6: Combination therapy with tolvaptan and peptides of formula (II) and formula (IV) on acute diuretic activity in Wistar rats (Table 6) In this study, male Wistar rats (approximately 8 weeks old; Envigo; Somerset, NJ) were fasted overnight (18 hours; water ad libitum) and then treated with 20 ml / kg saline by oral gavage to ensure uniform hydration in all animals. Animals were then treated with various concentrations of the test article administered subcutaneously (n = 4) (Table 5). A control vehicle group (9% Tween 80; Fisher Scientific, Waltham, MA) was administered subcutaneously, and the resulting data were subtracted from the individual test article data. After administration, animals were placed in metabolic cages (Tecniplast; Province of Varese, Italy), and urine was collected and measured at 2, 4, and 8 hours after test article administration. Urine volume was expressed as ml / 100 g body weight by dividing by body weight (pre-dose) × 100. Table 4 shows that at low doses of subcutaneous tolvaptan (0.3 mg / kg), combinations of terlipressin to tolvaptan weight ratios of 1:2 to 1:6 are preferred, resulting in additive effects on total urine output, equivalent to the sum of the individual doses. Higher doses of tolvaptan and ratios of 1:7 to 1:20 have subtractive effects on total urine output, resulting in less than the sum of the individual doses. However, at either ratio, a tolvaptan dose of approximately 0.3 mg / kg administered in rats (i.e., 0.3±0.05 mg / kg) (allometrically equivalent to approximately 2-7 mg / human depending on human body weight) is an ideal dose that provides more than 50% of the sum of the individual diuretic effects when administered alone in combination with the compositions of the present disclosure. A low dose of 0.3 mg / kg of subcutaneous tolvaptan is considered to be 1 / 13th the effective and safe human dose, thus providing additional benefits to patients with liver disease. This allows for an increase in mean arterial pressure (MAP), the V1a effect caused by the compositions of the present disclosure, while maintaining a significant (at least 50% of the sum of the individual diuretic effects when administered alone) of both.

[0301] [Table 6-1]

[0302] [Table 6-2]

[0303] Example 7: The compositions of the present disclosure have a much higher therapeutic index than other known V1a agonists. In this study, various test substances were administered intravenously (IV) or subcutaneously (SC) to 8- to 10-week-old male Sprague-Dawley rats (Charles River; Wilmington, MA) (n = 3 or 6) under isoflurane anesthesia. Prior to administration of the test substance, the area of ​​injection was shaved with clippers to clearly visualize the injection site, and the animals' weights were measured and recorded. Animals were housed in pairs per cage. After each injection, animals were observed at least every 30 minutes for up to 8 hours and examined the following day. The onset and end times of symptoms were recorded and summarized in Table 6. The no-observed-effect level (NOEL) was defined as the highest dose of test substance at which animals did not exhibit any symptoms within 24 hours after injection, compared to untreated controls. The no-observed-adverse-effect level (NOAEL) was defined as the highest dose at which animals showed ear pallor but no lethargy after injection, compared to untreated controls. A mild adverse effect was defined as the lowest dose at which animals exhibited lethargy in addition to pale ears when compared to untreated controls. A severe adverse effect was defined as the lowest dose at which animals exhibited lethargy and pale ears in addition to ataxia when compared to untreated controls. Lethargy was defined as when the animal's eyes were not fully open, accompanied by deep breathing, and limited movement despite human presence. Ataxia was defined as when the animal exhibited impaired mobility, evidenced by lying down. After 24 hours, the absence of any of the four symptom categories indicated that the test substance and / or drug activity had been eliminated / metabolized / degraded from the system / body.

[0304] [Table 7-1]

[0305] [Table 7-2]

[0306] [Table 7-3]

[0307] [Table 7-4]

[0308] [Table 7-5]

[0309] [Table 7-6]

[0310] [Table 7-7]

[0311] [Table 7-8]

[0312] [Table 7-9]

[0313] Example 8. Acute diuretic activity of combinations of peptides of formula (I) and tolvaptan by subcutaneous injection in Wistar rats (Table 8). Referring to Table 8, this study showed that at 4 and 8 hours, a combination of a V2 antagonist such as tolvaptan (Tol) and a peptide of formula (I) (Mpa-YFhomoQNCPK(GGGGGG)G-NH2 [SEQ ID NO: 13]; Mpa and C are disulfide-bonded; designated as TA-1) given 2 hours later showed a significant increase in urine volume compared to the vehicle group, and this combination demonstrated a synergistic / additive effect of these two drugs. Administering these drugs separately, particularly administering tolvaptan first, may be the best way to achieve the same or higher therapeutic efficacy by combining a peptide of formula (I) with a lower dose of tolvaptan than currently used or prescribed. Such a lower therapeutic dose of tolvaptan would reduce the known risk of liver toxicity for many patients.

[0314] For this test, the temperature of the animal room was set to be maintained at 20-22°C. Except for interruptions due to test procedures, the test was conducted under a 14-hour light, 10-hour dark cycle. Approximately 45 minutes before testing the diuretic effects of various test substances, male Wistar rats (approximately 8 weeks old, Charles Water content was standardized among animals by oral gavage (PO) of 20 ml / kg saline (supplied by River Laboratory; n=4 per group). The following test substances and combinations were administered subcutaneously: Group 1—vehicle (9% Tween 80); Group 2—TA-1 alone; Group 3—tolvaptan (Tol) alone; Group 4—TA-1 0.08 mg / kg + Tol 0.3 mg / kg administered together; Group 5—TA-1 0.08 mg / kg at time 0, followed by Tol 0.3 mg / kg 2 hours later; Group 6—Tol 0.3 mg / kg at time 0, followed by TA-1 0.08 mg / kg 2 hours later. Urine was collected and cumulative volume measured at various time points post-dose.

[0315] [Table 8]

[0316] Example 9. Telemetry assessment of the effects of MPA-YF homoQNCPK(GGGGGG)G-NH2 [SEQ ID NO: 13] and terlipressin on portal pressure in bile duct ligated rats. Referring to Table 9, the peptide of formula (I) (12 μg / kg dose) is more effective in providing sustained reduction in portal vein pressure compared to terlipressin (41 μg / kg dose). For this study, animals (Sprague-Dawley rats (240-300 g at time of surgery, Charles River Laboratory-supplied rats were maintained at room temperature (20-22°C) on a 14-hour light / 10-hour dark cycle when test procedures were not being performed. The effectiveness of the peptide of formula (I) (Mpa-YFhomoQNCPK(GGGGGG)G-NH2 [SEQ ID NO: 13]; Mpa and C are disulfide-bonded; designated TA-1) in reducing mean portal venous pressure (MPVP) was compared with terlipressin in telemetered bile duct ligated (BDL) and sham-operated male rats. On test day 1, rats underwent bile duct ligation surgery and implantation of a telemetry device. In the BDL group (n = 4), two silk sutures were tightly tied to occlude the bile duct; in the sham group (n = 3), the sutures were loosely tied around the bile duct. No obstruction occurred. After recovery from surgery, the portal vein pressure of all rats was continuously monitored by telemetry until day 22. Vehicle was administered subcutaneously on day 14; peptide of formula (I) was administered subcutaneously at various concentrations on days 15-19 and 23; terlipressin was administered by intravenous bolus into the lateral tail vein on days 20 and 21. All animals were manually restrained during dosing. Mean portal vein pressure (MPVP) was calculated by measuring systolic and diastolic portal vein pressure; MPVP was analyzed by averaging 5-minute intervals for the first 4 hours after dosing, and then averaging 1-hour intervals after dosing for up to 24 hours. Time point zero (T0) was calculated using the average from 45 minutes before dosing to 15 minutes before dosing.

[0317] Telemetry evaluation of Mpa-YF homo QNCPK(GGGGGG)G-NH2 [SEQ ID NO: 13] and terlipressin on portal vein pressure in bile duct-ligated rats. The temperature in the animal room was maintained at 20-22°C. Experiments were conducted under a 14-hour light, 10-hour dark cycle, except for interruptions due to experimental procedures. Efficacy was determined by assessing mean portal vein pressure (MPVP) with various concentrations of Formula 1 and terlipressin in telemetry-controlled bile duct-ligated (BDL) and sham-operated male Sprague-Dawley rats (240-300 g at the time of surgery, provided by Charles River Laboratory). On study day 1, rats underwent bile duct ligation surgery and implantation of a telemetry device. In the BDL group (n = 4), two silk sutures were tightly tightened and tied to occlude the bile duct; in the sham group (n = 3), the sutures were loosely tied around the bile duct, preventing occlusion. After recovery from surgery, the portal vein pressure of all rats was continuously monitored by telemetry until day 22. Vehicle was administered subcutaneously on day 14; Formula 1 was administered subcutaneously at various concentrations on days 15–19 and 23; terlipressin was administered by intravenous bolus into the lateral tail vein on days 20 and 21. All animals were manually restrained during dosing. Mean portal vein pressure (MPVP) was calculated by measuring systolic and diastolic portal vein pressure; MPVP was analyzed by averaging 5-minute intervals for the first 4 hours after dosing, followed by 1-hour intervals for up to 24 hours after dosing. Time point zero (T0) was calculated using the average from 45 minutes before dosing to 15 minutes before dosing.

[0318] [Table 9]

[0319] Example 10. Assays for binding / activity to various receptors and / or targets to assess specificity and safety. Inhibition assays for receptor binding, channel uptake activity, and enzyme activity (Safetyscreen87) were performed at Eurofins Cerep SA (France) on a fee-for-service basis under various conditions appropriate for each receptor / enzyme / channel. In each experiment, and where applicable, a reference compound was tested alongside the test compound, and the data were compared with historical values ​​determined by Eurofins. The experiments were accepted under Eurofins validation standard operating procedures. Each test compound was tested in duplicate, and the average values ​​were reported. Compound binding was calculated as the percent inhibition of binding of radioactively labeled ligand specific for each target. Compound enzyme inhibitory effects were calculated as the percent inhibition of control enzyme activity (receptor-specific results are not shown here). Results showing greater than 50% inhibition or stimulation were considered to represent a significant effect of the test compound. Fifty percent is the most common cutoff value; a test substance is considered safe if it does not exceed the 50% threshold in any of 87 off-target proteins critical to drug safety.

[0320] Generally, for competitive binding assays, cell membrane homogenates were prepared from the appropriate cell lines. Radiolabeled ligand was added to the homogenates in the absence or presence of test compound (10 μM) and incubated at the appropriate temperature for the appropriate time. Nonspecific binding was determined with appropriate controls. After incubation, the homogenates were harvested using a 96-sample cell harvester (Perkin Samples were rapidly filtered under vacuum through glass fiber filters (Perkin Elmer; Waltham, MA) using a Perkin Elmer (Waltham, MA) and rinsed several times with ice-cold buffer. Filters were dried and then counted for radioactivity using scintillation cocktail (Perkin Elmer; Waltham, MA) in a scintillation counter. Results are expressed as percent inhibition of control radioligand-specific binding.

[0321] For enzyme and uptake assays, test compound (10 μM), reference compound, or water (as a control) was mixed with enzyme in buffer. The reaction was initiated by adding the appropriate substrate solution, and the mixture was then incubated at the appropriate temperature for the appropriate duration for the compound. Fluorescence (related to enzyme activity) was measured using a microplate reader (Envision, Perkin Elmer; Waltham, MA). An identical plate without enzyme was simultaneously prepared to verify background fluorescence or compound interference with the fluorometric detection method at the appropriate wavelength. Enzyme activity was determined by subtracting the signal measured without enzyme from the signal measured with enzyme. Results were expressed as percent inhibition relative to control enzyme activity.

[0322] (X) a (Gly) 0~9The Formula (I) peptide, ##STR00001## showed a safety profile similar to that of lysine vasopressin (LVP) at 10 μM, a 280-fold increase over the maximum plasma level (50 ng / mL) predicted for therapeutic efficacy at the relevant receptor. As expected, the Formula (I) peptide showed no significant effects on these receptors, with the exception of the V1a receptor (where >50% inhibition would be significant). The Safetyscreens87 panel included mGluR5(h) (agonist radioligand), 5-HT transporter(h) (antagonist radioligand), 5-HT1A(h) (agonist radioligand), 5-HT1B(h) (antagonist radioligand), 5-HT2A(h) (agonist radioligand), 5-HT2B(h) (agonist radioligand), 5-HT2C(h) (antagonist radioligand), 5-HT3(h) (antagonist radioligand), A1(h) (antagonist radioligand), A2A(h) (agonist radioligand), ACE(h), acetylcholinesterase(h), adenosine transporter (antagonist radioligand), α1A(h) (antagonist radioligand), α1B(h) (antagonist radioligand), α1D(h) (antagonist radioligand), α2A(h) (antagonist Radioligand), α2B(h) (antagonist radioligand), AMPA (agonist radioligand), AR(h) (agonist radioligand), AT1(h) (antagonist radioligand), ATPase (Na+ / K+), B2(h) (agonist radioligand), β1(h) (agonist radioligand), β2(h) (antagonist radioligand), BZD(center) (agonist radioligand), Ca2+ channel, (L, Dihydropyridine site) (antagonist radioligand), Ca2+ channel (L, diltiazem site) (benzothiazepines) (antagonist radioligand), Ca2+ channel (L, verapamil site) (phenylalkylamines) (antagonist radioligand), Ca2+ channel (N) (antagonist radioligand), cathepsin G (h), CB1 (h) (agonist radioligand), CB2 (h) (agonist radioligand),CCK1 (CCKA) (h) (agonist radioligand), CCK2 (CCKB) (h) (agonist radioligand), CCR1 (h) (agonist radioligand), Cl- channel (GABA-gated) (TBOB site) (antagonist radioligand), COX1 (h), COX2 (h), CXCR2 (IL-8B) (h) (agonist radioligand), CysLT1 (LTD4) (h) (agonist radioligand), D1 (h) (antagonist radioligand), D2L (h) (antagonist radioligand), D2S (h) (agonist radioligand) agonist radioligand), δ(DOP)(h) (agonist radioligand), dopamine transporter(h) (antagonist radioligand), estrogen ERα(h) (agonist radioligand), ETA(h) (agonist radioligand), GABA transporter (antagonist radioligand), GABAA1(h)(α1, β2, γ2) (agonist radioligand), glycine (strychnine-insensitive) (antagonist radioligand), glycine (strychnine-sensitive) (antagonist radioligand), GR (h) (agonist radioligand), H1(h) (antagonist radioligand), H2(h) (antagonist radioligand), IRK(h) (InsR), kainate (agonist radioligand), κ(h) (KOP) (agonist radioligand), KV channel (antagonist radioligand), Lck kinase(h), M1(h) (antagonist radioligand), M2(h) (antagonist radioligand), M3(h) (antagonist radioligand), M4(h) (antagonist radioligand), MAO-A (antagonist radioligand) Antagonist radioligand), MAO-B (h) recombinant enzyme, MC1 (agonist radioligand), MC4 (h) (agonist radioligand), μ (MOP) (h) (agonist radioligand), N muscle type (h) (antagonist radioligand), N neuron α4β2 (h) (agonist radioligand), Na+ channel (site 2) (antagonist radioligand), NK1 (h) (agonist radioligand), NMDA (antagonist radioligand), norepinephrine transporter (h) (antagonist radioligand),These include PAF(h) (agonist radioligand), PCP (antagonist radioligand), PDE3A(h), PDE4D2(h), PKCα(h), potassium channel hERG (human)-[3H]dofetilide, PPARγ(h) (agonist radioligand), PR(h) (agonist radioligand), RARα(h) (agonist radioligand), V1a(h) (agonist radioligand), and Y1(h) (agonist radioligand).

[0323] By way of example and without limitation, embodiments are disclosed according to the following enumerated paragraphs:

[0324] A1. A composition comprising: V1a partial agonist peptide of formula (A) [Mpa-Tyr-Phe-Z-Asn-Cys-Pro-B(X) a -Gly-NH2][SEQ ID NOs: 1-2] (A) or a pharmaceutically effective salt thereof, (In the formula: The Mpa and Cys residues are covalently linked by a disulfide bond, Z is Hgn or Gln; Where Z is Hgn [SEQ ID NO: 1]: B is any one of L-Lys, D-Lys, L-Orn, D-Orn, L-Dab, D-Dab, L-Dap, or D-Dap; and X is an amino acid residue, where each occurrence of the amino acid residue is independently selected from Gly, L-Ala, D-Ala, L-Lys, D-Lys, L-Orn, D-Orn, L-Glu, D-Glu, L-Asp, and D-Asp, and a is an integer from 0 to 10 (e.g., 0 to 1, 1 to 2, 1 to 3, 1 to 10, 1 to 6, 4 to 10, or 6 to 10); or X is a non-α primary amino group-containing C 3~12 Fatty acids (e.g., C 3~6 , C 3~10 , C 4~12 , C 4~6 , C 4~10 , C6~10 , C 8~10 , or C 10~12 a moiety derived from a fatty acid, and a is an integer of 1 to 3; Where Z is Gln [SEQ ID NO: 2]: B is any one of L-Lys, D-Lys, L-Orn, D-Orn, L-Dab, D-Dab, L-Dap, or D-Dap; and X is an amino acid residue, wherein each occurrence of the amino acid residue is independently selected from Gly, L-Ala, D-Ala, L-Lys, D-Lys, L-Orn, D-Orn, L-Glu, D-Glu, L-Asp, and D-Asp, and a is an integer from 6 to 10; or X is a non-α primary amino group-containing C 3~12 Fatty acids (e.g., C 3~6 , C 3~10 , C 4~12 , C 4~6 , C 4~10 , C 6~10 , C 8~10 , or C 10~12 a is a moiety derived from a fatty acid, and a is an integer of 1 to 3 A composition comprising: A composition having a therapeutic index of at least 20 (e.g., at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100).

[0325] A2. The composition of paragraph A1, wherein Z is Hgn and B is Lys.

[0326] A3. The composition of paragraph A1 or A2, wherein Z is Hgn, X is Gly, and a is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0327] A4. The composition of any one of paragraphs A1-A3, wherein Z is Hgn, X is Gly, and a is 6, 7, 8, 9, or 10.

[0328] A5. The composition of paragraph A1, wherein Z is Gln and B is L-Lys.

[0329] A6. The composition of paragraph A1 or A5, wherein Z is Gln, B is L-Lys, X is Gly, and a is 6, 7, 8, 9, or 10.

[0330] A7. The composition of paragraph A1, wherein Z is Hgn and B is D-Lys.

[0331] A8. The composition of paragraph A1, wherein Z is Hgn and B is L-Orn.

[0332] A9. The composition of paragraph A1, wherein Z is Hgn and B is D-Orn.

[0333] A10. The composition of paragraph A1, wherein Z is Hgn and B is L-Dab.

[0334] A11. The composition of paragraph A1, wherein Z is Hgn and B is D-Dab.

[0335] A12. The composition of paragraph A1, wherein Z is Hgn and B is L-Dap.

[0336] A13. The composition of paragraph A1, wherein Z is Hgn and B is D-Dap.

[0337] A14. The composition according to any one of paragraphs A1 to A13, further comprising a pharmaceutically acceptable excipient, The pharmaceutically acceptable excipient optionally comprises a buffer comprising a buffer pH of 3.5 to 6.5; and The composition, wherein the buffer is optionally selected from an acetate buffer, a citrate buffer, a succinate buffer, a histidine buffer, or any combination thereof.

[0338] A15. A method for treating a subject, administering to a subject in need thereof a therapeutically effective dose of a composition of any one of paragraphs A1-A14. In a method comprising: the subject has a condition selected from liver fibrosis, liver cirrhosis, portal hypertension, ascites, esophageal varices, gastric fundal varices, hemorrhage, arterial hypotension, hepatorenal syndrome, and any combination thereof; or The subject has liver fibrosis; or The subject has cirrhosis; or The subject has portal hypertension; or The subject has ascites; or The subject has refractory ascites; or The subject has esophageal varices; or The subject has gastric varices in the fundus of the stomach; or The subject has bleeding varices; or The subject has arterial hypotension; or The method, wherein the subject has hepatorenal syndrome.

[0339] A16. The method of paragraph A15, comprising administering to a subject in need thereof a therapeutically effective dose of a composition of any one of paragraphs A2-A6.

[0340] A17. The method of paragraph A15, wherein Z is Hgn, B is L-Lys, and X is Gly.

[0341] The method of paragraph A17, wherein A18.a is 6.

[0342] A19. The method of paragraph A15, wherein Z is Gln and B is L-Lys.

[0343] A20. The method of any one of paragraphs A15-A19, wherein the subject has cirrhosis and portal hypertension.

[0344] A21. The method of any one of paragraphs A15-A20, wherein the subject has portal hypertension with a hepatic venous pressure gradient of 5 mmHg or greater.

[0345] A22. The method of any one of paragraphs A15-A21, wherein the subject has clinically significant portal hypertension with a hepatic venous pressure gradient of 10 mmHg or greater.

[0346] A23. The method of any one of paragraphs A15-A22, wherein the subject has ascites.

[0347] A24. The method of any one of paragraphs A15-A23, wherein the subject has refractory ascites.

[0348] A25. The method of any one of paragraphs A15-A24, wherein the subject has varicose veins.

[0349] A26. The method of any one of paragraphs A15-A25, wherein the subject has variceal bleeding.

[0350] A27. The method of any one of paragraphs A15-A26, wherein the subject has a mean arterial pressure below 95 mmHg (e.g., below 90 mmHg, below 85 mmHg, below 80 mmHg, below 75 mmHg, or below 70 mmHg).

[0351] A28. The method of any one of paragraphs A15-A27, wherein administering comprises parenteral administration.

[0352] A29. The method of any one of paragraphs A15-A28, wherein administering comprises intravenous administration.

[0353] A30. The method of any one of paragraphs A15-A28, wherein administering comprises subcutaneous administration.

[0354] A31. The method of any one of paragraphs A15-A28, wherein administering comprises slow infusion.

[0355] A32. The method of any one of paragraphs A15-A30, wherein administering comprises a bolus administration.

[0356] A33. The method of any one of paragraphs A15-A30 and A32, wherein administration comprises administration no more frequently than three times per day (e.g., one administration every 8 hours, one administration every 12 hours, or one administration every 24 hours).

[0357] A34. The method of paragraph A33, wherein administration occurs only during the daytime between 6:00 and 18:00 (24 hour clock) at a frequency of once every 4 to 6 hours, and administration does not occur during the night between 18:00 and 6:00 (24 hour clock).

[0358] A35. The method of any one of paragraphs A15-A34, further comprising administering a V2 antagonist.

[0359] A36. The method of paragraph A35, wherein the V2 antagonist is administered before or after administration of the V1a partial agonist, preferably within 1 to 8 hours, preferably 1 to 3 hours before administration of the V1a partial agonist.

[0360] A37. A method for treating a subject, comprising: 1. A peptide of formula (B) administered to a subject in need thereof before or after administration of a therapeutically effective dose of a V2 antagonist, preferably within 1 to 8 hours, preferably 1 to 3 hours after administration of a therapeutically effective dose of a V2 antagonist, V1a agonist peptide of formula (B) [X'-Tyr-Phe-Gln-Asn-Cys-Pro-Lys(Z) d -Gly-NH2][SEQ ID NOs: 3-4] (B) or a pharmaceutically acceptable salt thereof, (In the formula: X' is (U) c -Cys or Mpa, Here, X' is (U) c -Cys, and (Z) d When there is no [SEQ ID NO: 3], The two Cys residues are covalently linked by a disulfide bond; U is an amino acid residue, each occurrence independently selected from Gly, L-Ala, D-Ala, L-Lys, D-Lys, L-Orn, D-Orn, L-Glu, D-Glu, L-Asp, and D-Asp, and c is an integer from 0 to 10; and where X' is Mpa [SEQ ID NO: 4] The Mpa and Cys residues are covalently linked by a disulfide bond, Z is an amino acid residue, each occurrence of which is independently selected from Gly, D-Ala, L-Ala, D-Lys, L-Lys, D-Orn, L-Orn, D-Glu, L-Glu, D-Asp, and L-Asp, and d is an integer from 0 to 5, the subject has a condition selected from hepatic fibrosis, cirrhosis, portal hypertension, ascites, esophageal varices, gastric fundal varices, hemorrhage, arterial hypotension, hepatorenal syndrome, and any combination thereof; or The subject has liver fibrosis; or The subject has cirrhosis; or The subject has portal hypertension; or The subject has esophageal varices; or The subject has gastric fundus varices; or The subject has bleeding varices; or The subject has arterial hypotension; or The method, wherein the subject has hepatorenal syndrome.

[0361] A38. The V1a agonist peptide of formula (B) is a V1a agonist peptide of formula (III) [(U) c -Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Lys-Gly-NH2] [SEQ ID NO: 7] (III) or a pharmaceutically effective salt thereof, (In the formula: The two Cys residues are covalently linked by a disulfide bond, U is an amino acid residue, each occurrence independently selected from Gly, L-Ala, D-Ala, L-Lys, D-Lys, L-Orn, D-Orn, L-Glu, D-Glu, L-Asp, and D-Asp; and and c is an integer from 0 to 10.

[0362] A39. The V1a agonist peptide of formula (B) is a V1a agonist peptide of formula (IV) [Mpa-Tyr-Phe-Gln-Asn-Cys-Pro-Lys(Z) d -Gly-NH2][SEQ ID NO: 4] (IV) or a pharmaceutically effective salt thereof, (In the formula: The Mpa and Cys residues are covalently linked by a disulfide bond, Z is an amino acid residue, each occurrence independently selected from Gly, D-Ala, L-Ala, D-Lys, L-Lys, D-Orn, L-Orn, D-Glu, L-Glu, D-Asp, and L-Asp; and and d is an integer from 0 to 5.

[0363] A40. The method of any one of paragraphs A35-A39, wherein the V2 antagonist comprises mozavaptan, tolvaptan, tolvaptan phosphate, satavaptan, lixivaptan, conivaptan, RWJ-351647, VP-343, VP-393, [PmP1, D-Ile2, Ile4, Arg8, Ala9]vasopressin, [PmP1, D-Ile2, Ile4, Arg8]vasopressin, [PmP1, D-Ile2, Ile4, Arg8, Ala9]vasopressin-(1-8)-OH, or any combination thereof.

[0364] A41. The method of paragraph A35 or A40, wherein the V2 antagonist is tolvaptan, optionally administered parenterally at a dose of 1 μg / kg to 300 μg / kg (e.g., 1 μg / kg to 200 μg / kg, or 1 μg / kg to 100 μg / kg).

[0365] A42. The method of any one of paragraphs A35-A41, wherein the subject is a human and the V2 antagonist is tolvaptan, optionally administered parenterally at a dose of 2 mg to 7 mg.

[0366] A43. A pharmaceutical composition comprising a V1a agonist peptide of formula (III), or a pharmaceutically acceptable salt thereof (wherein U is Gly and c is 3); The V2 antagonist comprises tolvaptan; and The method of any one of paragraphs A38 and A40-A42, wherein the dose weight ratio of V1a agonist peptide to tolvaptan is 1:6 to 1:2.

[0367] A44. The method of any one of paragraphs A15 to A43, wherein the V1a partial agonist or V1a agonist is administered at a dose of less than 150 nmol / dose / Kg (e.g., less than 140 nmol / dose / Kg, less than 130 nmol / dose / Kg, less than 120 nmol / dose / Kg, less than 110 nmol / dose / Kg, less than 100 nmol / dose / Kg, less than 90 nmol / dose / Kg, less than 80 nmol / dose / Kg, less than 70 nmol / dose / Kg, or less than 50 nmol / dose / Kg).

[0368] While exemplary embodiments have been illustrated and described, it will be understood that various changes can be made thereto without departing from the spirit and scope of the invention. The present invention provides, for example, the following items: (Item 1) V1a partial agonist peptide of formula (A) [Mpa-Tyr-Phe-Z-Asn-Cys-Pro-B(X) a -Gly-NH2][SEQ ID NOs: 1-2] (A) or a pharmaceutically effective salt thereof, (In the formula: the Mpa and Cys residues are covalently linked by a disulfide bond; Z is Hgn or Gln; Where Z is Hgn [SEQ ID NO: 1]: B is any one of L-Lys, D-Lys, L-Orn, D-Orn, L-Dab, D-Dab, L-Dap, or D-Dap; and X is an amino acid residue, wherein each occurrence of said amino acid residue is independently selected from Gly, L-Ala, D-Ala, L-Lys, D-Lys, L-Orn, D-Orn, L-Glu, D-Glu, L-Asp, and D-Asp, and a is an integer from 0 to 10; or X is a non-α primary amino group-containing C 3~12 a moiety derived from a fatty acid, and a is an integer from 1 to 3; Where Z is Gln [SEQ ID NO: 2]: B is any one of L-Lys, D-Lys, L-Orn, D-Orn, L-Dab, D-Dab, L-Dap, or D-Dap; and X is an amino acid residue, wherein each occurrence of said amino acid residue is independently selected from Gly, L-Ala, D-Ala, L-Lys, D-Lys, L-Orn, D-Orn, L-Glu, D-Glu, L-Asp, and D-Asp, and a is an integer from 6 to 10; or X is a non-α primary amino group-containing C 3~12 a moiety derived from a fatty acid, and a is an integer from 1 to 3; and A composition having a therapeutic index of at least 20. (Item 2) 2. The composition of claim 1, wherein Z is Hgn and B is Lys. (Item 3) 3. The composition of claim 1 or 2, wherein Z is Hgn, X is Gly, and a is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. (Item 4) 4. The composition of any one of items 1 to 3, wherein Z is Hgn, X is Gly, and a is 6, 7, 8, 9, or 10. (Item 5) 2. The composition of claim 1, wherein Z is Gln and B is L-Lys. (Item 6) 6. The composition of claim 1 or 5, wherein Z is Gln, X is Gly, and a is 6, 7, 8, 9, or 10. (Item 7) 2. The composition of claim 1, wherein Z is Hgn and B is D-Lys. (Item 8) 2. The composition according to item 1, wherein Z is Hgn and B is L-Orn. (Item 9) 2. The composition of claim 1, wherein Z is Hgn and B is D-Orn. (Item 10) 2. The composition according to item 1, wherein Z is Hgn and B is L-Dab. (Item 11) 2. The composition according to item 1, wherein Z is Hgn and B is D-Dab. (Item 12) 2. The composition according to item 1, wherein Z is Hgn and B is L-Dap. (Item 13) 2. The composition according to item 1, wherein Z is Hgn and B is D-Dap. (Item 14) 14. The composition according to any one of items 1 to 13, further comprising a pharmaceutically acceptable excipient, the pharmaceutically acceptable excipient optionally comprises a buffer comprising a buffer pH of 3.5 to 6.5; and The composition, wherein the buffer is optionally selected from an acetate buffer, a citrate buffer, a succinate buffer, a histidine buffer, or any combination thereof. (Item 15) 1. A method of treating a subject, comprising: 15. A method comprising administering to a subject in need thereof a therapeutically effective dose of the composition according to any one of items 1 to 14, the subject has a condition selected from liver fibrosis, liver cirrhosis, portal hypertension, ascites, esophageal varices, gastric fundal varices, hemorrhage, arterial hypotension, hepatorenal syndrome, and any combination thereof; or the subject has liver fibrosis; or the subject has cirrhosis; or the subject has portal hypertension; or the subject has ascites; or the subject has refractory ascites; or the subject has esophageal varices; or the subject has gastric varices in the fundus; or the subject has bleeding varices; or the subject has arterial hypotension; or The method, wherein the subject has hepatorenal syndrome. (Item 16) Item 16. The method according to item 15, comprising administering to a subject in need thereof a therapeutically effective dose of the composition according to any one of items 2 to 6. (Item 17) 16. The method of item 15, wherein Z is Hgn, B is L-Lys, and X is Gly. (Item 18) Item 18. The method of item 17, wherein a is 6. (Item 19) 16. The method of item 15, wherein Z is Gln and B is L-Lys. (Item 20) 20. The method according to any one of items 15 to 19, wherein the subject has cirrhosis and portal hypertension. method. (Item 21) 21. The method according to any one of items 15 to 20, wherein the subject has portal hypertension accompanied by a hepatic venous pressure gradient of 5 mmHg or more. (Item 22) 22. The method according to any one of items 15 to 21, wherein the subject has clinically significant portal hypertension with a hepatic venous pressure gradient of 10 mmHg or greater. (Item 23) 23. The method of any one of items 15 to 22, wherein the subject has ascites. (Item 24) 24. The method according to any one of items 15 to 23, wherein the subject has refractory ascites. (Item 25) 25. The method according to any one of items 15 to 24, wherein the subject has varicose veins. (Item 26) 26. The method of any one of items 15 to 25, wherein the subject has variceal bleeding. (Item 27) 27. The method of any one of items 15 to 26, wherein the subject has a mean arterial pressure below 95 mmHg. (Item 28) 28. The method of any one of items 15 to 27, wherein administering comprises parenteral administration. (Item 29) 29. The method of any one of items 15 to 28, wherein administering comprises intravenous administration. (Item 30) 29. The method of any one of items 15 to 28, wherein administering comprises subcutaneous administration. (Item 31) 29. The method of any one of items 15 to 28, wherein the administration comprises slow infusion. (Item 32) 31. The method of any one of items 15 to 30, wherein administering comprises a bolus administration. (Item 33) 33. The method of any one of items 15 to 30 and 32, wherein administration comprises a frequency of no more than three times a day. (Item 34) Item 34. The method according to item 33, wherein the administration is performed only during the daytime from 6:00 to 18:00, once every 4 to 6 hours, and the administration is not performed during the nighttime from 18:00 to 6:00. (Item 35) 35. The method of any one of items 15 to 34, further comprising administering a V2 antagonist. (Item 36) 36. The method according to item 35, wherein the V2 antagonist is administered before or after administration of the V1a partial agonist, preferably within 1 to 8 hours, preferably 1 to 3 hours before administration of the V1a partial agonist. (Item 37) 1. A method of treating a subject, comprising: A peptide of formula (B) administered to a subject in need thereof before or after administration of a therapeutically effective dose of a V2 antagonist, preferably within 1 to 8 hours, preferably 1 to 3 hours after administration of a therapeutically effective dose of said V2 antagonist, V1a agonist peptide of formula (B) [X'-Tyr-Phe-Gln-Asn-Cys-Pro-Lys(Z) d -Gly-NH2][SEQ ID NOs: 3-4] (B) or a pharmaceutically acceptable salt thereof, (In the formula: X' is (U) c -Cys or Mpa, Here, X' is (U) c -Cys, and (Z) d When there is no [SEQ ID NO: 3], the two Cys residues are covalently linked by a disulfide bond; U is an amino acid residue, each occurrence independently selected from Gly, L-Ala, D-Ala, L-Lys, D-Lys, L-Orn, D-Orn, L-Glu, D-Glu, L-Asp, and D-Asp, and c is an integer from 0 to 10; and where X' is Mpa [SEQ ID NO: 4] the Mpa and Cys residues are covalently linked by a disulfide bond; Z is an amino acid residue, each occurrence of which is independently selected from Gly, D-Ala, L-Ala, D-Lys, L-Lys, D-Orn, L-Orn, D-Glu, L-Glu, D-Asp, and L-Asp, and d is an integer from 0 to 5, the subject has a condition selected from hepatic fibrosis, cirrhosis, portal hypertension, ascites, esophageal varices, gastric fundal varices, bleeding, arterial hypotension, hepatorenal syndrome, and any combination thereof; or the subject has liver fibrosis; or the subject has cirrhosis; or the subject has portal hypertension; or the subject has esophageal varices; or the subject has gastric fundal varices; or the subject has bleeding varices; or the subject has arterial hypotension; or The method, wherein the subject has hepatorenal syndrome. (Item 38) The V1a agonist peptide of formula (B) is a V1a agonist peptide of formula (III) [(U) c -Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Lys-Gly-NH2] [SEQ ID NO: 7] (III) or a pharmaceutically effective salt thereof, (In the formula: the two Cys residues are covalently linked by a disulfide bond; U is an amino acid residue, each occurrence independently selected from Gly, L-Ala, D-Ala, L-Lys, D-Lys, L-Orn, D-Orn, L-Glu, D-Glu, L-Asp, and D-Asp; and Item 38. The method according to Item 37, wherein c is an integer of 0 to 10. (Item 39) The V1a agonist peptide of formula (B) is a V1a agonist peptide of formula (IV) [Mpa-Tyr-Phe-Gln-Asn-Cys-Pro-Lys(Z) d -Gly-NH2][SEQ ID NO: 4] (IV) or a pharmaceutically effective salt thereof, (In the formula: the Mpa and Cys residues are covalently linked by a disulfide bond; Z is an amino acid residue, each occurrence independently selected from Gly, D-Ala, L-Ala, D-Lys, L-Lys, D-Orn, L-Orn, D-Glu, L-Glu, D-Asp, and L-Asp; and Item 38. The method according to Item 37, wherein d is an integer of 0 to 5. (Item 40) 40. The method of any one of items 35 to 39, wherein the V2 antagonist comprises mozavaptan, tolvaptan, tolvaptan phosphate, satavaptan, lixivaptan, conivaptan, RWJ-351647, VP-343, VP-393, [PmP1, D-Ile2, Ile4, Arg8, Ala9]vasopressin, [PmP1, D-Ile2, Ile4, Arg8]vasopressin, [PmP1, D-Ile2, Ile4, Arg8, Ala9]vasopressin-(l-8)-OH, or any combination thereof. (Item 41) 41. The method of item 35 or 40, wherein the V2 antagonist is tolvaptan, optionally administered parenterally at a dose of 1 μg / kg to 300 μg / kg. (Item 42) 42. The method of any one of items 35 to 41, wherein the subject is a human and the V2 antagonist is tolvaptan, optionally administered parenterally at a dose of 2 mg to 7 mg. (Item 43) The pharmaceutical composition comprises the V1a agonist peptide of formula (III), or a pharmaceutically acceptable salt thereof, wherein U is Gly and c is 3; the V2 antagonist comprises tolvaptan; and 43. The method according to any one of items 38 and 40 to 42, wherein the dose weight ratio of the V1a agonist peptide to tolvaptan is 1:6 to 1:2. (Item 44) 44. The method of any one of items 15 to 43, wherein the V1a partial agonist or V1a agonist is administered at a dose of less than 150 nmol / dose / Kg.

Claims

1. Formula (A) [Mpa-Tyr-Phe-Z-Asn-Cys-Pro-B(X) a -Gly-NH 2 ] (A) or a pharmaceutically effective salt thereof, the Mpa and Cys residues are covalently linked by a disulfide bond; Z is Hgn; B is L-Lys, D-Lys, L-Dap, D-Dap, L-Orn, D-Orn, L-Dab, or D-Dab; X, at each occurrence, is independently selected from Gly, L-Ala, D-Ala, L-Lys, D-Lys, L-Orn, D-Orn, L-Glu, D-Glu, L-Asp, and D-Asp; a is an integer from 0 to 9; 2. The peptide of claim 1, or a pharmaceutically effective salt thereof, wherein B is L-Lys.

3. The peptide of claim 1, or a pharmaceutically effective salt thereof, wherein B is L-Lys and X is Gly.

4. The peptide of claim 1, or a pharmaceutically effective salt thereof, wherein B is L-Lys, X is Gly, and a is 6, 7, 8, or 9.

5. The peptide of claim 1, or a pharmaceutically effective salt thereof, wherein B is D-Lys, L-Orn, D-Orn, L-Dab, D-Dab, L-Dap, or D-Dap.

6. The peptide of claim 1, or a pharmaceutically effective salt thereof, wherein the peptide has a therapeutic index of at least 20.

7. A composition comprising the peptide of claim 1 or a pharmaceutically effective salt thereof and a pharmaceutically acceptable excipient.

8. The composition of claim 7, wherein the pharmaceutically acceptable excipient comprises a buffer solution having a buffer pH of 3.5 to 6.

5.

9. The composition of claim 8, wherein the buffer is selected from an acetate buffer, a citrate buffer, a succinate buffer, a histidine buffer, or any combination thereof.

10. A composition for use in a method of treating a subject in need thereof, comprising the peptide of claim 1 or a pharmaceutically effective salt thereof, said method comprising administering to said subject a therapeutically effective dose of said peptide; The composition, wherein the subject has a condition selected from liver fibrosis, cirrhosis, portal hypertension, ascites, esophageal varices, gastric fundal varices, bleeding, arterial hypotension, hepatorenal syndrome, or any combination thereof.

11. The composition of claim 10, wherein B is L-Lys.

12. The composition of claim 10, wherein B is L-Lys and X is Gly.

13. The composition of claim 12, wherein a is 6.

14. The composition described in claim 10, wherein the subject has cirrhosis and portal hypertension.

15. The composition described in claim 10, wherein the subject has portal hypertension with a hepatic venous pressure gradient of 5 mmHg or more, or clinically significant portal hypertension with a hepatic venous pressure gradient of 10 mmHg or more.

16. The composition described in claim 10, wherein the subject has ascites or refractory ascites.

17. The composition of claim 10, wherein the subject has varicose veins or varicose vein bleeding.

18. The composition of claim 10, wherein the subject has a mean arterial pressure below 95 mmHg.

19. The composition of claim 10, wherein administration comprises parenteral administration, intravenous administration, subcutaneous administration, slow infusion, or bolus administration.

20. The composition of claim 10, wherein the peptide or a pharmaceutically effective salt thereof is administered no more than three times a day.

21. The composition of claim 20, wherein the peptide or a pharmaceutically effective salt thereof is administered only during the daytime between 6:00 and 18:00, once every 4 to 6 hours, and administration is not performed during the nighttime between 18:00 and 6:

00.

22. The composition described in claim 10, characterized in that the composition is administered together with a V2 antagonist.

23. The composition described in claim 22, characterized in that the V2 antagonist is administered within 1 to 8 hours before or after administration of the V1a partial agonist.

24. A peptide comprising SEQ ID NO: 13 or a pharmaceutically effective salt thereof.

25. A peptide comprising sequence number 25 or a pharmaceutically effective salt thereof.

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