Mixed vasopressin receptor agonist-antagonists for treating end-stage liver disease and its associated complications

Abstract

Provided herein are compositions, including those suitable for subcutaneous administration, and methods for treating ascites in individuals using mixed V1A receptor agonist-antagonists.

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 63 / 378,014, filed September 30, 2022, U.S. Provisional Patent Application No. 63 / 432,976, filed December 15, 2022, and U.S. Provisional Patent Application No. 63 / 471,713, filed June 7, 2023, each of which is incorporated by reference herein in its entirety. [Background technology]

[0002] End-stage liver disease complications are responsible for approximately one million deaths per year. Patients with end-stage liver disease often develop portal hypertension. Ascites represents the most common decompensation event and is associated with a high risk of developing further complications, including bacterial infection and acute kidney injury (AKI). Summary of the Invention [Means for solving the problem]

[0003] The management of decompensated cirrhosis often involves the use of vasoconstrictors that are full vasopressin 1a receptor (V1AR) agonists. Full (vasopressin V2 receptor (V2R), V1AR) agonists reduce portal vein pressure by increasing splanchnic arteriolar vasoconstriction, thereby redistributing blood volume to the systemic circulation, which can then lead to increased glomerular filtration rate and improved renal blood flow. However, (non-selective) full (V2R, V1AR) agonists (e.g., having only an agonist portion and no antagonist portion) can cause undesirable systemic events, such as vasoconstriction resulting in ischemia (e.g., organ ischemia and / or local (injection) site ischemia), administration (e.g., injection) site events (e.g., reactions), such as local (site) vasoconstriction resulting in administration site ischemia, or both (e.g., when administered subcutaneously). Such events may prevent such compounds from being used in outpatient settings (e.g., for home use), limiting their use, for example, to intravenous administration and short-term applications in inpatient settings under close specialist monitoring (e.g., thereby making them unsuitable for chronic and outpatient settings). Furthermore, given the risk profile of full (V2R, V1AR) agonists, careful dose titration and monitoring are often required to prevent the occurrence of serious adverse events (AEs), such as those associated with tissue hypoxia and ischemia due to excessive vasoconstriction.

[0004] Furthermore, using nonselective full (V1AR, V2R) agonists such as vasopressin, it is difficult to achieve a 10-15 mmHg increase in mean arterial pressure (MAP), which strongly correlates with reversal of HRS-AKI. In some instances, achieving and / or maintaining a 10-15 mmHg increase in MAP is the therapeutic goal of current therapies. Due to the pharmacokinetics and very steep concentration-response curve of the vasopressin system, it can be easier to either underdose (and reduce clinical efficacy) or cause excessive vasoconstriction, which can result in severe, potentially life-threatening adverse events (AEs). Secondarily, individuals with decompensated cirrhosis may already have high endogenous vasopressin levels, which promote water retention via V2-mediated antidiuretic effects. Clinical vasopressin agonists are primarily V2 agonists and secondarily act as V1a agonists at pharmacological concentrations. Intrinsic V2 activity may contribute to the adverse event profile associated with fluid overload and respiratory complications for clinical vasopressin agonists.

[0005] In some embodiments, provided herein are compounds (e.g., mixed agonist-antagonists) that have selectivity for the V1a receptor. In some embodiments, the compounds reach and maintain (target) levels of vasoconstriction and avoid water retention, e.g., via a uniform dosing profile. In some examples, the compounds have a reduced incidence of (serious) adverse events and improved clinical efficacy (e.g., compared to clinical vasopressin agonists). In some examples, it is not necessary to titrate the compounds to achieve, e.g., a reduced incidence of (serious) adverse events and improved clinical efficacy (e.g., compared to clinical vasopressin agonists). In some examples, the compounds (e.g., mixed V1a agonist-antagonists) described herein can be administered at higher doses (than necessary) to effectively achieve maximum efficacy. In contrast, administration of relatively high doses of non-selective full (V2, V1a) agonists such as terlipressin can be toxic and result in (serious) adverse events.

[0006] In some examples, a compound described herein (e.g., a mixed V1a agonist-antagonist such as Compound 1) is delivered (e.g., systemically) to an individual described herein after a composition comprising the compound is administered to the individual by subcutaneous administration (e.g., subcutaneous infusion or subcutaneous (bolus) injection). In some examples, a compound described herein (e.g., a mixed V1a agonist-antagonist such as Compound 1) produces a systemic effect, such as modulation of mean arterial pressure (MAP), in an individual described herein after a composition comprising the compound is administered to the individual by subcutaneous administration (e.g., subcutaneous infusion or subcutaneous (bolus) injection).

[0007] In some examples, a compound described herein (e.g., a mixed V1a agonist-antagonist such as Compound 1) is metabolized to a full vasopressin agonist, such as when administered subcutaneously. In some examples, the formation of a full vasopressin agonist is associated with a higher risk of an individual developing an adverse event, such as after subcutaneous (bolus) injection of the mixed V1a agonist-antagonist. In some examples, the adverse event is a systemic event, a local administration site event, or both. In some embodiments, the adverse event is associated with excessive vasopressin constriction. In some examples, a full vasopressin agonist is partially active (compared to a mixed V1a agonist-antagonist). In some examples, subcutaneous administration of a mixed V1a agonist-antagonist described herein (e.g., by subcutaneous (bolus) injection) results in overproduction of a full vasopressin agonist (e.g., in the subcutaneous space of an individual). Overproduction of a full vasopressin agonist (e.g., in an individual's subcutaneous space) is undesirable because, for example, less of the parent compound (e.g., a mixed V1a agonist-antagonist described herein, such as Compound 1) is delivered systemically, thereby increasing the risk of undesirable (systemic) events (e.g., toxicity associated with excessive (local and / or systemic) vasoconstriction), such as through full agonism of the V1a receptor by a full vasopressin agonist. Additional challenges arising from overproduction of a full vasopressin agonist (e.g., in an individual's subcutaneous space) following administration of a composition described herein include reduced efficacy, increased side effects, and / or difficulty in controlling efficacy (e.g., titration). As shown in Figure 32, full agonism of the vasopressin receptor can induce severe side effects and / or mortality.

[0008] In some embodiments, described herein are methods and formulations for reducing the formation of full vasopressin agonists (e.g., M1), such as after subcutaneous (bolus) injection of a mixed V1a agonist-antagonist described herein. In some embodiments, reducing the formation of full vasopressin agonists (e.g., M1), such as after subcutaneous administration of a mixed V1a agonist-antagonist described herein, reduces the risk of an individual experiencing undesirable (systemic) events (e.g., toxicity associated with excessive (local and / or systemic) vasoconstriction), such as through full agonism of the V1a receptor by a full vasopressin agonist. In some embodiments, reducing the formation of full vasopressin agonists (e.g., M1), such as after subcutaneous administration of a mixed V1a agonist-antagonist described herein, increases the efficacy of the (e.g., mixed V1a agonist-antagonist) treatment described herein, reduces side effects (e.g., associated with overproduction of the full agonist), and / or improves control of the efficacy (e.g., titration) of the (e.g., mixed V1a agonist-antagonist) treatment described herein. In some embodiments, subcutaneous infusion of a mixed V1a agonist-antagonist reduces metabolite (M1) formation (e.g., as measured systemically, such as by serum / plasma concentrations). In some embodiments, increasing the buffer concentration of a composition comprising a mixed V1a agonist-antagonist reduces metabolite (M1) formation (e.g., as measured systemically, such as by serum / plasma concentrations) in vitro (e.g., after subcutaneous administration) and in vivo, etc. In some embodiments, increasing the concentration of the mixed V1a agonist-antagonist in the composition reduces metabolite (M1) formation (e.g., as measured systemically, such as by serum / plasma concentrations) in vitro (e.g., after subcutaneous administration) and in vivo, etc.In some embodiments, subcutaneous injection and increasing the concentration of the mixed V1a agonist-antagonist in the composition, such as when the compositions described herein are administered at a relatively slow administration rate, reduces metabolite (M1) formation (e.g., as measured systemically, such as by serum / plasma concentrations) in vitro and in vivo (e.g., after subcutaneous administration). In some embodiments, any combination of subcutaneous injection, increasing the buffer concentration of the composition, and increasing the drug concentration in the composition reduces metabolite (M1) formation after subcutaneous administration. In some embodiments, subcutaneous injection of a compound described herein, increasing the buffer concentration of a composition described herein, and / or increasing the drug concentration in a composition described herein improves systemic delivery of the mixed agonist-antagonist described herein.

[0009] In some embodiments, provided herein are compounds (e.g., mixed V1AR receptor agonist-antagonists such as Compound 1) that reduce portal pressure (PP) in an individual (e.g., in need thereof), such as after subcutaneous administration, without excessive vasoconstriction over a wide dose range, such as 10 μg / kg to 500 μg / kg.

[0010] In some embodiments, provided herein are compounds (e.g., mixed V1a receptor agonist-antagonists such as Compound 1) that elevate mean arterial pressure (MAP) in an individual (e.g., in need thereof), such as after subcutaneous administration. In some embodiments, the increase in MAP reaches a peak plateau of approximately +10 to +15 mmHg (even at high doses, e.g., 100 to 500 μg / kg). In contrast, administration of a fully non-selective (V2, V1a) receptor agonist described herein, such as terlipressin, at similarly high doses results in significantly higher increases in MAP, such as well above the therapeutic range of +10 to +15 mmHg. Such large increases in MAP can significantly increase the likelihood of (serious) side effects (in the individual receiving treatment).

[0011] In some embodiments, the compounds described herein (e.g., mixed V1AR receptor agonist-antagonists such as Compound 1) achieve a therapeutic ceiling (e.g., when administered subcutaneously) such that the effect (e.g., increasing MAP) does not change (significantly) (e.g., increase or decrease) even after increasing the dose of the compound (e.g., up to higher doses of 100-500 μg / kg).

[0012] In some instances, increasing the dose of a compound described herein (e.g., a fully non-selective (V2R, V1AR) receptor agonist such as terlipressin) results in a (significant) change (e.g., an increase) in the effect (e.g., MAP). In some instances, increasing the dose of a compound described herein (e.g., a fully non-selective (V2, V1AR) receptor agonist such as terlipressin) continues to push the effect (e.g., MAP) to a level that may be harmful and / or cause (severe) side effects in the individual receiving the compound.

[0013] In some instances, increasing the dose of a mixed V1a agonist-antagonist described herein, such as Compound 1, does not continue to elevate MAP in an individual (e.g., even at high doses of 100-500 μg / kg), whereas increasing the dose of a fully non-selective (V2, V1a) agonist, such as terlipressin, continues to elevate MAP in an individual. In some instances, a mixed agonist-antagonist described herein, such as Compound 1, can be safely used subcutaneously to treat ESLD or its symptoms and / or complications, e.g., without the risk of the individual developing (serious) side effects and / or developing effects such as MAP to dangerous or harmful levels. In some instances, the therapeutic range (and safety profile) of a mixed V1AR agonist-antagonist described herein, such as Compound 1, is significantly improved compared to a V1AR agonist (e.g., not including a separate V1AR antagonist moiety), such as terlipressin.

[0014] In some embodiments, the compounds described herein have an agonist portion (e.g., D1). In some embodiments, the compounds described herein have an antagonist portion (e.g., D2). In some embodiments, the compounds described herein have an agonist portion (e.g., D1) and an antagonist portion (e.g., D2). In some embodiments, the antagonist moiety (e.g., D2) has no (agonist) activity or has substantially less (agonist) activity than the agonist moiety (e.g., D1), e.g., at least about 1.5-fold less agonist activity than the agonist moiety (e.g., D1), at least about 2-fold less agonist activity than the agonist moiety (e.g., D1), at least about 3-fold less agonist activity than the agonist moiety (e.g., D1), 5-fold less agonist activity than the agonist moiety (e.g., D1), at least about 10-fold less agonist activity than the agonist moiety (e.g., D1), or at least about 100-fold less agonist activity than the agonist moiety (e.g., D1). In some embodiments, the agonism and / or antagonism is at the V1AR.

[0015] In some embodiments, the compounds described herein (e.g., mixed V1a agonist-antagonists such as Compound 1) are not full or non-selective (V2, V1a) receptor agonists. In some embodiments, subcutaneous administration of the compounds described herein (e.g., mixed V1a agonist-antagonists such as Compound 1) is not toxic (at therapeutic levels), even at high doses, e.g., 100-500 μg / kg. In some embodiments, the compounds described herein (e.g., mixed V1a agonist-antagonists such as Compound 1) have a wide therapeutic index and are selective for the V1a receptor, e.g., at therapeutic doses. In some embodiments, the compounds described herein (e.g., mixed V1a agonist-antagonists such as Compound 1) are useful for subcutaneous administration. In some embodiments, a compound described herein (e.g., a mixed V1a agonist-antagonist such as Compound 1) increases mean arterial pressure (MAP) in individuals receiving one or more (subcutaneously administered) doses of the compound. In some embodiments, a compound described herein (e.g., a mixed V1a agonist-antagonist such as Compound 1) decreases portal vein pressure (PP) in individuals receiving one or more (subcutaneously administered) doses of the compound. In some embodiments, a compound described herein (e.g., a mixed V1a agonist-antagonist such as Compound 1) increases MAP and decreases PP in individuals receiving one or more (subcutaneously administered) doses of the compound. In some embodiments, such as after subcutaneous administration of a compound described herein (e.g., a mixed V1a agonist-antagonist such as Compound 1), the change in MAP plateaus or reaches a therapeutic maximum after a period of time (e.g., about 10 minutes). In some instances, such as after subcutaneous administration of a compound described herein (e.g., a fully non-selective (V2, V1a) agonist such as terlipressin), MAP rises rapidly and peaks after a period of time (e.g., about 20 minutes). In some embodiments, such as after subcutaneous administration of a compound described herein (e.g., a mixed V1a agonist-antagonist such as Compound 1), the change in PP reaches a plateau.In some embodiments, such as after subcutaneous administration of a compound described herein (e.g., a mixed V1a agonist-antagonist such as Compound 1), the changes in MAP and PP plateau or reach a therapeutic maximum after a period of time (e.g., after about 10 minutes).

[0016] In some embodiments, provided herein are mixed V1AR receptor agonist-antagonists suitable for subcutaneous administration that reduce ascites (and / or its production), such as by lowering portal vein pressure and improving renal excretion of excess sodium and water (e.g., thereby reducing the need for paracentesis and improving the patient's quality of life).

[0017] In some cases, systemic hemodynamic complications such as portal hypertension and reflex splanchnic arteriolar vasodilation are signs of decompensated cirrhosis.In some cases, splanchnic vasodilation causes blood to pool in the splanchnic circulation, causing fluid to leak into the abdomen and surrounding organs (ascites), and reducing arterial pressure.In some cases, such as in decompensated cirrhosis, these hemodynamic changes can cause systemic complications, including ascites, such as refractory ascites.

[0018] In some instances, treatment paradigms focus on restoring blood, portal vein, and splanchnic pressures to levels that will restore renal function. In some instances, successful treatment is measured by increasing mean arterial pressure (MAP) by 10-20 mmHg from baseline at presentation (e.g., as this correlates with improvement in renal function and / or hemodynamic parameters). Unfortunately, available vasoactive agents either have limited efficacy or pose significant risks of excessive vasoconstriction, fluid overload, or serious respiratory adverse events.

[0019] In some examples, the compounds described herein (e.g., Compound 1) are vasoconstrictors that selectively target the vasopressin V1a molecule as mixed agonist-antagonists. In some examples, the agonist domain of the compounds described herein (e.g., Compound 1) causes desired vasoconstriction of the splanchnic vasculature (e.g., thereby reducing portal blood flow and blood pressure and / or improving the individual's systemic hemodynamics). In some examples, the antagonist domain of the compounds described herein (e.g., Compound 1) prevents full activation of V1a-mediated vasoconstriction, which raises safety concerns with other drugs. In some examples, such as at therapeutic concentrations, the compounds described herein (e.g., Compound 1) do not activate the vasopressin V2 receptor (e.g., causing undesirable water retention).

[0020] In some embodiments, the compounds described herein (e.g., mixed V1A agonist-antagonists such as Compound 1) are useful for treating ESLD (or its manifestations), decompensated cirrhosis, and / or its complications (or symptoms), such as resistant ascites, refractory ascites, or circulatory disorders induced after paracentesis.

[0021] In some examples, the mixed V1A agonist-antagonists provided herein are used to treat ESLD or a complication thereof (e.g., refractory ascites) in an individual (e.g., in need thereof). In some examples, the mixed V1a agonist-antagonists provided herein are used to treat ESLD or a complication thereof (e.g., refractory ascites) in an individual (e.g., in need thereof) without (significant) injection site reactions (e.g., local vasoconstriction), such as at a subcutaneous injection site. In some examples, the mixed V1A agonist-antagonists are suitable for systemic delivery, provided, for example, that the mixed agonist-antagonist properties of the mixed V1A agonist-antagonist prevent (significant) injection site reactions (e.g., local vasoconstriction), such as at a subcutaneous injection site. In some examples, the mixed V1A agonist-antagonists provided herein lack (functional) vasopressin 2 (V2) receptor activity, such as at therapeutic concentrations. In some embodiments, the mixed V1A receptor agonist-antagonist is Compound 1.

[0022] In some embodiments, treating ESLD includes treating the disease itself and / or its associated symptoms or complications, such as ascites. In some embodiments, treating ESLD includes improving or managing quality of life, extending lifespan, such as through treatment of its associated symptoms and / or complications (e.g., ascites and liver decompensation events).

[0023] In some instances, the mixed V1A agonist-antagonists provided herein increase mean arterial pressure (MAP). In some instances, the mixed V1A agonist-antagonists provided herein increase MAP without (significant) injection site reactions (e.g., local vasoconstriction), such as at subcutaneous injection sites.

[0024] In some examples, the mixed V1A agonist-antagonists provided herein reduce portal pressure, such as by increasing splanchnic arteriolar vasoconstriction.

[0025] In some embodiments, the mixed V1A agonist-antagonists provided herein are used to treat complications of ESLD (e.g., cirrhotic portal hypertension), such as ascites (e.g., ascites that is refractory to treatment). In some embodiments, the mixed V1A agonist-antagonists provided herein are used to treat complications of ESLD (e.g., cirrhotic portal hypertension), such as refractory ascites.

[0026] In some embodiments, Compound 1 is used to treat complications of ESLD, such as ascites (e.g., cirrhosis portal hypertension). In some embodiments, Compound 1 is used to treat complications of ESLD, such as refractory ascites (e.g., cirrhosis portal hypertension).

[0027] In some examples, the mixed V1A agonist-antagonists provided herein (e.g., Compound 1) provide a significantly improved therapeutic index (e.g., resulting from a lower maximum vasoconstriction and a lower risk of tissue hypoxia), such as when compared to full, non-selective (V2, V1A) receptor agonists. In some examples, the mixed V1A agonist-antagonists provided herein (e.g., Compound 1) provide approximately half the maximum vasoconstriction provided by full agonists, e.g., without any concomitant signs of ischemia. In some examples, the mixed V1A agonist-antagonists provided herein (e.g., Compound 1) are (clinically) effective vasoconstrictors, e.g., with low or no local toxicity, such as when administered subcutaneously. In some examples, the mixed V1A agonist-antagonists provided herein (e.g., Compound 1) are (clinically) effective vasoconstrictors (e.g., with a favorable benefit / risk profile (e.g., when administered subcutaneously), e.g., with low or no local toxicity). In some examples, the mixed V1A agonist-antagonists provided herein (e.g., Compound 1) provide sufficient splanchnic vasoconstriction to reduce elevated portal vein pressure while minimizing the risk of excessive vasoconstriction in other vascular beds with associated adverse events, such as mesenteric ischemia.

[0028] In some embodiments, provided herein is a method of treating end-stage liver disease (ESLD) or a sign or symptom (e.g., a complication) thereof in an individual (e.g., in need thereof), comprising subcutaneously administering to the individual (e.g., in need thereof) an (effective) amount of a compound, wherein the compound is a mixed vasopressin receptor 1A (V1AR) agonist-antagonist.

[0029] In some embodiments, provided herein are methods for treating end-stage liver disease (ESLD) or a symptom (e.g., a complication) thereof in an individual (e.g., in need thereof), the method comprising subcutaneously injecting the individual (e.g., in need thereof) with a composition comprising an (effective) amount of a compound, wherein the compound is a mixed vasopressin receptor 1A (V1AR) agonist-antagonist.

[0030] In some embodiments, provided herein are methods for treating end-stage liver disease (ESLD) or a symptom (e.g., a complication) thereof in an individual (e.g., in need thereof), the method comprising subcutaneously injecting the individual (e.g., in need thereof) with a composition comprising an (effective) amount of a compound, wherein the compound is a mixed vasopressin receptor 1A (V1AR) agonist-antagonist.

[0031] In some embodiments, the mixed vasopressin receptor 1A (V1AR) agonist-antagonist is selective for V1AR over V2R, hi some embodiments, the mixed vasopressin receptor 1A (V1AR) agonist-antagonist has no V2R activity, such as at therapeutic concentrations.

[0032] In some embodiments, the compound comprises a first moiety having agonist activity and a second moiety having antagonist activity.

[0033] In some embodiments, modulating mean arterial pressure (MAP) in an individual comprises increasing MAP by at least 5% above baseline, hi some embodiments, modulating mean arterial pressure (MAP) in an individual comprises increasing MAP by at least 5 mmHg above baseline (e.g., by 5 mmHg or more, or by 10 mmHg or more).

[0034] In some embodiments, the compound has the structure represented by Formula I: D1-L-D2 Formula I or a pharmaceutically acceptable salt thereof (In the formula, D1 is a vasopressin receptor 1A (V1AR) agonist; D2 is a V1AR antagonist; and L is a linker It has.

[0035]

[0013] In some embodiments, provided herein is a method of treating end-stage liver disease (ESLD) or a sign or symptom (e.g., complication) thereof in an individual (e.g., in need thereof), comprising administering to the individual (e.g., in need thereof) an (effective) amount of a compound having a structure represented by Formula I: D1-L-D2 Formula I or a pharmaceutically acceptable salt thereof (In the formula, D1 is a vasopressin receptor 1A (V1AR) agonist; D2 is a V1AR antagonist; and L is a linker subcutaneous administration of

[0036]

[0013] In some embodiments, provided herein is a method of treating end-stage liver disease (ESLD) or a sign or symptom (e.g., complication) thereof in an individual (e.g., in need thereof), comprising administering to the individual (e.g., in need thereof) an (effective) amount of a compound having a structure represented by Formula I: D1-L-D2 Formula I or a pharmaceutically acceptable salt thereof (In the formula, D1 is a vasopressin receptor 1A (V1AR) agonist; D2 is a V1AR antagonist; and L is a linker The method includes subcutaneously administering a composition comprising:

[0037] In some embodiments, D1 is selective for V1AR over V2R.

[0038] In some embodiments, D1 is or comprises a (e.g., cyclic) peptide. In some embodiments, D1 is or comprises a cyclic nanopeptide. In some embodiments, D1 has the following structure: [ka] having or including

[0039] In some embodiments, D1 has the following structure: [ka] having or including

[0040] In some embodiments, D2 is or comprises a (e.g., linear) peptide. In some embodiments, D2 is a linear polypeptide comprising about 7 or more amino acid residues. In some embodiments, D2 has the following structure: [ka] having or including

[0041] In some embodiments, D2 has the following structure: [ka] having or including

[0042] In some embodiments, L is a non-hydrolyzable linker. In some embodiments, L comprises one or more linker groups, each linker group independently selected from the group consisting of substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl. In some embodiments, L is a bond, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. In some embodiments, L is or comprises a substituted or unsubstituted heteroalkyl. In some embodiments, L is a heteroalkyl substituted with one or more substituents (e.g., an alkylamine), each substituent independently selected from the group consisting of oxo, amino, and substituted heteroalkyl (e.g., an alkylamine substituted with oxo). In some embodiments, L is or comprises one or more (e.g., modified) amino acid residues. In some embodiments, L has the following structure: [ka] having or including

[0043] In some embodiments, L has the following structure: [ka] having or including

[0044] In some embodiments, the compound is Compound 1, or a pharmaceutically acceptable salt thereof.

[0045] In some embodiments, provided herein is a method of treating end-stage liver disease (ESLD) or a sign or symptom (e.g., a complication) thereof in an individual (e.g., in need thereof), comprising subcutaneously administering to the individual (e.g., in need thereof) an (effective) amount of Compound 1, or a pharmaceutically acceptable salt thereof.

[0046] In some embodiments, provided herein is a method of treating end-stage liver disease (ESLD) or a sign or symptom (e.g., a complication) thereof in an individual (e.g., in need thereof), comprising subcutaneously injecting to the individual (e.g., in need thereof) a composition comprising an (effective) amount of Compound 1, or a pharmaceutically acceptable salt thereof.

[0047] In some embodiments, provided herein is a method of reducing (the incidence of) local vasoconstriction, such as (injection site) ischemia, in an individual in need thereof, comprising subcutaneously injecting to the individual in need thereof a composition comprising a compound having a structure represented by Formula I, or a pharmaceutically acceptable salt thereof.

[0048] In some embodiments, the composition further comprises a liquid medium or solvent (eg, water or an aqueous medium).

[0049] In some embodiments, the method further includes attaching a subcutaneous infusion device to the skin of the individual, the subcutaneous infusion device comprising a chamber body and a hollow tube body, the composition being configured within the chamber body, the hollow tube body comprising a first opening and a second opening, the first opening being in fluid contact with the chamber body and the second opening being configured subcutaneously within the individual after attaching the subcutaneous infusion device to the skin.

[0050] In some embodiments, the subcutaneous infusion device further comprises a pump configured to subcutaneously infuse the composition into the individual at a constant or variable rate.

[0051] In some embodiments, subcutaneous injection of the composition into an individual improves tolerability compared to subcutaneous (bolus) injection (e.g., due to reduced M1 overproduction, such as subcutaneously). In some embodiments, subcutaneous injection of the composition into an individual reduces undesirable systemic events (e.g., undesirable vasoconstriction resulting in ischemia, etc.), reduces undesirable administration site events (e.g., local site vasoconstriction resulting in administration site ischemia, etc.), or reduces both.

[0052] In some embodiments, provided herein are methods of treating end-stage liver disease (ESLD) in an individual in need thereof, comprising subcutaneously injecting to the individual in need thereof a composition comprising a compound having a structure represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein less than 50% of the compound of Formula I is degraded (e.g., subcutaneously).

[0053] In some embodiments, provided herein are methods of treating end-stage liver disease (ESLD) in an individual in need thereof, comprising subcutaneously injecting to the individual in need thereof a composition comprising a compound having a structure represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein less than 50% of the compound of Formula I is degraded (e.g., subcutaneously).

[0054] In some embodiments, when the composition is administered subcutaneously to an individual (e.g., by subcutaneous (bolus) injection or subcutaneous infusion), less than 50% of the compound of Formula I degrades (e.g., subcutaneously). In some embodiments, when the composition is administered subcutaneously to an individual (e.g., by subcutaneous (bolus) injection or subcutaneous infusion), less than 30% of the compound of Formula I degrades (e.g., subcutaneously). In some embodiments, when the composition is administered subcutaneously to an individual (e.g., by subcutaneous (bolus) injection or subcutaneous infusion), less than 50% of the compound of Formula I degrades (e.g., subcutaneously) to form M1. In some embodiments, when the composition is administered subcutaneously to an individual (e.g., by subcutaneous (bolus) injection or subcutaneous infusion), less than 30% of the compound of Formula I degrades (e.g., subcutaneously) to form M1. In some embodiments, when the composition is administered subcutaneously to an individual (e.g., by subcutaneous (bolus) injection or subcutaneous infusion), less M1 is formed compared to administration of an otherwise identical composition administered by subcutaneous (bolus) injection. In some embodiments, less M1 is formed systemically compared to administration of an otherwise identical composition administered by subcutaneous (bolus) injection, such as when the composition is injected subcutaneously into an individual. In some embodiments, less M1 is formed locally (at the injection / infusion site) compared to administration of an otherwise identical composition administered by subcutaneous (bolus) injection, such as when the composition is injected subcutaneously into an individual.

[0055] In some embodiments, the composition is subcutaneously infused into the individual continuously for at least 1 hour, hi some embodiments, the composition is subcutaneously infused into the individual at a rate of about 0.005 milliliters per hour (mL / hr) to about 1 mL / hr for the administration period.

[0056] In some embodiments, the compound is administered to an individual (eg, continuously) in an amount of about 0.001 milligrams (mg) to about 100 mg, such as over a period of one or more days.

[0057] In some embodiments, the composition comprises the compound at a concentration of about 0.001 milligrams per milliliter (mg / mL) to about 100 mg / mL. In some embodiments, the composition comprises the compound at a concentration of about 0.1 mg / mL to about 100 mg / mL. In some embodiments, the composition comprises the compound at a concentration of about 1 mg / mL to about 10 mg / mL.

[0058] In some embodiments, the compound is administered (continuously) to an individual in need thereof at a dose of about 0.1 mg / day to about 100 mg / day.

[0059] In some embodiments, the composition further comprises a preservative, hi some embodiments, the preservative is present in an amount of about 1 mg / mL to about 20 mg / mL.

[0060] In some embodiments, the composition further comprises a solubilizing agent, in some embodiments, the solubilizing agent is present in an amount of about 1 mg / mL to about 100 mg / mL (e.g., about 60-80 mg / mL).

[0061] In some embodiments, the composition comprises a buffering agent. In some embodiments, the buffering agent is selected from the group consisting of acetate buffer, succinate buffer, and citrate buffer. In some embodiments, the composition comprises a buffering agent at a concentration of about 1 millimolar (mM) to about 1 molar (M). In some embodiments, the composition comprises a buffering agent at a concentration of about 5 mM to about 250 mM. In some embodiments, the composition comprises a buffering agent at a concentration of about 5 mM to about 25 mM. In some embodiments, the composition comprises a buffering agent at a concentration of about 50 mM to about 250 mM.

[0062] In some embodiments, the composition has a pH of about 4 to about 8. In some embodiments, the composition has a pH of about 4 to about 6. In some embodiments, the composition has a pH of about 4.5 to about 5.

[0063] In some embodiments, the individual's urine output (e.g., within the first 24 hours, such as within the first 4 hours) is (significantly) increased (e.g., compared to a solvent control) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the individual's urine output is increased by about 25% or more, 50% or more, 100% or more, 200% or more, 300% or more, 400% or more, or 500% or more (e.g., compared to a solvent control) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the individual's urine output is about 50% or more or 100% or more greater at least one day (e.g., three or more days) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual.

[0064] In some embodiments, the parameters described herein, such as urine volume, are measured at a time point described in the Examples, such as 4 hours or more after a compound described herein is administered to an individual.

[0065] In some embodiments, the individual's urinary sodium (excretion) is (significantly) increased (e.g., compared to a vehicle control) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the individual's urinary sodium and / or urinary potassium (excretion) is increased by about 100% or more, 250% or more, 500% or more, 750% or more, 1000% or more, 1500% or more, or 2000% or more (e.g., compared to a vehicle control, such as within the first 4 hours of treatment) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual.

[0066] In some embodiments, the volume of ascites fluid in an individual is (significantly) reduced (e.g., compared to a vehicle control) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the volume of ascites fluid in an individual is reduced by about 25% or more, 50% or more, 100% or more, about 200% or more, or about 300% or more (e.g., compared to a vehicle control, such as when measured 3 days after treatment) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual.

[0067] In some embodiments, an individual's body weight is (significantly) reduced (e.g., compared to a solvent control) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, an individual's body weight is reduced by about 1% or more, 2.5% or more, 5% or more, or about 10% or more (e.g., compared to a solvent control) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, an individual's body weight is at least about 1%, at least about 2.5%, at least about 5%, or at least about 10% less at least one day (e.g., three or more days (e.g., five days)) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual.

[0068] In some embodiments, the mean arterial pressure (MAP) of an individual is increased (e.g., compared to a baseline measurement before treatment) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the MAP of the individual is increased by about 1% to about 10% (e.g., compared to a baseline measurement before treatment) after administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the MAP of the individual is increased in a dose-dependent manner after administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual.

[0069] In some embodiments, the individual's diastolic blood pressure is increased (e.g., compared to a pre-treatment baseline measurement) after administering a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual.

[0070] In some embodiments, the individual's systolic blood pressure is increased (e.g., compared to a pre-treatment baseline measurement) after administering a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual.

[0071] In some embodiments, the diastolic blood pressure and / or systolic blood pressure of an individual is increased in a dose-dependent manner after administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual.

[0072] In some embodiments, the pulse rate and / or peripheral blood flow of an individual is decreased after administering a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual.

[0073] In some embodiments, (subcutaneous) administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to an individual improves systemic hemodynamics in the individual.

[0074] In some embodiments, (subcutaneous) administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to an individual reduces water retention and / or fluid overload in the individual.

[0075] In some embodiments, the method comprises administering to the individual a compound described herein, or a pharmaceutically acceptable salt thereof, on a first day and a second day (e.g., the second day is one or more days after the first day). In some embodiments, the method further comprises administering (subcutaneously) to the individual a compound described herein, or a pharmaceutically acceptable salt thereof, one or more days after the first day. In some embodiments, the method comprises administering (subcutaneously) to the individual a compound described herein, or a pharmaceutically acceptable salt thereof, every day for two or more days (e.g., after the first day). In some embodiments, the method further comprises administering (subcutaneously) to the individual a compound described herein, or a pharmaceutically acceptable salt thereof, on consecutive days after the first day. In some embodiments, the method comprises administering (subcutaneously) to the individual a compound described herein, or a pharmaceutically acceptable salt thereof, on multiple days.

[0076] In some embodiments, the individual is administered multiple subcutaneous doses, e.g., over several days, of a compound described herein, or a pharmaceutically acceptable salt thereof, hi some embodiments, the compound is administered to the individual continuously, such as over several days.

[0077] In some embodiments, the individual receives repeated subcutaneous injections of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0078] In some embodiments, the method comprises subcutaneously administering to the individual a compound described herein, or a pharmaceutically acceptable salt thereof, once or twice daily (e.g., for two or more consecutive days).

[0079] In some embodiments, the method includes administering to the individual a compound described herein, or a pharmaceutically acceptable salt thereof, by subcutaneous (bolus) injection, e.g., the compound is administered to the individual as a single dose (e.g., all at once).

[0080] In some embodiments, the method comprises administering to the individual a compound described herein, or a pharmaceutically acceptable salt thereof, by subcutaneous infusion. In some embodiments, the method comprises administering to the individual a compound described herein, or a pharmaceutically acceptable salt thereof, by continuous subcutaneous infusion.

[0081] In some embodiments, the method includes administering (e.g., subcutaneously) to the individual a compound described herein, or a pharmaceutically acceptable salt thereof, in an amount of about 0.01 milligram (mg) per day to about 100 mg per day (e.g., about 0.01 milligram (mg) per day to about 10 mg per day (e.g., about 0.01 mg / day to about 1 mg / day)).

[0082] In some embodiments, the individual has end-stage liver disease (ESLD).

[0083] In some embodiments, the individual has ascites. In some embodiments, the individual has refractory ascites.

[0084] In some embodiments, the individual develops (refractory) ascites as a complication of ESLD.

[0085] In some embodiments, the method further comprises decreasing serum creatinine (sCr) in the individual (e.g., compared to a pre-treatment baseline measurement). In some embodiments, the method comprises administering a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual at least until the individual has an sCr value of 1.5 milligrams (mg) per deciliter (dL) or less. In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1), is administered (e.g., subcutaneously) to an individual (e.g., described herein) at least until the individual's sCr value returns to normal (e.g., baseline).

[0086] In some embodiments, the individual has improved renal function after administration of a compound described herein, such as after completing a treatment regimen.

[0087] In some embodiments, provided herein are pharmaceutical compositions comprising an effective amount of a compound, or a pharmaceutically acceptable salt thereof, wherein the compound is a mixed vasopressin receptor 1A (V1AR) agonist-antagonist, and the composition is formulated for subcutaneous administration.

[0088] In some embodiments, the compound has the structure represented by Formula I: D1-L-D2 Formula I or a pharmaceutically acceptable salt thereof (In the formula, D1 is a vasopressin receptor 1A (V1AR) agonist; D2 is a V1AR antagonist; and L is a linker It has.

[0089] In some embodiments, the compound is Compound 1.

[0090] In some embodiments, provided herein is an effective amount of a compound having a structure represented by Formula I: D1-L-D2 Formula I or a pharmaceutically acceptable salt thereof (In the formula, D1 is a vasopressin receptor 1A (V1AR) agonist; D2 is a V1AR antagonist; and L is a linker A pharmaceutical composition comprising:

[0091] In some embodiments, the pharmaceutical composition comprises an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, and the composition is formulated for subcutaneous administration.

[0092] In some embodiments, the compositions are suitable for a route of administration other than intravenous administration, such as subcutaneous administration.

[0093] In some embodiments, the compositions are suitable for systemic delivery of active agents such as Compound 1.

[0094] In some embodiments, a pharmaceutical composition is provided comprising an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, wherein the composition is formulated for subcutaneous administration.

[0095] In some embodiments, the compound is Compound 1.

[0096] In some embodiments, the compositions are suitable for systemic delivery of active agents such as Compound 1.

[0097] In some embodiments, provided herein are subcutaneous formulations comprising a compound having a structure represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein less than 50% of the compound of Formula I degrades (e.g., subcutaneously).

[0098] In some embodiments, provided herein are subcutaneous formulations comprising a compound having a structure represented by Formula I, or a pharmaceutically acceptable salt thereof, the formulation having a concentration of the compound of Formula I from about 0.1 mg / mL to about 100 mg / mL.

[0099] In some embodiments, provided herein are subcutaneous formulations comprising a compound having a structure represented by Formula I, or a pharmaceutically acceptable salt thereof, and a buffering agent at a concentration of about 1 millimolar (mM) to about 1 M.

[0100] In some embodiments, the formulation comprises a buffering agent at a concentration of about 1 millimolar (mM) to about 1 M. In some embodiments, the buffering agent has a pKa of about 3.0 to about 6.0, such as at 25° C. In some embodiments, the buffering agent is selected from the group consisting of acetate, citrate, succinate, and phosphate.

[0101] In some embodiments, the formulation comprises a pH sufficient to inhibit (e.g., inactivate or deactivate) proteases (e.g., trypsin), such as in the subcutaneous layer of an individual to whom the formulation is administered subcutaneously. In some embodiments, the pH of the formulation is about 4 to about 5 (e.g., about 4.5).

[0102] In some embodiments, the pH of the subcutaneous formulation does not (substantially) change when administered subcutaneously to an individual (eg, by subcutaneous (bolus) injection or subcutaneous infusion).

[0103] In some embodiments, the formulation has an ionic strength of about 5 mM to about 200 mM (eg, about 10 mM to about 100 mM).

[0104] In some embodiments, the subcutaneous formulation further comprises a preservative.

[0105] In some embodiments, provided herein are subcutaneous formulations comprising a compound having a structure represented by Formula I, or a pharmaceutically acceptable salt thereof, and a preservative.

[0106] In some embodiments, the preservative is any suitable preservative, such as meta-(m)-cresol. In some embodiments, the formulation comprises a preservative (e.g., m-cresol) at a concentration of about 1 mg / mL to about 100 mg / mL.

[0107] In some embodiments, provided herein are subcutaneous formulations comprising a compound having a structure represented by Formula I, or a pharmaceutically acceptable salt thereof, and a solubilizing agent.

[0108] In some embodiments, the preservative is any suitable solubilizing agent, such as cyclodextrin. In some embodiments, the formulation comprises a solubilizing agent (e.g., cyclodextrin) at a concentration of about 1 mg / mL to about 100 mg / mL (e.g., about 60-80 mg / mL).

[0109] In some embodiments, the compound of formula I is not susceptible to degradation, such as in the subcutaneous layer of an individual to whom the formulation is administered subcutaneously.

[0110] In some embodiments, less than 50% of the compound of Formula I degrades (e.g., in the vial and / or subcutaneously), such as over a period of about 1 day or more (e.g., about 1 day, about 2 days, or more).

[0111] In some embodiments, the compound of Formula I is present in the formulation at a concentration of about 0.1 mg / mL to about 100 mg / mL. In some embodiments, the compound of Formula I is present in the formulation at a concentration of about 1 mg / mL to about 50 mg / mL.

[0112] In some examples, the mixed V1a agonist-antagonist provided herein (eg, Compound 1) is administered in the form of an acetate salt.

[0113] In some examples, the mixed V1a agonist-antagonist provided herein (e.g., Compound 1) is administered in the form described in any of the examples described herein, such as any one of Examples 1-6.

[0114] In some embodiments, provided herein is a system for treating end-stage liver disease (ESLD), the system comprising: a composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof; and a device configured to provide subcutaneous infusion of the composition to an individual when placed on the individual's skin.

[0115] In some embodiments, the system includes an adhesive for (e.g., reversibly) affixing the (subcutaneous infusion) device to the surface of the individual's skin. In some embodiments, the system includes a chamber body and a hollow tube body, and the composition is configured within the chamber body. In some embodiments, the hollow tube body includes a first opening and a second opening. In some embodiments, the first opening is in fluid contact with the chamber body. In some embodiments, the second opening is configured subcutaneously within the individual after affixing the subcutaneous infusion device to the individual's skin.

[0116] In some embodiments, the (subcutaneous infusion) device further comprises a pump configured to subcutaneously infuse the composition into the individual at a constant or variable rate.

[0117] In some embodiments, the system is configured to provide the composition to the individual (continuously) for a period of about 24 hours or more.

[0118] In some embodiments, the device is configured to accept a vial and / or cartridge of the composition.

[0119] In some embodiments, the device is a subcutaneous infusion device (eg, a pump).

[0120] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings (also referred to herein as "FIG" and "FIG"). [Brief explanation of the drawings]

[0121] [Figure 1] The study design described in Example 1 is shown for each subject in Period 1 (intravenous infusion) and Period 2 (subcutaneous injection). [Figure 2] 1 shows the time course of Compound 1 concentration after intravenous administration period 1. [Figure 3A] 1 shows the time course of Compound 1 concentration after the first subcutaneous dose, period 2. [Figure 3B] 1 shows the time course of Compound 1 concentration after the fifth subcutaneous dose, period 2. [Figure 4A] Diastolic blood pressure and intravenous infusion (mean values) are shown. [Figure 4B] Diastolic blood pressure, intravenous infusion (mean percent change) is shown. [Figure 5A] Diastolic blood pressure, repeated subcutaneous injections (mean values) are shown. [Figure 5B] Diastolic blood pressure, repeated subcutaneous injections (mean percent change) are shown. [Figure 6A] Systolic blood pressure and intravenous infusion (mean values) are shown. [Figure 6B] Systolic blood pressure, intravenous infusion (mean percent change) is shown. [Figure 7A] Systolic blood pressure and subcutaneous injection (mean values) are shown. [Figure 7B] Systolic blood pressure, subcutaneous injection (mean percent change) is shown. [Figure 8A] Change in mean arterial pressure over time (mean percentage change from baseline in mean arterial pressure after intravenous infusion) is shown. [Figure 8B] Change in mean arterial pressure over time (mean percentage change from baseline in mean arterial pressure after repeated subcutaneous injections) is shown. [Figure 9A] Pulse rates (mean values) after intravenous injection are shown. [Figure 9B] Pulse rate (mean percent change) after intravenous infusion is shown. [Figure 10A] The pulse rate (mean value) after subcutaneous injection is shown. [Figure 10B] Pulse rate (mean percent change) after subcutaneous injection is shown. [Figure 11] The amount of Compound 1 excreted unchanged in the urine after intravenous injection is shown. [Figure 12A] The amount of Compound 1 excreted after the first intravenous injection is shown. [Figure 12B]The amount of Compound 1 excreted after the fifth intravenous injection is shown. [Figure 13A] 1 shows the mean plasma concentrations of metabolite M1 after the first sc injection of Compound 1. [Figure 13B] 1 shows the mean plasma concentrations of metabolite M1 after the fifth sc injection of Compound 1. [Figure 14] The structure of M1 (circled) for Compound 1 is shown. [Figure 15] 1 shows the time course of urine volume after subcutaneous administration of Compound 1. [Figure 16] 1 shows the time course of urinary sodium excretion after subcutaneous administration of Compound 1. [Figure 17] 1 shows the time course of body weight after subcutaneous administration of Compound 1. [Figure 18] 1 shows the time course of urine volume after intravenous administration of Compound 1. [Figure 19] 1 shows the time course of urinary sodium excretion after intravenous administration of Compound 1. [Figure 20] 1 shows the time course of glomerular filtration rate after intravenous administration of Compound 1. [Figure 21] 1 shows the time course of portal vein pressure after intravenous administration of Compound 1. [Figure 22] 1 shows the time course of cardiac output after intravenous administration of Compound 1. [Figure 23] 1 shows the time course of mean arterial pressure after intravenous administration of Compound 1. [Figure 24] 1 shows the time course of systemic vascular resistance after intravenous administration of Compound 1. [Figure 25] 1 shows the effect of Compound 1 on body weight after subcutaneous administration. [Figure 26A] The effect of Compound 1 on urine volume measured 4 hours after subcutaneous administration is shown. [Figure 26B] The effect of Compound 1 on urine volume measured 5 to 24 hours after subcutaneous administration is shown. [Figure 26C] The effect of Compound 1 on urine volume measured 24 hours after subcutaneous administration is shown. [Figure 27]1 shows the effect of subcutaneous administration of Compound 1 on net water balance measured 24 hours after administration. [Figure 28A] The effect of Compound 1 on urinary sodium measured 4 hours after subcutaneous administration is shown. [Figure 28B] 1 shows the effect of Compound 1 on urinary sodium measured 5 to 24 hours after subcutaneous administration. [Figure 28C] 1 shows the effect of Compound 1 on urinary potassium measured 4 hours after subcutaneous administration. [Figure 28D] 1 shows the effect of Compound 1 on urinary potassium measured 5 to 24 hours after subcutaneous administration. [Figure 28E] The effect of Compound 1 on urinary creatinine measured 4 hours after subcutaneous administration is shown. [Figure 28F] 1 shows the effect of Compound 1 on urinary creatinine measured 5 to 24 hours after subcutaneous administration. [Figure 29] 1 shows the effect of Compound 1 on ascites volume after subcutaneous administration. [Figure 30] 1 shows the effect of Compound 1 on spleen weight after subcutaneous administration. [Figure 31A] 1 shows the effect of Compound 1 on BUN after subcutaneous administration. [Figure 31B] 1 shows the effect of Compound 1 on Cl after subcutaneous administration. [Figure 31C] 1 shows the effect of Compound 1 on PHOS after subcutaneous administration. [Figure 31D] 1 shows the effect of Compound 1 on Na after subcutaneous administration. [Figure 31E] 1 shows the effect of Compound 1 on BUN / CREA after subcutaneous administration. [Figure 32] Exemplary dose-response curves for a full agonist, a partial agonist, and a weak agonist are shown. Figure 32 shows that, in general, a wider therapeutic window for vasoconstriction can be achieved with curve 2 than with curves 1 or 3. Part A indicates the level of full agonist where vasoconstriction may be lethal. Part B indicates the level of full agonist where vasoconstriction may induce severe side effects. [Figure 33]1 shows the change in portal pressure (ΔPP) over time in rats with bile duct ligation (BDL) after subcutaneous administration of various doses of a mixed V1a agonist-antagonist. [Figure 34] Figure 1 shows the change in portal mean arterial pressure (ΔMAP) over time in methionine / choline deficient (MCD) diet-fed rats after subcutaneous administration of a full non-selective (V2, V1a) agonist and various doses of a mixed V1a agonist-antagonist. [Figure 35] Figure 1 shows the change in portal pressure (ΔPP) over time in methionine / choline deficient (MCD) diet-fed rats after subcutaneous administration of a full non-selective (V2, V1a) agonist and various doses of a mixed V1a agonist-antagonist. [Figure 36] 1 shows exemplary dose-response curves of the maximum possible effect at the human V1a (hV1a) receptor for a full non-selective (V2, V1a) agonist and a mixed V1a agonist-antagonist. [Figure 37] 1 shows exemplary dose-response curves of the maximum possible effect at human V1a (hV1a) and human V2 (hV2) receptors for mixed V1a agonist-antagonists. [Figure 38] 1 shows exemplary dose-response curves for contractile force of human mesenteric resistance arteries in response to mixed V1a agonist-antagonists. [Figure 39A] 1 shows the normalized plasma concentration time profile of Compound 1 following IV administration (10 mg / kg) in an individual (eg, a mammal). [Figure 39B] 1 shows the normalized plasma concentration time profile of Compound 1 following subcutaneous administration (1.0 mg / kg) in an individual (eg, a mammal). [Figure 40A] 1 shows the dose response of Compound 1, vasopressin, and vehicle on skin blood flow (SBF) (% baseline) in an individual (eg, a mammal) after IV administration. [Figure 40B] 1 shows the dose response of Compound 1, vasopressin, and vehicle on blood lactate concentration (mM) in an individual (eg, a mammal) after IV administration. [Figure 40C] 1 shows a comparison of blood lactate concentrations in individuals (eg, mammals) following administration of vehicle, Compound 1, or vasopressin (AVP). [Figure 41A] 1 shows mean arterial pressure (MAP) following subcutaneous administration of Compound 1 in an individual (eg, a mammal). [Figure 41B] 1 shows systolic arterial blood pressure following subcutaneous administration of Compound 1 in an individual (eg, a mammal). [Figure 41C] 1 shows diastolic arterial blood pressure following subcutaneous administration of Compound 1 in an individual (eg, a mammal). [Figure 41D] 1 shows heart rate following subcutaneous administration of Compound 1 in an individual (eg, a mammal). [Figure 42A] 1 shows the normalized plasma concentration (ng / mL) time profile of Compound 1 following IV bolus (0.05 mg / kg) administration in an individual (e.g., a mammal). [Figure 42B] 1 shows the normalized plasma concentration time profile of Compound 1 following subcutaneous bolus (0.5 mg / kg) administration in an individual (eg, a mammal). [Figure 43A] 1 shows the change from baseline in mean arterial pressure (ΔMAP) following administration of Compound 1 over 480 minutes in an individual (eg, a mammal). [Figure 43B] 1 shows the change from baseline in mean arterial pressure (ΔMAP) following administration of terlipressin over 480 minutes in an individual (eg, a mammal). [Figure 44] Panel A shows that little or no metabolism of Compound 1 occurs in healthy humans after intravenous (IV) infusion, and that concentrations of Compound 1 and M1 are approximately equimolar in healthy humans after subcutaneous (bolus) injection (Panel B). [Figure 45] 1 shows that little or no metabolism of Compound 1 occurs in minipigs following subcutaneous (SC) injection of relatively low (Panels A and B) and high (Panels C and D) doses of Compound 1. [Figure 46] Figure 45, panels A and B show the Compound 1 / M1 ratios. [Figure 47] 1 shows that little or no metabolism of Compound 1 occurs in minipigs following relatively slow subcutaneous (SC) injection of relatively low (Panels A and B) and high (Panels C and D) doses of Compound 1. [Figure 48] Figure 47, panels AD show the compound 1 / M1 ratios. DETAILED DESCRIPTION OF THE INVENTION

[0122] Specific Definitions As used in this specification and the appended claims, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to "an agent" includes a plurality of such agents; a reference to "the cell" includes a reference to one or more cells (or cells) and equivalents thereof known to those of skill in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulas, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term "about," when referring to a number or numerical range, means that the referenced number or numerical range is an approximation within experimental variability (or within statistical experimental error); thus, the number or numerical range may vary between 1% and 15% of the stated number or numerical range. Any recitation of "about" provided herein also includes a disclosure of the number itself. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude that in other particular embodiments, the embodiments, such as, for example, any composition of matter, composition of matter, method, or process described herein, may "consist of" or "consist essentially of" the described features.

[0123] The terms "treat," "treating," or "treatment," as used herein, include reducing, alleviating, ameliorating, ameliorating, managing, mitigating, or relieving symptoms associated with a disease, disease state, condition, or symptom (e.g., as provided herein) in either a chronic or acute treatment scenario. Treatment of a disease or disease state described herein also includes disclosure of the use of such compounds or compositions for the treatment of such disease, disease state, disorder, or symptom.

[0124] The term "modulate" or "modulating," as used herein, refers to a change in a biological, chemical, and / or biochemical response, such as a physiological response, in an individual. In some examples, the change is an increase in the individual's biological, chemical, and / or biochemical response. In some examples, the change is a decrease in the individual's biological, chemical, and / or biochemical response. In some examples, the change is observed after a compound described herein is administered to the individual (e.g., immediately, 30 minutes or more, 1 hour or more, 6 hours or more, 12 hours or more, 24 hours or more, or 1 week or more).

[0125] The term "adverse event" or "AE," as used herein, refers to an untoward medical occurrence in an individual, such as an individual participating in a clinical trial. In some instances, an AE is an untoward and / or unintended sign, symptom, or illness, such as one temporally associated with the use of an investigational product (IMP), regardless of whether it is considered to be caused by the IMP. For example, an AE may include accidental injury, a reason for any change in medication (drug and / or dose), a reason for any medical, nursing, or pharmacy consultation, or a reason for hospitalization or surgical procedure, as well as overdoses and medication errors with or without clinical consequences. In some instances, an AE is predicted based on the pharmacological effect of the IMP. In some instances, an AE is a laboratory abnormality, vital signs, or a finding from a physical or gynecological examination assessed by the investigator as clinically significant. In some instances, a pretreatment adverse event is any untoward medical occurrence occurring or observed between the signing of informed consent and the first administration of the IMP. In some examples, a treatment-emergent adverse event is an AE that occurs after administration of the IMP and within the time of residual drug effect, or a pre-treatment adverse event or pre-existing medical condition that worsens in intensity after administration of the IMP and within the time of residual drug effect. In some examples, the time of residual drug effect is the estimated period after administration of the IMP during which the product's effects are still believed to exist based on PK, PD, or other substance characteristics. In some examples, the residual drug effect is five times the terminal half-life. In some examples, the terminal half-life of Compound 1 is approximately 1.5 to 2 hours. In some examples, the residual drug effect exists within the time between the last assessment in Period 1 and the follow-up visit in Period 2 (as described in the Examples herein below). In some examples, a treatment-emergent adverse event is an AE that occurs after the time of residual drug effect of the IMP (e.g., before the first administration in Period 2 after the last assessment in Period 1 and after the follow-up visit in Period 2).

[0126] "Amino" refers to the -NH2 radical.

[0127] "Cyano" refers to the -CN radical.

[0128] "Nitro" refers to the -NO2 radical.

[0129] "Oxo" refers to the =O radical.

[0130] "Hydroxyl" refers to the -OH radical.

[0131] "Alkyl" generally refers to an alkyl group having 1 to 15 carbon atoms (e.g., C1-C 15 "Alkyl" refers to an acyclic (e.g., straight or branched) or cyclic hydrocarbon (e.g., chain) radical consisting solely of carbon and hydrogen atoms, such as an alkyl (e.g., alkyl). Unless otherwise specified, an alkyl is saturated or unsaturated (e.g., alkenyl containing at least one carbon-carbon double bond). The disclosure provided herein of "alkyl" is intended to include independent recitation of saturated "alkyl" unless otherwise specified. Alkyl groups described herein are generally monovalent, but may also be divalent (and may also be described herein as "alkylene" or "alkylenyl" groups). In certain embodiments, an alkyl contains 1 to 13 carbon atoms (e.g., C1 to C8). 13 In certain embodiments, alkyl contains 1 to 8 carbon atoms (e.g., C1-C8 alkyl). In other embodiments, alkyl contains 1 to 5 carbon atoms (e.g., C1-C5 alkyl). In other embodiments, alkyl contains 1 to 4 carbon atoms (e.g., C1-C4 alkyl). In other embodiments, alkyl contains 1 to 3 carbon atoms (e.g., C1-C3 alkyl). In other embodiments, alkyl contains 1 to 2 carbon atoms (e.g., C1-C2 alkyl). In other embodiments, alkyl contains 1 carbon atom (e.g., C1 alkyl). In other embodiments, alkyl contains 5 to 15 carbon atoms (e.g., C5-C6 alkyl). 15alkyl). In other embodiments, an alkyl contains 5 to 8 carbon atoms (e.g., C5-C8 alkyl). In other embodiments, an alkyl contains 2 to 5 carbon atoms (e.g., C2-C5 alkyl). In other embodiments, an alkyl contains 3 to 5 carbon atoms (e.g., C3-C5 alkyl). In other embodiments, an alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), and 1-pentyl (n-pentyl). An alkyl is attached to the remainder of the molecule by a single bond. Generally, each alkyl group is independently substituted or unsubstituted. Each recitation of "alkyl" provided herein includes specific and explicit recitation of unsaturated "alkyl" groups unless otherwise specified. Similarly, unless otherwise specifically stated in the specification, alkyl groups may contain the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t R a (t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t R a (t is 1 or 2) and -S(O) t N(R a )2 (t is 1 or 2), and each R aare independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0132] "Alkoxy" refers to a radical attached through an oxygen atom of the formula --O-alkyl, where alkyl is an alkyl chain as defined above.

[0133] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from 2 to 12 carbon atoms. In certain embodiments, an alkenyl contains from 2 to 8 carbon atoms. In other embodiments, an alkenyl contains from 2 to 4 carbon atoms. An alkenyl is optionally substituted as described for an "alkyl" group.

[0134] "Alkylene" or "alkylene chain" generally refers to a straight or branched divalent alkyl group, such as having 1 to 12 carbon atoms, that connects the remainder of the molecule to a radical group, e.g., methylene, ethylene, propylene, i-propylene, n-butylene, etc. Unless stated otherwise specifically in the specification, the alkylene chain is optionally substituted as described for alkyl groups herein.

[0135] "Aryl" refers to a radical derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and carbon atoms of 5 to 18 carbon atoms, and at least one ring in the ring system is fully unsaturated, i.e., it contains a cyclic delocalized (4n+2) π-electron system according to the Hückel theory. Ring systems from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin, and naphthalene. Unless stated otherwise specifically in this specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") means any of alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, R b -C-(O)-R a , -R b -C(O)ORa , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2) and -R b -S(O) t N(R a )2 (t is 1 or 2), and each R aare independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl); and each R b are independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, and each of the above substituents is unsubstituted unless otherwise specified.

[0136] An "aralkyl" or "aryl-alkyl" is an alkyl group of the formula -R c -refers to the aryl radical, R c is an alkylene chain as defined above, e.g., methylene, ethylene, etc. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0137] "Carbocyclyl" or "cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical, consisting solely of carbon and hydrogen atoms, including fused or bridged ring systems, having 3 to 15 carbon atoms. In certain embodiments, a carbocyclyl contains 3 to 10 carbon atoms. In other embodiments, a carbocyclyl contains 5 to 7 carbon atoms. A carbocyclyl is attached to the remainder of the molecule by a single bond. A carbocyclyl or cycloalkyl can be saturated (i.e., containing only single C-C bonds) or unsaturated (i.e., containing one or more double or triple bonds). Examples of saturated cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Unsaturated carbocyclyls are also referred to as "cycloalkenyls." Examples of monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, etc. Unless otherwise specifically stated herein, the term "carbocyclyl" includes alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a)2, -R b -C(O)R a , R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2) and -R b -S(O) t N(R a )2 (t is 1 or 2), and each R aare independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl); and each R b are independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, and each of the above substituents is unsubstituted unless otherwise specified.

[0138] A "carbocyclylalkyl" is a group of the formula -R c -Carbocyclyl (R c refers to a radical of the formula: wherein R is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical are optionally substituted as defined above.

[0139] "Carbocyclylalkenyl" refers to a group of the formula -R c -Carbocyclyl (R c refers to a radical of the formula: wherein R is an alkylene chain as defined above. The alkenylene chain and the carbocyclyl radical are optionally substituted as defined above.

[0140] "Carbocyclylalkoxy" refers to a group of the formula -OR c -Carbocyclyl (R c refers to a radical attached through an oxygen atom of a carbocyclyl radical, which is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical are optionally substituted as defined above.

[0141] "Halo" or "halogen" refers to a fluoro, bromo, chloro, or iodo substituent.

[0142] "Haloalkyl" refers to an alkyl radical, as defined above, substituted by one or more halogen radicals, as defined above, e.g., trihalomethyl, dihalomethyl, halomethyl, etc. In some embodiments, the haloalkyl is a fluoroalkyl, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.

[0143] The term "heteroalkyl" refers to an alkyl group, as defined above, in which one or more skeletal carbon atoms of the alkyl are replaced with a heteroatom (with the appropriate number of substituents or valences, e.g., -CH- can be replaced with -NH- or -O-). For example, each substituted carbon atom is independently replaced with a heteroatom, e.g., carbon is replaced with nitrogen, oxygen, sulfur, or other suitable heteroatom. In some examples, each substituted carbon atom is independently replaced with oxygen, nitrogen (e.g., -NH-, -N(alkyl)-, or -N(aryl)- or another substituent contemplated herein), or sulfur (e.g., -S-, -S(=O)-, or -S(=O)-). In some embodiments, a heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In some embodiments, a heteroalkyl is attached to the remainder of the molecule at a heteroatom of the heteroalkyl. In some embodiments, a heteroalkyl is a C1-C618 In some embodiments, heteroalkyl is C1-C 12 Heteroalkyl. In some embodiments, heteroalkyl is C1-C6 heteroalkyl. In some embodiments, heteroalkyl is C1-C4 heteroalkyl. In some embodiments, heteroalkyl includes alkylamino, alkylaminoalkyl, aminoalkyl, heterocycloalkyl, heterocycloalkyl, heterocyclyl, and heterocycloalkylalkyl, as defined herein. Unless stated otherwise specifically herein, heteroalkyl does not include alkoxy, as defined herein. Unless stated otherwise specifically herein, heteroalkyl groups are optionally substituted as defined above for alkyl groups.

[0144] "Heteroalkylene" refers to a divalent heteroalkyl group, as defined above, that links one portion of the molecule to another portion of the molecule. Unless otherwise specifically stated, the heteroalkylene is optionally substituted as defined above for an alkyl group.

[0145] "Heterocyclyl" refers to a stable 3- to 18-membered non-aromatic ring radical containing 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise specifically stated herein, a heterocyclyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, optionally including fused or bridged ring systems. The heteroatoms in a heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. A heterocyclyl radical is partially saturated or fully saturated. A heterocyclyl radical is saturated (i.e., contains only single C-C bonds) or unsaturated (e.g., contains one or more double or triple bonds in the ring system). In some examples, a heterocyclyl radical is saturated. In some examples, a heterocyclyl radical is both saturated and substituted. In some examples, a heterocyclyl radical is unsaturated. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl.Unless stated otherwise specifically in this specification, the term "heterocyclyl" includes alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R. b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, R b -N(R a )2, R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2) and -R b -S(O) t N(R a)2 (t is 1 or 2), and each R a are independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl); and each R b are independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, and each of the above substituents is unsubstituted unless otherwise specified.

[0146] "N-heterocyclyl" or "N-linked heterocyclyl" refers to a heterocyclyl radical as defined above containing at least one nitrogen, and the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. The N-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such N-heterocyclyl radicals include, but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

[0147] "C-heterocyclyl" or "C-linked heterocyclyl" refers to a heterocyclyl radical as defined above containing at least one heteroatom, and the point of attachment of the heterocyclyl radical to the rest of the molecule is through a carbon atom in the heterocyclyl radical. The C-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such C-heterocyclyl radicals include, but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.

[0148] "Heterocyclylalkyl" refers to a group of the formula -R c -heterocyclyl(R c refers to a radical of the formula: (wherein R is an alkylene chain as defined above). If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl portion of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group.

[0149] "Heterocyclylalkoxy" refers to a group of the formula -OR c -heterocyclyl(R crefers to a radical attached through the oxygen atom of a heterocyclyl group (wherein the heterocyclyl group is an alkylene chain as defined above). If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl portion of the heterocyclylalkoxy radical is optionally substituted as defined above for a heterocyclyl group.

[0150] "Heteroaryl" refers to a radical derived from a 3- to 18-membered aromatic ring radical containing 2 to 17 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, a heteroaryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, in which at least one ring in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) π-electron system according to Hückel theory. Heteroaryl includes fused or bridged ring systems. Heteroatoms in a heteroaryl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. A heteroaryl is attached to the remainder of the molecule through any atom of the ring. Examples of heteroaryl include azepinyl, acridinyl, benzimidazolyl, benzoindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H- Cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexa Hydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-Methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl thieno[2,3-d]pyridinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in this specification, the term "heteroaryl" includes alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R, b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b-OC(O)-N(R a ) 2 , -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2) and -R b -S(O) t N(R a )2 (t is 1 or 2), wherein each R aare independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl); and each R b are independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, and each of the above substituents is unsubstituted unless otherwise specified.

[0151] "N-heteroaryl" refers to a heteroaryl radical as defined above containing at least one nitrogen, and the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. The N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0152] "C-heteroaryl" refers to a heteroaryl radical as defined above, where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical. The C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0153] "Heteroarylalkyl" refers to a group of the formula -R c - refers to the heteroaryl radical, R c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl portion of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.

[0154] "Heteroarylalkoxy" refers to a group of the formula -OR c -heteroaryl (R c refers to a radical attached through the oxygen atom of a heteroaryl (wherein the heteroaryl is an alkylene chain as defined above). If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heteroaryl portion of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.

[0155] The compounds disclosed herein, in some embodiments, contain one or more asymmetric centers and thus result in enantiomers, diastereomers, and other stereoisomeric forms defined in terms of absolute stereochemistry as (R)- or (S)-. Unless otherwise specified, all stereoisomeric forms of the compounds disclosed herein are intended to be contemplated by the present disclosure. When a compound described herein contains an alkene double bond, unless otherwise specified, the present disclosure is intended to include both E and Z geometric isomers (e.g., cis or trans). Similarly, all possible isomers, including their racemic and optically pure forms, and all tautomeric forms, are also intended to be included. The term "geometric isomer" refers to the E or Z geometric isomers (e.g., cis or trans) of the alkene double bond. The term "positional isomer" refers to structural isomers around a central ring, such as ortho-, meta-, and para-isomers around a benzene ring.

[0156] In general, each optionally substituted group is independently substituted or unsubstituted. Each enumeration of optionally substituted groups provided herein includes, unless otherwise specified, an independent and explicit enumeration of both the unsubstituted group and the substituted group (e.g., substituted in certain embodiments and unsubstituted in certain other embodiments). Unless otherwise specified, substituted groups (e.g., substituted alkyl) provided herein are substituted with one or more substituents, each of which may be halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR, or the like. a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O)t R a (t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t R a (t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), and each R a are independently hydrogen, alkyl (e.g., optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (e.g., optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (e.g., optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (e.g., optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (e.g., optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (e.g., optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (e.g., optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (e.g., optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (e.g., optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0157] "Pharmaceutically acceptable salts" includes both acid addition salts and base addition salts. A pharmaceutically acceptable salt of any one of the pharmacological agents described herein is intended to encompass any pharmaceutically suitable salt form. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0158] "Pharmaceutically acceptable acid addition salts" refer to those salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like, which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable. Also included are salts formed with organic acids, such as aliphatic monocarboxylic and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Thus, exemplary salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, malate, tartrate, methanesulfonate, and the like. Salts of amino acids such as arginate, gluconate, and galacturonate are also contemplated (see, e.g., Berge SM et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt, according to methods and techniques familiar to those skilled in the art.

[0159] "Pharmaceutically acceptable base addition salts" refer to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from the addition of inorganic or organic bases to the free acids. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. See Berge et al., supra.

[0160] The compounds disclosed herein, in some embodiments, contain one or more asymmetric centers and thus result in enantiomers, diastereomers, and other stereoisomeric forms defined in terms of absolute stereochemistry as (R)- or (S)-. Unless otherwise specified, all stereoisomeric forms of the compounds disclosed herein are intended to be contemplated by the present disclosure. When a compound described herein contains an alkene double bond, unless otherwise specified, the present disclosure is intended to include both E and Z geometric isomers (e.g., cis or trans). Similarly, all possible isomers, including their racemic and optically pure forms, and all tautomeric forms, are also intended to be included. The term "geometric isomer" refers to the E or Z geometric isomers (e.g., cis or trans) of the alkene double bond. The term "positional isomer" refers to structural isomers around a central ring, such as ortho-, meta-, and para-isomers around a benzene ring.

[0161] Systemic hemodynamic complications may manifest as cirrhosis and portal hypertension (PHT). Individuals often develop elevated portal vein pressure (PP) due to increased intrahepatic resistance. The combination of increased blood flow and elevated intrahepatic resistance can lead to the development of PHT and the common manifestation of decompensated cirrhosis. Clinical PHT can occur when the hepatic venous pressure gradient (HVPG) is >5 mmHg. PHT can then lead to a hyperkinetic state characterized by decreased splanchnic and systemic vascular resistance, which can further increase portal blood flow. As advanced cirrhosis develops, splanchnic arteriolar vasodilation can worsen PHT, which in turn can cause a further increase in HVPG, further reducing renal blood flow above 10 mmHg. The kidneys can sense low perfusion pressure and reduced glomerular filtration rate as hypovolemia, which in turn activates the renin-angiotensin-aldosterone (RAAS) and vasopressin systems, leading to severe vasoconstriction within the kidney and retention of sodium and water. If renal hypoperfusion is severe enough, it can lead to the development of ascites and kidney damage in the form of hepatorenal syndrome-acute kidney injury (HRS-AKI).

[0162] Ascites is a common complication of liver cirrhosis, and ascites requiring paracentesis is a frequent liver-related cause of hospitalization. HRS-AKI is a severe complication of liver cirrhosis; only 50% of patients with HRS-AKI are expected to respond to currently available treatments, and more than half die within 90 days. However, with early intervention, HRS-AKI is reversible.

[0163] Ascites is a serious and rapidly progressing consequence of end-stage liver disease (ESLD) that can lead to acute renal failure and often death. For example, refractory ascites, the end-stage form of ascites, affects an estimated 60,000 to 100,000 individuals annually (e.g., worldwide) and is associated with a roughly 50% mortality rate three years after diagnosis, with a one-year survival rate of less than 50%. As the incidence of (chronic) liver disease increases, the prevalence of ascites is predicted to increase as well. There has been no therapeutic innovation for ascites in over 20 years, and there is no FDA-approved treatment for this disease. Therapeutic interventions often provide only modest benefits in severely ill patients and / or are insufficient to achieve the goals of reversing renal failure and prolonging survival. Patients are often managed symptomatically to remove the ascites, either mechanically via paracentesis or by surgical placement of a shunt (transjugular intrahepatic portosystemic shunt [TIPS]). Such treatment can provide symptomatic relief of ascites, but does not improve the underlying circulatory disorder and does not affect survival. Cirrhotic symptoms can also lead to other complications, such as bleeding esophageal varices, spontaneous bacterial peritonitis, and renal failure.

[0164] Patients with refractory ascites often have abnormally high splanchnic blood flow, due to excessive hepatic vascular resistance and systemic vasodilation. Vasoconstrictors that constrict splanchnic blood vessels can reduce ascites formation by reducing venous blood flow. Studies with terlipressin, a nonselective vasopressin receptor full agonist, have demonstrated a reduction in ascites formation, but such compounds are limited to continuous (e.g., 24-hour) intravenous infusion due to local vasoconstriction at the injection site, which prevents alternative administration routes, such as subcutaneous administration.

[0165] Management of HRS-AKI often focuses on restoring systemic arterial blood pressure and reducing PHT through splanchnic vasoconstriction, targeting the vasopressin system, with the long-term goal being liver transplantation. Although monitoring and titration are challenging, increased vasoconstriction (i.e., mean arterial pressure (MAP)) correlates with improved hemodynamic parameters. Vasoconstrictors, including terlipressin, norepinephrine, and midodrine / octreotide, have been used as therapy for patients with HRS-AKI in an attempt to restore renal blood flow and function. Terlipressin (a vasopressin analog) and albumin have been used as first-line therapy for HRS-AKI because they reduce short-term mortality compared with placebo. Albumin is added to increase circulating volume. Terlipressin is approved by the US Food and Drug Administration for the treatment of adults with HRS accompanied by a rapid decline in renal function.

[0166] There are three vasopressin receptors: V1a, V1b, and V2. V1a receptors are found throughout the circulatory system and regulate vasoconstriction. V2 receptors regulate aquaresis through antidiuretic action at the kidney level by mediating water reabsorption in the collecting duct. V1b receptors are found in the anterior pituitary gland and peripheral tissues, and one potential role is to mediate the release of adrenocorticotropic hormone, which can stimulate water retention. Vasopressin, also known as arginine vasopressin (AVP) or antidiuretic hormone, is a peptide involved in water balance and vascular tone. At normal physiological concentrations, there is little or no activity on the V1a system; only at supraphysiological concentrations is there significant vasoconstriction. Pharmacological application can achieve strong vasoconstriction in a concentration-dependent manner.

[0167] Arginine vasopressin (AVP) is the endogenous ligand for the vasopressin V1A, V1B, and V2 G-protein-coupled receptors (V1AR, V1BR, V2R). Homeostatic functions of the vasopressin system, such as regulation of blood osmolality and vasopressor effects, are mediated by the V2 and V1A receptor subtypes. Activation of V2 receptors, located in the collecting ducts, plays a role in regulating water balance through antidiuretic effects. Activation of V1A receptors, located on vascular smooth muscle cells, results in an increase in vascular smooth muscle cell and arterial blood pressure.

[0168] Lysine vasopressin (LVP), the active metabolite of terlipressin, is active at V1a, V1b, and V2 receptors and is a full agonist. Despite significantly improving renal function, the use of terlipressin is associated with serious adverse events, including gastrointestinal disorders, sepsis, and respiratory failure. These adverse effects, which may be due to the strength of LVP binding to V1a and off-target effects on V2, can lead to further fluid retention. As a result of the potential for serious side effects, terlipressin has received a black box warning from the US FDA regarding severe or fatal respiratory failure.

[0169] The hypertensive activity of vasopressin receptor agonists is clinically interesting, as demonstrated by the use of AVP and its analogs (e.g., terlipressin and ornithine vasopressin). However, a significant drawback of existing V1A receptor full agonists is that they can induce severe vasoconstriction and tissue hypoperfusion when used at therapeutic doses. The pharmacological activity of V1AR partial agonists (e.g., compounds with reduced maximum potency at V1A receptors) can be used in various conditions where a moderate increase in blood flow and / or blood pressure without hypoperfusion is desirable. For example, such indications include hepatorenal syndrome, refractory ascites, hemorrhagic esophageal varices, anesthesia-induced hypotension, vasodilatory shock, puncture-induced circulatory disorders, and spontaneous bacterial peritonitis.

[0170] Individuals with cirrhosis often develop numerous clinical complications, among which ascites accumulation is prominent and indicates a poor prognosis. In some instances, ascites formation is due to the homeostatic activation of endogenous sodium and water retention systems to counteract circulatory disorders, such as those occurring in patients with advanced liver disease. In some instances, circulatory disorders are characterized by the presence of splanchnic vasodilation and portal hypertension. In some embodiments, the compounds described herein (e.g., Compound 1) affect ascites volume, sodium and water excretion, portal hypertension, and systemic hemodynamics after administration of the compound or vehicle to cirrhotic rats with ascites.

[0171] In some embodiments, a compound described herein (e.g., a mixed V1a agonist / antagonist such as Compound 1) is delivered systemically in an individual after intravenous (IV) and / or subcutaneous (SC) administration of a composition comprising the compound (see Example 1). In some embodiments, an individual experiences systemic effects, such as changes in MAP, after the compound is administered intravenously and / or subcutaneously. In some embodiments, the compound is administered by intravenous infusion. In some embodiments, the compound is administered by subcutaneous (bolus) injection. While systemic effects observed after IV infusion and SC (bolus) injection were comparable, more adverse events were measured in individuals receiving SC (bolus) injection of the composition (see Example 1). In general, the compound was well tolerated by individuals receiving the composition by IV infusion.

[0172] In some instances, metabolites (e.g., substantial amounts of metabolite M1) are formed (e.g., overproduction of M1) after SC (bolus) injection of a composition comprising a compound described herein (e.g., a mixed V1a agonist / antagonist such as Compound 1) (see Figure 44, panel B). In some instances, trace amounts of metabolites (e.g., less than 15% of metabolite M1) are formed after IV infusion of a composition comprising a compound described herein (e.g., a mixed V1a agonist / antagonist such as Compound 1) (see Figure 44, panel A). As discussed herein, full vasopressin receptor agonists (e.g., terlipressin) are known to cause (serious) adverse events when administered subcutaneously. Therefore, overproduction of the full agonist (M1) after SC (bolus) injection provides an explanation for the difference in tolerability profiles of the compositions in healthy individuals after IV infusion and after SC bolus injection.

[0173] As described herein, in some examples, metabolite (M1) formation is reduced by subcutaneously injecting a composition comprising a compound described herein into an individual (see Example 3). Additionally, in some examples, metabolite (M1) formation is reduced by increasing the buffer concentration of a composition comprising a compound described herein (see Example 4). Furthermore, in some examples, metabolite (M1) formation is reduced by increasing the parent drug (e.g., Compound 1) concentration of a composition comprising a compound described herein (see Example 4). In some examples, metabolite (M1) formation is reduced by a combination of any one or more of subcutaneous injection, increasing buffer concentration, and increasing drug concentration.

[0174] In some embodiments, provided herein are methods of treating end-stage liver disease (ESLD) in an individual in need thereof, comprising subcutaneously injecting to the individual in need thereof a composition comprising a compound described herein, such as a compound having a structure represented by Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, less than 50% of the compound, such as the compound of Formula I, is degraded. In some embodiments, less than 50% of the compound, such as the compound of Formula I, is degraded subcutaneously.

[0175] In some embodiments, a composition described herein is administered subcutaneously to an individual and less than 50% of the compound of Formula I degrades (e.g., subcutaneously). In some embodiments, a composition described herein is administered subcutaneously to an individual by subcutaneous (bolus) injection and less than 50% of the compound of Formula I degrades (e.g., subcutaneously). In some embodiments, a composition described herein is administered subcutaneously to an individual by subcutaneous infusion and less than 50% of the compound of Formula I degrades (e.g., subcutaneously). In some embodiments, the compound of Formula I degrades subcutaneously to form M1.

[0176] In some embodiments, greater than 50% of the parent compound (e.g., Compound 1) degrades (e.g., forming M1), such as after subcutaneous (bolus) injection. In some embodiments, greater than 60% of the parent compound (e.g., Compound 1) degrades (e.g., forming M1), such as after subcutaneous (bolus) injection. In some embodiments, greater than 70% of the parent compound (e.g., Compound 1) degrades (e.g., forming M1), such as after subcutaneous (bolus) injection. In some embodiments, greater than 80% of the parent compound (e.g., Compound 1) degrades (e.g., forming M1), such as after subcutaneous (bolus) injection.

[0177] In some embodiments, a composition described herein is administered subcutaneously to an individual and less than 30% of the compound of Formula I degrades (e.g., subcutaneously). In some embodiments, a composition described herein is administered subcutaneously to an individual by subcutaneous (bolus) injection and less than 30% of the compound of Formula I degrades (e.g., subcutaneously). In some embodiments, a composition described herein is administered subcutaneously to an individual by subcutaneous infusion and less than 30% of the compound of Formula I degrades (e.g., subcutaneously). In some embodiments, the compound of Formula I degrades subcutaneously to form M1.

[0178] In some embodiments, the composition is injected subcutaneously into an individual, resulting in less M1 formation compared to administration of an otherwise identical composition administered by subcutaneous (bolus) injection.

[0179] In some embodiments, the composition is injected subcutaneously into an individual, and less M1 is formed systemically compared to administration of an otherwise identical composition administered by subcutaneous (bolus) injection.

[0180] In some embodiments, the composition is injected subcutaneously into an individual, resulting in less M1 being formed locally (at the injection / infusion site) compared to administration of an otherwise identical composition administered by subcutaneous (bolus) injection.

[0181] In some embodiments, subcutaneous injection of the composition into an individual improves tolerability, hi some embodiments, subcutaneous injection of the composition into an individual improves tolerability compared to subcutaneous (bolus) injection, e.g., based on reduced M1 overproduction, such as subcutaneously.

[0182] In some embodiments, subcutaneous injection of the composition into an individual reduces undesired systemic events, such as undesired vasoconstriction causing ischemia. In some embodiments, subcutaneous injection of the composition into an individual reduces undesired administration site events, such as local site vasoconstriction causing administration site ischemia. In some embodiments, subcutaneous injection of the composition into an individual reduces undesired systemic events and undesired administration site events.

[0183] In some embodiments, provided herein are methods of reducing (the incidence of) local vasoconstriction in an individual in need thereof. In some embodiments, the methods are for reducing the incidence of local vasoconstriction in an individual in need thereof. In some embodiments, the methods are for reducing (the incidence of) ischemia in an individual in need thereof. In some embodiments, the methods are for reducing (the incidence of) injection site ischemia in an individual in need thereof. In some embodiments, the methods comprise subcutaneously injecting to an individual in need thereof a composition comprising a compound described herein, such as a compound having a structure represented by Formula I, or a pharmaceutically acceptable salt thereof.

[0184] In some examples, the compounds described herein (eg, Compound 1) are used to treat complications of ESLD, such as refractory ascites.

[0185] In some embodiments, provided herein is a method for treating ESLD in an individual (e.g., as described herein), comprising subcutaneously administering to the individual (e.g., as described herein) an amount of a compound, wherein the compound is a mixed vasopressin receptor 1A (V1AR) agonist-antagonist. In some embodiments, the amount of the compound is an effective amount of the compound.

[0186] In some embodiments, provided herein are methods of treating symptoms of ELSD in an individual (e.g., as described herein), comprising subcutaneously administering to the individual (e.g., as described herein) an amount of a compound, wherein the compound is a mixed vasopressin receptor 1A (V1AR) agonist-antagonist. In some embodiments, the amount of the compound is an effective amount of the compound.

[0187] In some embodiments, provided herein are methods of treating a complication of ELSD in an individual (e.g., as described herein), comprising subcutaneously administering to the individual (e.g., as described herein) an amount of a compound, wherein the compound is a mixed vasopressin receptor 1A (V1AR) agonist-antagonist. In some embodiments, the complication is ascites. In some embodiments, the complication is refractory ascites. In some embodiments, the amount of the compound is an effective amount of the compound.

[0188] In some embodiments, provided herein are methods of treating end-stage liver disease (ESLD) or a symptom (e.g., a complication) thereof in an individual (e.g., in need thereof), comprising subcutaneously injecting the individual (e.g., in need thereof) with an (effective) amount of a composition comprising a compound described herein, such as a mixed vasopressin receptor 1A (V1AR) agonist-antagonist described herein. In some embodiments, the compound has a structure represented by Formula I. In some embodiments, the compound is Compound 1.

[0189] In some embodiments, the method further includes affixing a subcutaneous infusion device to the skin (e.g., skin surface) of the individual. In some embodiments, the subcutaneous infusion device includes a chamber body and a hollow tube body. In some embodiments, the composition is configured within the chamber body. In some embodiments, the hollow tube body includes a first opening and a second opening. In some embodiments, the first opening is in fluid contact with the chamber body. In some embodiments, the second opening is configured subcutaneously within the individual after affixing the subcutaneous infusion device to the skin. In some embodiments, the hollow tube is a needle, such as one having any gauge suitable for subcutaneous administration (e.g., subcutaneous injection).

[0190] In some embodiments, the subcutaneous infusion device further comprises a pump configured to subcutaneously infuse the composition into the individual at a constant rate. In some embodiments, the subcutaneous infusion device further comprises a pump configured to subcutaneously infuse the composition into the individual at a variable rate. In some embodiments, the rate is a flow rate. In some embodiments, a continuous infusion is a flow rate that is insufficient to provide a stream of the composition. In some embodiments, a continuous infusion is a flow rate that provides a continuous drip into the individual. In some embodiments, the composition is subcutaneously infused into the individual at a rate of about 0.001 milliliters per hour (mL / hr) or greater. In some embodiments, the composition is subcutaneously infused into the individual at a rate of about 1 mL / hr or less. In some embodiments, the composition is subcutaneously infused into the individual at a rate of about 0.005 mL / hr to about 1 mL / hr during the administration period. In some embodiments, the composition is subcutaneously infused into the individual at a rate of about 0.01 mL / hr to about 1 mL / hr during the administration period. In some embodiments, the composition is subcutaneously infused into the individual at a rate of about 0.04 mL / hr to about 1 mL / hr during the administration period. In some embodiments, the administration period is at least about 1 hour. In some embodiments, the administration period is at least about 1 day. In some embodiments, the administration period is at least about 1 week. In some embodiments, the administration period is at least about 1 month. In some embodiments, the administration period is about 1 month or longer. In some embodiments, the administration period is about 2 months or longer. In some embodiments, the administration period is about 3 months or longer. In some embodiments, the administration period is about 4 months or longer. In some embodiments, the administration period is about 5 months or longer. In some embodiments, the administration period is about 6 months or longer. In some embodiments, the administration period is about 9 months or longer. In some embodiments, the administration period is about 12 months or longer.

[0191] In some embodiments, the compositions described herein are subcutaneously infused into an individual for at least 1 hour. In some embodiments, the compositions are subcutaneously infused into an individual for at least 1 day. In some embodiments, the compositions are subcutaneously infused into an individual for at least 1 week. In some embodiments, the compositions are subcutaneously infused into an individual for at least 1 month.

[0192] In some embodiments, the compositions described herein are continuously infused subcutaneously into an individual for at least 1 hour. In some embodiments, the compositions are continuously infused subcutaneously into an individual for at least 1 day. In some embodiments, the compositions are continuously infused subcutaneously into an individual for at least 1 week. In some embodiments, the compositions are continuously infused subcutaneously into an individual for at least 1 month.

[0193] In some embodiments, a compound described herein is administered to an individual (e.g., continuously) in an amount of about 0.001 milligrams (mg) to about 100 mg. In some embodiments, a compound is administered to an individual (e.g., continuously) in an amount of about 0.01 mg to about 50 mg. In some embodiments, a compound is administered to an individual (e.g., continuously) in an amount of about 0.01 mg to about 20 mg. In some embodiments, a compound is administered to an individual (e.g., continuously) in an amount of about 0.01 mg to about 10 mg. In some embodiments, a compound is administered to an individual (e.g., continuously) in an amount of about 0.1 mg to about 1 mg. In some embodiments, a compound is administered to an individual (e.g., continuously) in an amount of about 0.2 mg. In some embodiments, a composition is administered to an individual for a period of one or more days.

[0194] In some embodiments, the compositions described herein comprise a compound at a concentration of about 0.001 milligrams per milliliter (mg / mL) or greater. In some embodiments, the compositions comprise a compound at a concentration of about 100 mg / mL or less. In some embodiments, the compositions comprise a compound at a concentration of about 0.001 mg / mL to about 100 mg / mL. In some embodiments, the compositions comprise a compound at a concentration of about 0.01 mg / mL to about 100 mg / mL. In some embodiments, the compositions comprise a compound at a concentration of about 0.1 mg / mL to about 100 mg / mL. In some embodiments, the compositions comprise a compound at a concentration of about 1 mg / mL to about 100 mg / mL. In some embodiments, the compositions comprise a compound at a concentration of about 0.1 mg / mL to about 50 mg / mL. In some embodiments, the compositions comprise a compound at a concentration of about 1 mg / mL to about 50 mg / mL. In some embodiments, the compositions comprise a compound at a concentration of about 0.1 mg / mL to about 10 mg / mL. In some embodiments, the composition comprises the compound at a concentration of about 1 mg / mL to about 10 mg / mL.

[0195] In some embodiments, a compound described herein is administered to an individual described as requiring a dose of about 0.1 milligram (mg) / day. In some embodiments, a compound described herein is administered to an individual described as requiring a dose of about 100 mg / day. In some embodiments, a compound described herein is administered to an individual described as requiring a dose of about 0.1 mg / day to about 100 mg / day. In some embodiments, a compound described herein is administered to an individual described as requiring a dose of about 0.1 mg / day to about 50 mg / day. In some embodiments, a compound described herein is administered to an individual described as requiring a dose of about 1 mg / day to about 50 mg / day. In some embodiments, a compound described herein is administered to an individual described as requiring a dose of about 1 mg / day to about 10 mg / day. In some embodiments, a compound described herein is administered to an individual described as requiring a dose of about 1 mg / day to about 10 mg / day. In some embodiments, the compound is administered to the individual continuously.

[0196] In some embodiments, provided herein are methods for regulating mean arterial pressure (MAP) in an individual, comprising subcutaneously administering to the individual an effective amount of a compound, wherein the compound is a mixed vasopressin receptor 1A (V1AR) agonist-antagonist. In some embodiments, the individual is in need of an increase in MAP. In some embodiments, the individual has end-stage liver disease (ESLD) or a complication thereof. In some embodiments, the individual has ascites. In some embodiments, the individual has developed ascites as a complication of ESLD. In some embodiments, the individual has refractory ascites. In some embodiments, the individual has developed refractory ascites as a complication of ESLD.

[0197] In some embodiments, the individual's MAP is elevated (e.g., compared to a baseline measurement before treatment) after subcutaneous administration of a compound described herein (e.g., Compound 1). In some embodiments, the individual's MAP is elevated (e.g., compared to a baseline measurement before treatment) after subcutaneous administration of Compound 1.

[0198] In some embodiments, the individual's MAP increases by about 1% or more (e.g., compared to a pre-treatment baseline measurement) after administering a compound described herein or a pharmaceutically acceptable salt thereof (e.g., Compound 1). In some embodiments, the individual's MAP increases by about 5% or more (e.g., compared to a pre-treatment baseline measurement) after administering a compound described herein or a pharmaceutically acceptable salt thereof (e.g., Compound 1). In some embodiments, the individual's MAP increases by about 10% or more (e.g., compared to a pre-treatment baseline measurement) after administering a compound described herein or a pharmaceutically acceptable salt thereof (e.g., Compound 1). In some embodiments, the individual's MAP increases by about 15% or more (e.g., compared to a pre-treatment baseline measurement) after administering a compound described herein or a pharmaceutically acceptable salt thereof (e.g., Compound 1). In some embodiments, the individual's MAP increases by about 20% or more (e.g., compared to a pre-treatment baseline measurement) after administering a compound described herein or a pharmaceutically acceptable salt thereof (e.g., Compound 1). In some embodiments, an individual's MAP increases by about 1% to about 20% (e.g., compared to a pre-treatment baseline measurement) after administration of a compound described herein or a pharmaceutically acceptable salt thereof (e.g., Compound 1). In some embodiments, an individual's MAP increases by about 5% to about 20% (e.g., compared to a pre-treatment baseline measurement) after administration of a compound described herein or a pharmaceutically acceptable salt thereof (e.g., Compound 1). In some embodiments, an individual's MAP increases by about 10% to about 20% (e.g., compared to a pre-treatment baseline measurement) after administration of a compound described herein or a pharmaceutically acceptable salt thereof (e.g., Compound 1). In some embodiments, an individual's MAP increases by about 1% to about 10% (e.g., compared to a pre-treatment baseline measurement) after administration of a compound described herein or a pharmaceutically acceptable salt thereof (e.g., Compound 1). In some embodiments, the increase in MAP occurs about 1 hour or more after the compound, or a pharmaceutically acceptable salt thereof, is administered to the individual.In some embodiments, the increase in MAP occurs about 2 hours or more after the compound, or a pharmaceutically acceptable salt thereof, is administered to the individual. In some embodiments, the increase in MAP occurs about 3 hours or more after the compound, or a pharmaceutically acceptable salt thereof, is administered to the individual. In some embodiments, the increase in MAP occurs about 4 hours or more after the compound, or a pharmaceutically acceptable salt thereof, is administered to the individual. In some embodiments, the increase in MAP occurs about 5 hours or more after the compound, or a pharmaceutically acceptable salt thereof, is administered to the individual. In some embodiments, the increase in MAP occurs about 6 hours or more after the compound, or a pharmaceutically acceptable salt thereof, is administered to the individual. In some embodiments, the increase in MAP occurs about 12 hours or more after the compound, or a pharmaceutically acceptable salt thereof, is administered to the individual. In some embodiments, the increase in MAP occurs about 1 to 12 hours after the compound, or a pharmaceutically acceptable salt thereof, is administered to the individual. In some embodiments, the increase in MAP occurs about 1 to 6 hours after the compound, or a pharmaceutically acceptable salt thereof, is administered to the individual, hi some embodiments, the increase in MAP occurs about 4 to 6 hours after the compound, or a pharmaceutically acceptable salt thereof, is administered to the individual.

[0199] In some embodiments, the individual's MAP is increased in a dose-dependent manner after administration of the compound, or a pharmaceutically acceptable salt thereof.

[0200] In some embodiments, the compounds provided herein have a maximum therapeutic range concentration. In some embodiments, the maximum therapeutic range concentration includes an increase in concentration that does not result in a dose-dependent increase in MAP. In some embodiments, the compounds provided herein have a non-linear dose-dependence, such as one that exceeds the maximum therapeutic range concentration. In some embodiments, the dose-dependent increase in MAP includes the maximum therapeutic range concentration. In some embodiments, dose-dependence includes a situation where the effect increases with dose, at least for a certain dose range. For example, a higher dose may not result in a dose-dependent increase or may result in a less dose-dependent increase.

[0201] In some embodiments, a compound described herein (e.g., Compound 1) is a selective vasopressin V1a receptor partial agonist. In some embodiments, a compound described herein (e.g., Compound 1) is a mixed agonist-antagonist. In some embodiments, a compound described herein (e.g., Compound 1) is selective for the V1AR. In some embodiments, a compound described herein (e.g., Compound 1) is selective for the V1AR over the vasopressin 2 (V2) receptor (V2R). In some examples, a compound described herein (e.g., Compound 1) does not have functional V2R activity. In some examples, a compound described herein (e.g., Compound 1) does not have functional V2R activity at therapeutic concentrations. In some embodiments, the therapeutic concentration is a concentration sufficient to modulate the V1AR.

[0202] In some examples, the activity and selectivity of the compounds described herein (e.g., mixed agonist-antagonists such as Compound 1) are demonstrated by Tables 35 and 36. In some examples, the activity and selectivity of the compounds described herein (e.g., mixed agonist-antagonists such as Compound 1) are demonstrated by Tables 36-38.

[0203] In some embodiments, a compound described herein (e.g., Compound 1) is more than 10-fold selective for V1AR over V2R. In some embodiments, a compound described herein (e.g., Compound 1) is more than 100-fold selective for V1AR over V2R. In some embodiments, a compound described herein (e.g., Compound 1) is more than 1,000-fold selective for V1AR over V2R. In some embodiments, a compound described herein (e.g., Compound 1) is more than 10,000-fold selective for V1AR over V2R. In some embodiments, a compound described herein (e.g., Compound 1) is inactive at V2R.

[0204] In some embodiments, a compound described herein (e.g., Compound 1) comprises a first moiety having agonist activity. In some embodiments, a compound described herein (e.g., Compound 1) comprises a second moiety having antagonist activity. In some embodiments, a compound described herein (e.g., Compound 1) comprises a first moiety having agonist activity and a second moiety having antagonist activity.

[0205] In some embodiments, the compounds provided herein have a ratio of agonist to antagonist activity of about 90:10 to about 10:90, hi some embodiments, the compounds provided herein have a ratio of agonist to antagonist activity of about 50:50.

[0206] In some embodiments, agonist-antagonist refers to a compound having an agonist portion and an antagonist portion. In certain embodiments, the agonist portion and the antagonist portion are separate.

[0207] In some embodiments, the V1AR agonist-antagonist has a wider therapeutic window than the V1AR agonist. In some embodiments, the V1AR agonist-antagonist described herein has a selective V1a agonist portion and a selective V1a antagonist portion. In some examples, either the selective V1a agonist portion or the selective V1a antagonist portion binds to the V1AR, such that both the selective V1a agonist portion and the selective V1a antagonist portion do not bind to the V1AR simultaneously. In some examples, the V1a antagonist portion competes with the selective V1a agonist portion for binding to the V1AR. In some examples, V1AR agonism produces a (desired) vasoconstrictor effect. In some examples, V1AR antagonism prevents maximum activation of the V1a pathway.

[0208] In some examples, curve 1 in Figure 32 shows the concentration-response curve for a compound (e.g., a full non-selective (V2, V1a) agonist such as terlipressin) that produces lethal levels of vasoconstriction (e.g., at relatively high doses shown as portion A in Figure 32) and / or serious adverse events (e.g., at supratherapeutic doses and sublethal vasoconstriction doses shown as portion B in Figure 32). In some embodiments, a compound described herein (e.g., a full non-selective (V2, V1a) agonist such as terlipressin) has the concentration-response curve shown in Figure 32, line 1. In some examples, Figure 32, line 1 shows that a compound described herein (e.g., a full non-selective (V2, V1a) agonist such as terlipressin) has a relatively narrow therapeutic window. In some examples, Figure 32, line 1 shows that at relatively high doses, compounds described herein (e.g., full non-selective (V2, V1a) agonists such as terlipressin) produce levels of vasoconstriction that are lethal (shown as part A in Figure 32) and / or associated with serious adverse events, such as vasoconstriction with elevated lactate and / or ischemia (shown as part B in Figure 32).

[0209] In some embodiments, Figure 32, curve 2 shows the concentration-response curve for a compound (e.g., a mixed V1a agonist-antagonist such as Compound 1) that has a safety and efficacy profile. In some embodiments, a compound described herein (e.g., a mixed V1a agonist-antagonist such as Compound 1) has the concentration-response curve shown in Figure 32, line 2. In some examples, Figure 32, line 2 shows that even at high doses, a compound described herein (e.g., a mixed V1a agonist-antagonist such as Compound 1) has a relatively large therapeutic window. In some examples, Figure 32, line 2 shows that even at high doses, a compound described herein (e.g., a mixed V1a agonist-antagonist such as Compound 1) is safe and effective.

[0210] In some instances, Figure 32, curve 3 shows a concentration-response curve for a subtherapeutic compound. In some instances, Figure 32, curve 3 shows a concentration-response curve for a full agonist or partial agonist, such as a compound with relatively low activity at the V1AR.

[0211] In some examples, Figures 32-38 demonstrate that compounds described herein (e.g., mixed V1a agonist-antagonists such as Compound 1) can be safely used (over a large dose range) to treat ESLD or its symptoms and / or complications. In some examples, Figure 32 demonstrates that even at excessively high concentrations, compounds described herein (e.g., mixed V1a agonist-antagonists such as Compound 1) produce maximal effects (e.g., changes (increases) in MAP) in individuals (e.g., after subcutaneous administration). In some examples, Figures 32-38 demonstrate that compounds described herein (e.g., mixed V1a agonist-antagonists such as Compound 1) produce robust effects (e.g., changes (increases) in MAP) in individuals (e.g., after subcutaneous administration). In some examples, Figures 32-38 demonstrate that a compound described herein (e.g., a mixed V1a agonist-antagonist such as Compound 1) reaches, maintains, and does not exceed a safe and effective therapeutic effect (e.g., a change (increase) in MAP), such as after subcutaneous administration. In some examples, Figures 32-38 demonstrate that a compound described herein (e.g., a mixed V1a agonist-antagonist such as Compound 1) maintains (safe levels of) therapeutic efficacy for extended periods of time (e.g., after subcutaneous administration), such as for at least 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 minutes or more. In some examples, Figures 32-38 demonstrate that a compound described herein (e.g., a fully non-selective (V2, V1a) agonist such as terlipressin) rapidly reaches toxic and potentially harmful concentrations, such as at relatively high doses. In some examples, Figures 32-38 demonstrate that compounds described herein (e.g., full non-selective (V2, V1a) agonists such as terlipressin) rapidly reduce the effects of full non-selective (V2, V1a) agonists, e.g., rapidly falling below therapeutic levels after a relatively short period of time (e.g., after about 80 minutes or more).

[0212] In some embodiments, a compound described herein (e.g., Compound 1) modulates (e.g., increases) mean arterial pressure (MAP). In some embodiments, a compound described herein (e.g., Compound 1) is administered subcutaneously and modulates (e.g., increases) MAP. In some embodiments, a compound described herein (e.g., Compound 1) is administered subcutaneously and modulates (e.g., increases) MAP without (significant) injection site reactions (e.g., local vasoconstriction), such as at the subcutaneous injection site. In some embodiments, a compound described herein (e.g., Compound 1) is suitable for subcutaneous administration for the treatment of one or more complications of ESLD, such as refractory ascites.

[0213] In some embodiments, modulating mean arterial pressure (MAP) in an individual comprises increasing MAP by at least 5% from baseline (e.g., levels before administration of a compound described herein (e.g., Compound 1)). In some embodiments, modulating MAP in an individual comprises increasing MAP by at least 10% from baseline (e.g., levels before administration of a compound described herein (e.g., Compound 1)). In some embodiments, modulating MAP in an individual comprises increasing MAP by at least 15% from baseline (e.g., levels before administration of a compound described herein (e.g., Compound 1)). In some embodiments, the baseline is a level before administration of a compound described herein (e.g., Compound 1). In some examples, the baseline is a level compared to a control, such as a placebo.

[0214] In some embodiments, modulating mean arterial pressure (MAP) in an individual comprises increasing MAP by up to 5% from baseline (e.g., levels before administration of a compound described herein (e.g., Compound 1)). In some embodiments, modulating MAP in an individual comprises increasing MAP by up to 10% from baseline (e.g., levels before administration of a compound described herein (e.g., Compound 1)). In some embodiments, modulating MAP in an individual comprises increasing MAP by up to 15% from baseline (e.g., levels before administration of a compound described herein (e.g., Compound 1)). In some embodiments, the baseline is a level before administration of a compound described herein (e.g., Compound 1). In some examples, the baseline is a level compared to a control, such as a placebo.

[0215] In some embodiments, modulating MAP in an individual comprises increasing MAP by at least 5 mmHg above baseline (e.g., levels before administration of a compound described herein (e.g., Compound 1)). In some embodiments, modulating MAP in an individual comprises increasing MAP by 1 mmHg or more above baseline (e.g., levels before administration of a compound described herein (e.g., Compound 1)). In some embodiments, modulating MAP in an individual comprises increasing MAP by 5 mmHg or more above baseline (e.g., levels before administration of a compound described herein (e.g., Compound 1)). In some embodiments, modulating MAP in an individual comprises increasing MAP by 10 mmHg or more above baseline (e.g., levels before administration of a compound described herein (e.g., Compound 1)). In some embodiments, modulating MAP in an individual comprises increasing MAP by about 20 mmHg or more above baseline (e.g., levels before administration of a compound described herein (e.g., Compound 1)). In some embodiments, the baseline is a level before administration of a compound described herein (e.g., Compound 1).

[0216] In some embodiments, provided herein are methods of regulating mean arterial pressure (MAP) in an individual (e.g., as described herein above), comprising subcutaneously administering to the individual an effective amount of a compound having the structure D1-L-D2 represented by Formula I. In some embodiments, D1 is a vasopressin receptor 1A (V1AR) agonist. In some embodiments, D2 is a V1AR antagonist. In some embodiments, L is a linker. In some embodiments, the compound is administered to the individual as a pharmaceutically acceptable salt.

[0217] In some embodiments, a compound described herein (e.g., Compound 1) has a structure represented by Formula I: D1-L-D2. In some embodiments, D1 is a vasopressin receptor 1A (V1AR) agonist. In some embodiments, D2 is a V1AR antagonist. In some embodiments, L is a linker. In some embodiments, the compound is administered to an individual as a pharmaceutically acceptable salt.

[0218] In some embodiments, D1 is selective for V1AR. In some embodiments, D1 is selective for V1AR over V2R. In some embodiments, D1 is more than 10-fold selective for V1AR over V2R. In some embodiments, D1 is more than 100-fold selective for V1AR over V2R. In some embodiments, D1 is more than 1,000-fold selective for V1AR over V2R. In some embodiments, D1 is more than 10,000-fold selective for V1AR over V2R. In some embodiments, D1 is inactive at V2R.

[0219] In some embodiments, D1 comprises a peptide. In some embodiments, D1 is a peptide. In some embodiments, D1 comprises a cyclic peptide. In some embodiments, D1 is a cyclic peptide. In some embodiments, D1 comprises a cyclic nanopeptide. In some embodiments, D1 is a cyclic nanopeptide.

[0220] In some embodiments, D1 has the following structure: [ka] having or including

[0221] In some embodiments, D1 has the following structure: [ka] having or including

[0222] In some examples, D2 is selective for V1AR. In some embodiments, D2 is selective for V1AR over V2R. In some examples, D2 is more than 10-fold selective for V1AR over V2R. In some examples, D2 is more than 100-fold selective for V1AR over V2R. In some examples, D2 is more than 1,000-fold selective for V1AR over V2R. In some examples, D2 is more than 10,000-fold selective for V1AR over V2R. In some examples, D2 is inactive at V2R.

[0223] In some embodiments, at least one of D1 and D2 is selective for the V1AR. In some embodiments, at least one of D1 and D2 is selective for the V1AR over the V2R.

[0224] In some embodiments, D2 comprises a peptide. In some embodiments, D2 is a peptide. In some embodiments, D2 comprises a linear peptide. In some embodiments, D2 is a linear peptide. In some embodiments, D2 is a linear polypeptide comprising about 7 or more amino acid residues. In some embodiments, D2 comprises 7-12 amino acid residues.

[0225] In some embodiments, D2 has the following structure: [ka] having or including

[0226] In some embodiments, D2 has the following structure: [ka] having or including

[0227] In some embodiments, L is a non-hydrolyzable linker.

[0228] In some embodiments, L comprises a peptide bond. In some embodiments, L comprises one or more amino acid residues. In some embodiments, L is one or more amino acid residues. In some embodiments, L comprises one or more modified amino acid residues. In some embodiments, L is one or more modified amino acid residues.

[0229] In some embodiments, L comprises one or more linker groups, each linker group independently selected from the group consisting of substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl. In some embodiments, L is a bond, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. In some embodiments, L is or comprises substituted or unsubstituted heteroalkyl. In some embodiments, L is heteroalkyl substituted with one or more substituents, each substituent independently selected from the group consisting of oxo, amino, and substituted heteroalkyl. In some embodiments, L is an alkylamine substituted with one or more substituents, each substituent independently selected from the group consisting of oxo, amino, and substituted heteroalkyl. In some embodiments, L is an alkylamine substituted with oxo.

[0230] In some embodiments, L has the following structure: [ka] having or including

[0231] In some embodiments, L has the following structure: [ka] having or including

[0232] In some embodiments, the compound described herein is Compound 1, or a pharmaceutically acceptable salt thereof.

[0233] In some examples, compound 1 is glycinamide, L-cysteinyl-L-phenylalanyl-L-isoleucyl-L-glutaminyl-L-asparaginyl-L-cysteinyl-L-prolyl-N4-(phenylacetyl-O-methyl-D-tyrosyl-L-phenylalanyl-L-glutaminyl-L-asparaginyl-L-alanyl-L-prolyl-L-arginyl-L-isoglutamyl-N5-acetyl-L-lysyl-Lc-lysyl)-L-2,4-diaminobutyryl-, cyclic (1→6)-disulfide.

[0234] In some instances, compound 1 is C 110 H 161 N 31 0 27 It has the empirical molecular formula of S2.

[0235] In some examples, compound 1 has an average molecular mass of 2413.78 u.

[0236] In some examples, the mixed V1A agonist-antagonists provided herein (eg, Compound 1) are white to off-white powders.

[0237] In some examples, a mixed V1A agonist-antagonist provided herein (eg, Compound 1) has a solubility in water of at least 10 mg / mL.

[0238] In some embodiments, compound (IA) has the structure represented by formula I: [ka] or a pharmaceutically acceptable salt thereof.

[0239] In some examples, the mixed V1A agonist-antagonists provided herein (e.g., Compound 1) are 20-mer monocyclic branched peptides, including those containing natural and unnatural amino acids, including those of non-animal origin. In some examples, the mixed V1A agonist-antagonists provided herein (e.g., Compound 1) are 20-mer monocyclic branched peptides, including those containing natural and unnatural amino acids, including those of non-animal origin. 1 and Cys 6 There is an S--S bridge between the residues. In some instances, the branch is linked via the side chain amino functionality at position 8.

[0240] In some examples, compounds having a structure represented by formula (IB) are described herein: [ka] or a pharmaceutically acceptable salt thereof (In the formula, Dab is 2,4-diaminobutyric acid, D-Tyr(Me) is O-methyl-D-tyrosine, and PhAc is provided as a phenylacetic acid (e.g., L-2,4-diaminobutyric acid, Nc-acetyl-L-lysine, L-isoglutamine, and O-methyl-D-tyrosine are unnatural and the N-terminal moiety is substituted with phenylacetic acid).

[0241] In some examples, the mixed V1A agonist-antagonist provided herein (e.g., Compound 1) is provided as a pharmaceutically acceptable salt. In some examples, the mixed V1A agonist-antagonist provided herein (e.g., Compound 1) is provided as an acetate salt. In some examples, the mixed V1A agonist-antagonist provided herein (e.g., Compound 1) is administered in the form described in Example 1.

[0242] In some embodiments, the compounds described herein are any of the compounds described in either U.S. Pat. No. 9,644,000 or U.S. Pat. No. 9,388,214, each of which is incorporated herein by reference in its entirety, particularly for the compounds provided herein.

[0243] In some instances, compound 1 is C 110 H 161 N 31 O 27 S2(AcOH) z (wherein z is any integer (eg, 1 to 100)).

[0244] In some embodiments, provided herein are methods of regulating mean arterial pressure (MAP) in an individual (e.g., as described herein), comprising subcutaneously administering to the individual an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof.

[0245] In some embodiments, provided herein is a pharmaceutical composition comprising an amount of a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1). In some embodiments, the amount of the compound is an effective amount of the compound. In some embodiments, the compound is a mixed vasopressin receptor 1A (V1AR) agonist-antagonist. In some embodiments, the composition is formulated for subcutaneous administration. In some embodiments, the compound has a structure represented by Formula I. In some embodiments, the compound is Compound 1.

[0246] In some embodiments, provided herein are subcutaneous formulations comprising a compound described herein, such as a compound having a structure represented by Formula I, or a pharmaceutically acceptable salt thereof.

[0247] In some embodiments, less than 50% of the compound, such as a compound of Formula I, degrades. In some embodiments, less than 50% of the compound, such as a compound of Formula I, degrades to form M1. In some embodiments, less than 50% of the compound, such as a compound of Formula I, degrades subcutaneously. In some embodiments, less than 50% of the compound, such as a compound of Formula I, degrades to form M1 subcutaneously.

[0248] In some embodiments, less than 30% of the compound, such as a compound of Formula I, degrades. In some embodiments, less than 30% of the compound, such as a compound of Formula I, degrades to form M1. In some embodiments, less than 30% of the compound, such as a compound of Formula I, degrades subcutaneously. In some embodiments, less than 30% of the compound, such as a compound of Formula I, degrades to form M1 subcutaneously.

[0249] In some embodiments, the compositions described herein further comprise a liquid medium or solvent (eg, water or a liquid medium).

[0250] In some embodiments, provided herein are subcutaneous formulations having a concentration of a compound described herein, such as a compound having a structure represented by Formula I, of about 0.001 milligram (mg) / milliliter (mL) or greater. In some embodiments, the subcutaneous formulation has a concentration of a compound described herein, such as a compound having a structure represented by Formula I, of about 100 mg / mL or less. In some embodiments, the subcutaneous formulation has a concentration of a compound described herein, such as a compound having a structure represented by Formula I, of about 0.001 mg / mL to 100 mg / mL. In some embodiments, the subcutaneous formulation comprises the compound at a concentration of about 0.01 mg / mL to about 100 mg / mL. In some embodiments, the subcutaneous formulation comprises the compound at a concentration of about 0.1 mg / mL to about 100 mg / mL. In some embodiments, the subcutaneous formulation comprises the compound at a concentration of about 1 mg / mL to about 100 mg / mL. In some embodiments, the subcutaneous formulation comprises the compound at a concentration of about 0.1 mg / mL to about 50 mg / mL. In some embodiments, the subcutaneous formulation comprises the compound at a concentration of about 1 mg / mL to about 50 mg / mL. In some embodiments, the subcutaneous formulation comprises the compound at a concentration of about 0.1 mg / mL to about 10 mg / mL. In some embodiments, the subcutaneous formulation comprises the compound at a concentration of about 1 mg / mL to about 10 mg / mL.

[0251] In some embodiments, the compound is formulated as described in the Examples herein. In some embodiments, the compound is formulated as an aqueous solution. In some embodiments, the compound is formulated as an aqueous solution having a compound concentration of at least about 0.01 mg / mL. In some embodiments, the compound is formulated as an aqueous solution having a compound concentration of at least about 0.1 mg / mL. In some embodiments, the compound is formulated as an aqueous solution having a compound concentration of at least about 1 mg / mL. In some embodiments, the compound is formulated as an aqueous solution having a compound concentration of at least about 10 mg / mL. In some embodiments, the compound is formulated as an aqueous solution having a compound concentration of up to about 50 mg / mL. In some embodiments, the compound is formulated as an aqueous solution having a compound concentration of up to about 10 mg / mL. In some embodiments, the compound is formulated as an aqueous solution having a compound concentration of up to about 1 mg / mL. In some embodiments, the compound is formulated as an aqueous solution having a compound concentration of up to about 0.1 mg / mL. In some embodiments, the compound is formulated as an aqueous solution having a compound concentration of up to about 0.01 mg / mL. In some embodiments, the compound is formulated as an aqueous solution having a compound concentration of about 0.01 mg / mL to about 50 mg / mL. In some embodiments, the compound is formulated as an aqueous solution having a compound concentration of about 0.01 mg / mL to about 10 mg / mL. In some embodiments, the compound is formulated as an aqueous solution having a compound concentration of about 1 mg / mL to about 10 mg / mL. In some embodiments, the composition is formulated in an acetate buffer. In some embodiments, the composition is formulated at a pH of 4.5. In some embodiments, the composition is formulated in mannitol.

[0252] In some embodiments, an additive (e.g., a preservative) is added to a (e.g., subcutaneous) composition having a pH of about 3-6 (e.g., 4.5) and comprising at least about 1 millimolar (mM) acetate buffer (e.g., about 5 mM sodium acetate to about 150 mM sodium acetate) and about 10 milligrams per milliliter (mg / mL) to about 100 mg / mL mannitol (e.g., about 43.6 mg / mL mannitol). In some examples, the additive is a preservative. In some examples, a preservative is added to a (e.g., subcutaneous) composition having a pH of about 4.5 and comprising about 10 mM sodium acetate and about 43.6 mg / mL mannitol.

[0253] In some embodiments, provided herein are compositions comprising Compound 1. In some embodiments, the compositions are suitable for subcutaneous administration. In some embodiments, the formulations are suitable for subcutaneous (bolus) injection. In some embodiments, the subcutaneous (bolus) injection is provided to an individual as a single dose (e.g., all at once). In some embodiments, the formulations are suitable for subcutaneous infusion.

[0254] In some embodiments, the compositions described herein include an additive. In some embodiments, the compositions described herein are subcutaneous compositions and include an additive. In some embodiments, the additive is selected from the group consisting of a preservative, a solubilizing agent (e.g., cyclodextrin), a buffering agent, and a chelating agent (e.g., zinc acetate or ethylenediaminetetraacetic acid (EDTA)). In some embodiments, the additive is a preservative.

[0255] In some embodiments, provided herein are subcutaneous formulations comprising a compound having a structure represented by Formula I and a preservative.

[0256] In some embodiments, the compositions described herein further comprise a preservative. In some embodiments, the preservative is any suitable preservative, such as meta-cresol, phenol, chlorobutanol, or benzyl alcohol. In some embodiments, the preservative is present in the composition in an amount of about 0.1 mg / mL or greater. In some embodiments, the preservative is present in the composition in an amount of about 50 mg / mL or less. In some embodiments, the preservative is present in the composition in an amount of about 0.1 mg / mL to about 50 mg / mL. In some embodiments, the preservative is present in the composition in an amount of about 1 mg / mL to about 20 mg / mL.

[0257] In some examples, compositions containing the preservatives described herein did not exhibit any physical interaction (e.g., aggregation) with any of the screened preservatives (e.g., between the preservative and Compound 1), even at relatively high concentrations of the preservative.

[0258] In some embodiments, provided herein are subcutaneous formulations comprising a compound having a structure represented by Formula I and a solubilizing agent.

[0259] In some embodiments, the compositions described herein further comprise a solubilizing agent. In some embodiments, the preservative is any suitable solubilizing agent, such as a cyclodextrin (e.g., sulfobutylether-β-cyclodextrin (SBECD)). In some embodiments, the solubilizing agent is present in the composition in an amount of about 0.1 mg / mL or greater. In some embodiments, the solubilizing agent is present in the composition in an amount of about 500 mg / mL or less. In some embodiments, the solubilizing agent is present in the composition in an amount of about 250 mg / mL or less. In some embodiments, the solubilizing agent is present in the composition in an amount of about 100 mg / mL or less. In some embodiments, the solubilizing agent is present in the composition in an amount of about 0.1 mg / mL to about 250 mg / mL. In some embodiments, the solubilizing agent is present in the composition in an amount of about 0.1 mg / mL to about 100 mg / mL. In some embodiments, the solubilizing agent is present in the composition in an amount of about 1 mg / mL to about 250 mg / mL. In some embodiments, the solubilizing agent is present in the composition in an amount of about 1 mg / mL to about 100 mg / mL, hi some embodiments, the solubilizing agent is present in the composition in an amount of about 60 mg / mL to about 80 mg / mL.

[0260] In some embodiments, the composition further comprises a buffering agent. In some embodiments, the buffering agent has a pKa of about 3.0 to about 6.0, such as at 25°C. In some embodiments, the buffering agent is selected from the group consisting of acetate buffer, succinate buffer, phosphate buffer, and citrate buffer. In some embodiments, the composition further comprises an acetate buffer. In some embodiments, the acetate buffer is a combination of acetate and acetic acid. In some embodiments, the composition further comprises a succinate buffer. In some embodiments, the succinate buffer is a combination of succinate and succinic acid. In some embodiments, the composition further comprises a citrate buffer. In some embodiments, the citrate buffer is a combination of citrate and citric acid.

[0261] In some embodiments, provided herein are subcutaneous formulations comprising a compound having a structure represented by Formula I and a buffering agent at a concentration of about 1 millimolar (mM) to about 1M.

[0262] In some embodiments, the compositions described herein comprise a buffering agent at a concentration of about 1 millimolar (mM) or greater. In some embodiments, the compositions described herein comprise a buffering agent at a concentration of about 1 molar (M) or less. In some embodiments, the compositions described herein comprise a buffering agent at a concentration of about 1 mM to about 1 M. In some embodiments, the compositions described herein comprise a buffering agent at a concentration of about 1 mM to about 500 mM. In some embodiments, the compositions described herein comprise a buffering agent at a concentration of about 1 mM to about 250 mM. In some embodiments, the compositions described herein comprise a buffering agent at a concentration of about 50 mM to about 250 mM. In some embodiments, the compositions described herein comprise a buffering agent at a concentration of about 50 mM to about 150 mM. In some embodiments, the compositions described herein comprise a buffering agent at a concentration of about 100 mM. In some embodiments, the compositions described herein comprise a buffering agent at a concentration of about 1 mM to about 50 mM. In some embodiments, the compositions described herein comprise a buffering agent at a concentration of about 5 mM to about 25 mM. In some embodiments, the compositions described herein comprise a buffering agent at a concentration of about 10 mM.

[0263] In some embodiments, the compositions described herein have a pH sufficient to inhibit (e.g., inactivate or deactivate) proteases (e.g., trypsin), such as in the subcutaneous layer of an individual to whom the formulation is administered subcutaneously.

[0264] In some embodiments, the pH of the compositions described herein does not change (substantially) when administered subcutaneously to an individual. In some embodiments, the pH of the compositions described herein does not change (substantially) when administered subcutaneously to an individual by subcutaneous (bolus) injection. In some embodiments, the pH of the compositions described herein does not change (substantially) when administered subcutaneously to an individual by subcutaneous infusion.

[0265] In some embodiments, the compositions described herein have a pH of at least about 3. In some embodiments, the compositions described herein have a pH of about 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, or 4 or less. In some embodiments, the compositions described herein have a pH of about 4 to about 8. In some embodiments, the compositions described herein have a pH of about 4 to about 6. In some embodiments, the compositions described herein have a pH of about 4.5 to about 5. In some embodiments, the compositions described herein have a pH of about 4. In some embodiments, the compositions described herein have a pH of about 4.5.

[0266] In some embodiments, the compositions described herein have an ionic strength of about 1 mM or greater. In some embodiments, the compositions described herein have an ionic strength of about 1 M or less. In some embodiments, the compositions described herein have an ionic strength of about 1 mM to about 500 mM. In some embodiments, the compositions described herein have an ionic strength of about 5 mM to about 200 mM. In some embodiments, the compositions described herein have an ionic strength of about 5 mM to about 10 mM to about 100 mM.

[0267] In some embodiments, compounds described herein, such as compounds having a structure represented by Formula I, are (e.g., substantially) less susceptible to (e.g., protease) degradation. In some embodiments, compounds described herein, such as compounds having a structure represented by Formula I, are (e.g., substantially) less susceptible to (e.g., protease) degradation in the subcutaneous layer of an individual to whom a composition comprising the compound is subcutaneously administered.

[0268] In some embodiments, the compounds described herein, such as compounds having a structure represented by Formula I, are stable in the compositions described herein. In some embodiments, less than 50% of the compounds described herein, such as compounds having a structure represented by Formula I, degrade in a vial. In some embodiments, less than 50% of the compounds described herein, such as compounds having a structure represented by Formula I, degrade in a vial over a period of at least about one week (e.g., about one week or more, two weeks or more, three weeks or more, or four weeks or more). In some embodiments, less than 50% of the compounds described herein, such as compounds having a structure represented by Formula I, degrade subcutaneously. In some embodiments, less than 50% of the compounds described herein, such as compounds having a structure represented by Formula I, degrade subcutaneously over a period of at least about one hour (e.g., about one hour or more, six hours or more, 12 hours or more, or 24 hours or more).

[0269] In some embodiments, compositions described herein, such as those having an acidic pH, a relatively high buffer (e.g., acetate buffer) concentration, and / or a relatively high concentration of a compound described herein (e.g., Compound 1), are well tolerated following subcutaneous (e.g., injection or infusion) administration (see Examples 3 and 4).

[0270] In some embodiments, the compositions described herein comprise a pH and / or buffer (e.g., acetate buffer) concentration sufficient to inhibit, reduce, or eliminate the formation of undesired metabolites of a compound described herein (e.g., Compound 1), such as a full (V1a) agonist like M1. In some examples, a composition comprising a relatively high buffer concentration (e.g., 50 mM or higher buffer) extends the amount of time that the local environment (e.g., at or near the injection site) maintains a particular pH (e.g., a pH of about 3 or higher) sufficient to inhibit, reduce, or eliminate the formation of undesired metabolites of a compound described herein (e.g., Compound 1), such as a full (V1a) agonist like M1. In some examples, a composition having an acidic pH (e.g., a pH of 1-6) produces undesirable effects when injected (subcutaneously), including burning, stinging, pain, etc., at the injection site. Injecting (subcutaneously) a composition having a relatively acidic pH or buffer concentration that extends the amount of time the local environment (e.g., at or near the injection site) maintains a particular (e.g., acidic) pH would be expected to extend such undesirable effects. In contrast, compositions described herein having a relatively acidic pH (e.g., a pH of 4 or 4.5) and / or buffer concentration that extends the amount of time the local environment (e.g., at or near the injection site) maintains a particular (e.g., acidic) pH do not produce any (notable) undesirable effects when administered subcutaneously (e.g., by injection or infusion). In some instances, higher buffer concentrations inhibit, reduce, or eliminate the formation of M1, providing a sufficient amount of time for absorption of a compound described herein, such as by extending the amount of time the local environment (e.g., at or near the injection site) maintains an acidic pH (e.g., 4.5) after administration. In some embodiments, the buffer concentration of a composition provided herein that extends the amount of time the local environment (e.g., at or near the injection site) maintains a particular (e.g., acidic) pH is about 50 mM or greater.In some embodiments, the pH of a composition provided herein that sufficiently inhibits, reduces, or eliminates the formation of undesired metabolites of a compound described herein, such as a full (V1a) agonist such as M1 (e.g., Compound 1), is acidic when administered subcutaneously (e.g., by injection or infusion). In some embodiments, the pH of a composition provided herein that sufficiently inhibits, reduces, or eliminates the formation of undesired metabolites of a compound described herein, such as a full (V1a) agonist such as M1 (e.g., Compound 1), is about 3 or greater when administered subcutaneously (e.g., by injection or infusion). In some embodiments, the pH of a composition provided herein that sufficiently inhibits, reduces, or eliminates the formation of undesired metabolites of a compound described herein, such as a full (V1a) agonist such as M1 (e.g., Compound 1), is about 4 or 4.5 when administered subcutaneously (e.g., by injection or infusion).

[0271] In some embodiments, compositions described herein (e.g., compositions suitable for intravenous or subcutaneous administration) comprise an acetate buffer at a concentration of about 10 mM or greater, hi some embodiments, compositions described herein comprise an acetate buffer at a concentration of about 50 mM or greater.

[0272] In some embodiments, compositions described herein (eg, compositions suitable for intravenous or subcutaneous administration) have a pH of about 3 or greater.

[0273] In some embodiments, a composition described herein (e.g., a composition suitable for intravenous or subcutaneous administration) comprises acetate buffer at a concentration of 10 mM and has a pH of 4.5. In some embodiments, the composition is suitable for intravenous administration. In some embodiments, the composition is preservative-free. In some embodiments, the composition is suitable for subcutaneous administration. In some embodiments, the composition is suitable for subcutaneous injection.

[0274] In some embodiments, compositions described herein (e.g., compositions suitable for subcutaneous administration) comprise acetate buffer at a concentration of 100 mM (or greater) and have a pH of about 4 or 4.5. In some embodiments, the compositions are suitable for subcutaneous administration. In some embodiments, the compositions are suitable for subcutaneous (bolus) injection. In some embodiments, the compositions are suitable for subcutaneous infusion.

[0275] In some embodiments, compositions described herein (e.g., compositions suitable for intravenous or subcutaneous administration) comprise an acetate buffer at a concentration of about 10 mM or greater, hi some embodiments, compositions described herein comprise an acetate buffer at a concentration of about 50 mM or greater.

[0276] In some embodiments, the compositions described herein include a compound described herein (e.g., Compound 1) at a concentration sufficient to inhibit, reduce, or eliminate the formation of undesired metabolic products of a compound, such as a full (V1a) agonist like M1. In some examples, a composition including a relatively high drug concentration (e.g., 0.1 milligrams per milliliter (mg / mL) or greater) saturates the local environment (e.g., at or near the injection site) with drug, such that more drug is absorbed before substantial formation of undesired metabolic products of the drug, such as a full (V1a) agonist. In some embodiments, a composition described herein having a relatively high concentration of a compound provided herein, when administered subcutaneously (e.g., by injection or infusion), sufficiently inhibits, reduces, or eliminates the formation of undesired metabolic products of a compound described herein (e.g., Compound 1), such as a full (V1a) agonist like M1. In some embodiments, the drug concentration in the composition (e.g., the concentration of a compound described herein) is about 0.1 mg / mL or greater.

[0277] In some embodiments, the compositions provided herein have a concentration of a compound described herein that is about 0.1 mg / mL or greater. In some embodiments, the compositions provided herein have a concentration of a compound described herein that is about 1 mg / mL or greater. In some embodiments, the compositions provided herein have a concentration of a compound described herein that is about 100 mg / mL or less. In some embodiments, the compositions provided herein have a concentration of a compound described herein that is about 0.1 mg / mL to about 100 mg / mL. In some embodiments, the compositions provided herein have a concentration of a compound described herein that is about 0.1 mg / mL to about 10 mg / mL. In some embodiments, the compositions are suitable for subcutaneous administration. In some embodiments, the compositions are suitable for subcutaneous (bolus) injection. In some embodiments, the compositions are suitable for subcutaneous infusion. In some embodiments, the compositions provided herein have a concentration of a compound described herein that is about 0.1 mg / mL or less. In some embodiments, the compositions are suitable for intravenous administration.

[0278] In some embodiments, the compositions described herein are suitable for subcutaneous injection. In some embodiments, compositions suitable for subcutaneous injection are administered to an individual in a manner that reduces (injection site) injury or trauma. In some embodiments, compositions suitable for subcutaneous injection are administered to an individual over a (long) period of time. In some embodiments, compositions suitable for subcutaneous injection are administered to an individual at a (relatively slow) rate, such as an infusion. In some embodiments, the composition is administered at a rate sufficient to provide an infusion (e.g., not a stream) of the composition. In some embodiments, the composition is administered at a rate that is about 0.1 milliliters per hour (mL / hr), such as over an extended period of time (e.g., a period of about 24 hours or more).

[0279] In some embodiments, provided herein are pharmaceutical compositions comprising an amount of a compound having a structure represented by Formula I. In some embodiments, the composition is formulated for subcutaneous administration. In some embodiments, the amount of the compound is an effective amount of the compound.

[0280] In some embodiments, a pharmaceutical composition is provided comprising an amount of Compound 1, or a pharmaceutically acceptable salt thereof, wherein the composition is formulated for subcutaneous administration. In some embodiments, the amount of the compound is an effective amount of the compound.

[0281] In some embodiments, the compositions described herein are suitable for systemic delivery of an active agent described herein, such as a compound having a structure represented by Formula I. In some embodiments, the compositions described herein are suitable for administration of an active agent described herein, such as a compound having a structure represented by Formula I, in an outpatient setting, such as at home. In some embodiments, the compositions described herein are suitable for systemic delivery of Compound 1. In some embodiments, the compositions described herein are suitable for administration of Compound 1 in an outpatient setting, such as at home.

[0282] In some embodiments, provided herein is a system for treating end-stage liver disease (ESLD), the system comprising: a composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof; and a device configured to provide subcutaneous infusion of the composition to an individual when placed on the individual's skin.

[0283] In some embodiments, the system comprises an adhesive for affixing the (subcutaneously injected) device to the surface of the skin of an individual, hi some embodiments, the system comprises an adhesive for reversibly affixing the (subcutaneously injected) device to the surface of the skin of an individual.

[0284] In some embodiments, the system includes a chamber body and a hollow tube body. In some embodiments, the composition is configured within the chamber body. In some embodiments, the hollow tube body includes a first opening and a second opening. In some embodiments, the first opening is in fluid contact with the chamber body. In some embodiments, the second opening is configured subcutaneously within the individual after affixing the subcutaneous injection device to the individual's skin. In some embodiments, the hollow tube is a needle, such as one having any gauge suitable for subcutaneous administration (e.g., subcutaneous injection).

[0285] In some embodiments, the system does not include an adhesive. In some embodiments, the device is not attached to the surface of the individual's skin. In some embodiments, the chamber body is attached to an injection port. In some embodiments, the system does not include an adhesive and the chamber body is attached to an injection port.

[0286] In some embodiments, the (subcutaneous infusion) device further comprises a pump configured to subcutaneously infuse the composition into the individual at a constant or variable rate (e.g., as described herein). In some embodiments, the system is configured to provide the composition to the individual over a period of about 24 hours or more. In some embodiments, the system is configured to continuously provide the composition to the individual over a period of about 24 hours or more.

[0287] In some embodiments, the device is configured to accept a vial and / or cartridge of the composition.

[0288] In some embodiments, the device is a subcutaneous infusion device. In some embodiments, the device is a pump.

[0289] In some examples, provided herein are pharmaceutical compositions comprising an effective amount of a first compound, or a pharmaceutically acceptable salt thereof, and an effective amount of a second compound, or a pharmaceutically acceptable salt thereof, wherein the first compound is a vasoconstrictor, and the second compound sufficiently blocks the (e.g., local) vasoconstrictor action of the first compound, e.g., provides sufficient uptake of the first compound into the circulatory system and / or internal organs (e.g., kidneys) of an individual (e.g., in need thereof). In some embodiments, the pharmaceutical composition is injectable. In some examples, the pharmaceutical composition is suitable for intravitreal administration. In some examples, the pharmaceutical composition is suitable for subcutaneous administration. In some examples, the first compound is a vasopressin receptor 1A (V1AR) agonist. In some examples, the first compound is a selective V1AR agonist. In some examples, the second compound is a V1AR antagonist. In some examples, the second compound is a selective V1AR antagonist. In some examples, the second compound is a vasodilator.

[0290] In some examples, such as in the carbon tetrachloride model described in Example 6, a compound described herein (e.g., Compound 1) administered (e.g., subcutaneously) to an individual (e.g., in need thereof) improves renal blood flow, renal excretory function, and systemic hemodynamics in the individual (e.g., in need thereof) (e.g., compared to vehicle-treated animals).

[0291] In some examples, a compound described herein (e.g., Compound 1) administered subcutaneously improves excretory renal function (see Example 6). In some examples, a compound described herein (e.g., Compound 1) administered twice daily by subcutaneous injection improves excretory renal function (see Example 6). In some examples, a compound described herein (e.g., Compound 1) administered twice daily by subcutaneous bolus injection improves excretory renal function (see Example 6). In some examples, a compound described herein (e.g., Compound 1) administered twice daily by subcutaneous injection for three days improves excretory renal function (see Example 6).

[0292] In some examples, a compound described herein (e.g., Compound 1) administered (e.g., subcutaneously) to an individual (e.g., in need thereof), such as in the bile duct ligation (BDL) and ascites model described in Example 6, reduces ascites volume, splenic vasodilation, water retention, body weight, and / or net water balance in the individual (e.g., in need thereof) (e.g., compared to vehicle-treated animals). In some examples, a compound described herein (e.g., Compound 1) administered (e.g., subcutaneously) to an individual (e.g., in need thereof), such as in the bile duct ligation (BDL) and ascites model described in Example 6, results in improved urinary potassium and urinary sodium excretion in the individual (e.g., in need thereof) (e.g., compared to vehicle controls).

[0293] In some examples, such as in the bile duct ligation (BDL) and ascites models described in Example 6, repeated subcutaneous administration of a compound described herein (e.g., Compound 1) results in a reduction in ascites volume, a reduction in splanchnic vasodilation, a reduction in water retention, and / or significant urinary potassium and sodium excretion immediately after the compound is administered without hyponatremia. In some embodiments, repeated subcutaneous administration of a compound described herein (e.g., Compound 1) results in a significant reduction in urinary potassium excretion (e.g., compared to a vehicle control), such as 5-24 hours after the compound is administered.

[0294] In some examples, a compound described herein (e.g., Compound 1) administered subcutaneously reduces ascites volume, spleen weight, and body weight (e.g., compared to a vehicle control). In some examples, a compound described herein (e.g., Compound 1) administered via subcutaneous bolus administration reduces ascites volume, spleen weight, and body weight (e.g., compared to a vehicle control). In some examples, a compound described herein (e.g., Compound 1) administered daily via subcutaneous administration reduces ascites volume, spleen weight, and body weight (e.g., compared to a vehicle control). In some examples, a compound described herein (e.g., Compound 1) administered twice daily via subcutaneous administration reduces ascites volume, spleen weight, and body weight (e.g., compared to a vehicle control). In some examples, a compound described herein (e.g., Compound 1) administered twice daily via subcutaneous bolus administration reduces ascites volume, spleen weight, and body weight (e.g., compared to a vehicle control). In some examples, a compound described herein (e.g., Compound 1) administered twice daily via subcutaneous administration for consecutive days reduces ascites volume, spleen weight, and body weight (e.g., compared to a vehicle control). In some examples, a compound described herein (e.g., Compound 1) administered twice daily via subcutaneous administration for two or more days reduces ascites volume, spleen weight, and body weight (e.g., compared to a vehicle control). In some examples, a compound described herein (e.g., Compound 1) administered twice daily via subcutaneous administration for five or more days reduces ascites volume, spleen weight, and body weight (e.g., compared to a vehicle control).

[0295] In some examples, a compound described herein (e.g., Compound 1) administered subcutaneously increases urine volume, urinary sodium excretion, and urinary potassium excretion (e.g., compared to a vehicle control). In some examples, a compound described herein (e.g., Compound 1) administered via subcutaneous bolus administration increases urine volume, urinary sodium excretion, and urinary potassium excretion (e.g., compared to a vehicle control). In some examples, a compound described herein (e.g., Compound 1) administered daily via subcutaneous administration increases urine volume, urinary sodium excretion, and urinary potassium excretion (e.g., compared to a vehicle control). In some examples, a compound described herein (e.g., Compound 1) administered twice daily via subcutaneous administration increases urine volume, urinary sodium excretion, and urinary potassium excretion (e.g., compared to a vehicle control). In some examples, a compound described herein (e.g., Compound 1) administered twice daily via subcutaneous bolus administration increases urine volume, urinary sodium excretion, and urinary potassium excretion (e.g., compared to a vehicle control). In some examples, a compound described herein (e.g., Compound 1) administered twice daily via subcutaneous administration for consecutive days increases urine volume, urinary sodium excretion, and urinary potassium excretion (e.g., compared to a vehicle control). In some examples, a compound described herein (e.g., Compound 1) administered twice daily via subcutaneous administration for two or more days increases urine volume, urinary sodium excretion, and urinary potassium excretion (e.g., compared to a vehicle control). In some examples, a compound described herein (e.g., Compound 1) administered twice daily via subcutaneous administration for five or more days increases urine volume, urinary sodium excretion, and urinary potassium excretion (e.g., compared to a vehicle control).

[0296] In some examples, a compound described herein (e.g., Compound 1) administered subcutaneously reduces urinary potassium excretion (e.g., compared to a vehicle control). In some examples, a compound described herein (e.g., Compound 1) administered via subcutaneous bolus administration reduces urinary potassium excretion (e.g., compared to a vehicle control). In some examples, a compound described herein (e.g., Compound 1) administered daily via subcutaneous administration reduces urinary potassium excretion (e.g., compared to a vehicle control). In some examples, a compound described herein (e.g., Compound 1) administered twice daily via subcutaneous administration reduces urinary potassium excretion (e.g., compared to a vehicle control). In some examples, a compound described herein (e.g., Compound 1) administered twice daily via subcutaneous bolus administration reduces urinary potassium excretion (e.g., compared to a vehicle control). In some examples, a compound described herein (e.g., Compound 1) administered twice daily via subcutaneous administration on consecutive days reduces urinary potassium excretion (e.g., compared to a vehicle control). In some examples, a compound described herein (e.g., Compound 1) administered twice daily via subcutaneous administration for two or more days reduces urinary potassium excretion (e.g., compared to a vehicle control). In some examples, a compound described herein (e.g., Compound 1) administered twice daily via subcutaneous administration for five or more days reduces urinary potassium excretion (e.g., compared to a vehicle control).

[0297] In some embodiments, an individual's urine output is increased (e.g., compared to a solvent control) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, such as within the first 24 hours, an individual's urine output is significantly increased (e.g., compared to a solvent control) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, such as within the first 4 hours, an individual's urine output is significantly increased (e.g., compared to a solvent control) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual.

[0298] In some embodiments, the individual's urine volume increases by about 25% or more (e.g., compared to a solvent control) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the individual's urine volume increases by about 50% or more (e.g., compared to a solvent control) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the individual's urine volume increases by about 100% or more (e.g., compared to a solvent control) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the individual's urine volume increases by about 200% or more (e.g., compared to a solvent control) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the individual's urine volume increases by about 300% or more (e.g., compared to a solvent control) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the individual's urine output increases by about 400% or more (e.g., compared to a solvent control) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the individual's urine output increases by about 500% or more (e.g., compared to a solvent control) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual.

[0299] In some embodiments, the individual's urine volume increases by no more than about 25% (e.g., compared to a solvent control) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the individual's urine volume increases by no more than about 50% (e.g., compared to a solvent control) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the individual's urine volume increases by no more than about 100% (e.g., compared to a solvent control) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the individual's urine volume increases by no more than about 200% (e.g., compared to a solvent control) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the individual's urine volume increases by no more than about 300% (e.g., compared to a solvent control) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the individual's urine output increases by no more than about 400% (e.g., compared to a solvent control) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the individual's urine output increases by no more than about 500% (e.g., compared to a solvent control) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual.

[0300] In some embodiments, the individual's urine output increases by about 10% to about 1000% (e.g., compared to a solvent control) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the individual's urine output increases by about 50% to about 500% (e.g., compared to a solvent control) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the individual's urine output increases by about 100% to about 500% (e.g., compared to a solvent control) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual.

[0301] In some embodiments, the individual's urine output is about 10% or more greater at least one day after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the individual's urine output is about 50% or more greater at least one day after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the individual's urine output is about 100% or more greater at least one day after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the individual's urine output is greater for at least two days or more after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the individual's urine output is greater for at least three days or more after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual.

[0302] In some embodiments, the individual's urinary sodium is increased (e.g., compared to a solvent control) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the individual's urinary sodium is significantly increased (e.g., compared to a solvent control) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the individual's urinary sodium excretion is increased (e.g., compared to a solvent control) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the individual's urinary sodium excretion is significantly increased (e.g., compared to a solvent control) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual.

[0303] In some embodiments, the individual's urinary potassium is increased (e.g., compared to a solvent control) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the individual's urinary potassium is significantly increased (e.g., compared to a solvent control) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the individual's urinary potassium excretion is increased (e.g., compared to a solvent control) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the individual's urinary potassium excretion is significantly increased (e.g., compared to a solvent control) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual.

[0304] In some embodiments, the urinary potassium excretion of an individual is reduced (e.g., compared to a solvent control) following subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the urinary potassium excretion of an individual is substantially reduced (e.g., compared to a solvent control) following subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual.

[0305] In some embodiments, the urinary sodium excretion of an individual increases by about 10% or more (e.g., compared to a solvent control, such as within the first 4 hours of treatment) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the urinary sodium excretion of an individual increases by about 100% or more (e.g., compared to a solvent control, such as within the first 4 hours of treatment) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the urinary sodium excretion of an individual increases by about 250% or more (e.g., compared to a solvent control, such as within the first 4 hours of treatment) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the urinary sodium excretion of an individual increases by about 500% or more (e.g., compared to a solvent control, such as within the first 4 hours of treatment) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the urinary sodium excretion of an individual increases by about 750% or more (e.g., compared to a solvent control, such as within the first 4 hours of treatment) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the urinary sodium excretion of an individual increases by about 1000% or more (e.g., compared to a solvent control, such as within the first 4 hours of treatment) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the urinary sodium excretion of an individual increases by about 1500% or more (e.g., compared to a solvent control, such as within the first 4 hours of treatment) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the urinary sodium excretion of an individual increases by about 2000% or more (e.g., compared to a solvent control, such as within the first 4 hours of treatment) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual.

[0306] In some embodiments, the urinary sodium excretion of an individual is increased by about 10% to about 5000% (e.g., compared to a solvent control, such as within the first 4 hours of treatment) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the urinary sodium excretion of an individual is increased by about 10% to about 2500% (e.g., compared to a solvent control, such as within the first 4 hours of treatment) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the urinary sodium excretion of an individual is increased by about 10% to about 2000% (e.g., compared to a solvent control, such as within the first 4 hours of treatment) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the urinary sodium excretion of an individual is increased by about 100% to about 2000% (e.g., compared to a solvent control, such as within the first 4 hours of treatment) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the individual's urinary sodium excretion is increased by about 100% to about 1000% (e.g., compared to a vehicle control, such as within the first 4 hours of treatment) following subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual.

[0307] In some embodiments, the urinary sodium excretion of an individual increases by about 10% or more (e.g., compared to a solvent control, such as within the first 4 hours of treatment) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the urinary sodium excretion of an individual increases by about 100% or more (e.g., compared to a solvent control, such as within the first 4 hours of treatment) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the urinary sodium excretion of an individual increases by about 250% or more (e.g., compared to a solvent control, such as within the first 4 hours of treatment) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the urinary sodium excretion of an individual increases by about 500% or more (e.g., compared to a solvent control, such as within the first 4 hours of treatment) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the urinary sodium excretion of an individual increases by about 750% or more (e.g., compared to a solvent control, such as within the first 4 hours of treatment) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the urinary sodium excretion of an individual increases by about 1000% or more (e.g., compared to a solvent control, such as within the first 4 hours of treatment) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the urinary sodium excretion of an individual increases by about 1500% or more (e.g., compared to a solvent control, such as within the first 4 hours of treatment) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the urinary sodium excretion of an individual increases by about 2000% or more (e.g., compared to a solvent control, such as within the first 4 hours of treatment) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual.

[0308] In some embodiments, the urinary sodium excretion of an individual is increased by about 10% to about 5000% (e.g., compared to a solvent control, such as within the first 4 hours of treatment) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the urinary sodium excretion of an individual is increased by about 10% to about 2500% (e.g., compared to a solvent control, such as within the first 4 hours of treatment) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the urinary sodium excretion of an individual is increased by about 10% to about 2000% (e.g., compared to a solvent control, such as within the first 4 hours of treatment) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the urinary sodium excretion of an individual is increased by about 100% to about 2000% (e.g., compared to a solvent control, such as within the first 4 hours of treatment) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the individual's urinary sodium excretion is increased by about 100% to about 1000% (e.g., compared to a vehicle control, such as within the first 4 hours of treatment) following subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual.

[0309] In some embodiments, the urinary potassium excretion of an individual increases by about 10% or more (e.g., compared to a vehicle control, such as within the first 4 hours of treatment) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the urinary potassium excretion of an individual increases by about 100% or more (e.g., compared to a vehicle control, such as within the first 4 hours of treatment) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the urinary potassium excretion of an individual increases by about 250% or more (e.g., compared to a vehicle control, such as within the first 4 hours of treatment) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the urinary potassium excretion of an individual increases by about 500% or more (e.g., compared to a vehicle control, such as within the first 4 hours of treatment) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the urinary potassium excretion of an individual increases by about 750% or more (e.g., compared to a vehicle control, such as within the first 4 hours of treatment) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the urinary potassium excretion of an individual increases by about 1000% or more (e.g., compared to a vehicle control, such as within the first 4 hours of treatment) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the urinary potassium excretion of an individual increases by about 1500% or more (e.g., compared to a vehicle control, such as within the first 4 hours of treatment) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the urinary potassium excretion of an individual increases by about 2000% or more (e.g., compared to a vehicle control, such as within the first 4 hours of treatment) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual.

[0310] In some embodiments, the urinary potassium excretion of an individual is increased by about 10% to about 5000% (e.g., compared to a vehicle control, such as within the first 4 hours of treatment) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the urinary potassium excretion of an individual is increased by about 10% to about 2500% (e.g., compared to a vehicle control, such as within the first 4 hours of treatment) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the urinary potassium excretion of an individual is increased by about 10% to about 2000% (e.g., compared to a vehicle control, such as within the first 4 hours of treatment) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the urinary potassium excretion of an individual is increased by about 100% to about 2000% (e.g., compared to a vehicle control, such as within the first 4 hours of treatment) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the urinary potassium excretion of an individual is increased by about 100% to about 1000% (e.g., compared to a vehicle control, such as within the first 4 hours of treatment) following subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual.

[0311] In some embodiments, the urinary potassium excretion of an individual is reduced by about 10% or more (e.g., compared to a solvent control, such as at about 5 hours after treatment) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the urinary potassium excretion of an individual is reduced by about 100% or more (e.g., compared to a solvent control, such as at about 5 hours after treatment) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the urinary potassium excretion of an individual is reduced by about 250% or more (e.g., compared to a solvent control, such as at about 5 hours after treatment) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the urinary potassium excretion of an individual is reduced by about 500% or more (e.g., compared to a solvent control, such as at about 5 hours after treatment) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual.

[0312] In some embodiments, the urinary potassium excretion of an individual is reduced by about 10% to about 5000% (e.g., compared to a vehicle control, such as at about 5 hours after treatment) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the urinary potassium excretion of an individual is reduced by about 10% to about 2500% (e.g., compared to a vehicle control, such as at about 5 hours after treatment) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the urinary potassium excretion of an individual is reduced by about 10% to about 2000% (e.g., compared to a vehicle control, such as at about 5 hours after treatment) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the urinary potassium excretion of an individual is reduced by about 10% to about 500% (e.g., compared to a vehicle control, such as at about 5 hours after treatment) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the individual's urinary potassium excretion is reduced by about 10% to about 100% (e.g., compared to a vehicle control, such as at about 5 hours after treatment) following subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual.

[0313] In some embodiments, the amount of ascites fluid in an individual is reduced (e.g., compared to a vehicle control) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the amount of ascites fluid in an individual is significantly reduced (e.g., compared to a vehicle control) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual.

[0314] In some embodiments, the ascites volume of an individual is reduced by about 10% or more (e.g., compared to a vehicle control, such as when measured three days after treatment) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the ascites volume of an individual is reduced by about 50% or more (e.g., compared to a vehicle control, such as when measured three days after treatment) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the ascites volume of an individual is reduced by about 100% or more (e.g., compared to a vehicle control, such as when measured three days after treatment) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the ascites volume of an individual is reduced by about 200% or more (e.g., compared to a vehicle control, such as when measured three days after treatment) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the volume of ascites in an individual is reduced by about 300% or more (e.g., compared to a vehicle control, such as when measured 3 days after treatment) following subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual.

[0315] In some embodiments, the volume of ascites fluid in an individual is reduced by about 10% to about 1000% (e.g., compared to a vehicle control, such as when measured three days after treatment) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the volume of ascites fluid in an individual is reduced by about 10% to about 500% (e.g., compared to a vehicle control, such as when measured three days after treatment) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the volume of ascites fluid in an individual is reduced by about 50% to about 300% (e.g., compared to a vehicle control, such as when measured three days after treatment) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual.

[0316] In some embodiments, the body weight of an individual is reduced (e.g., compared to a solvent control) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the body weight of an individual is significantly reduced (e.g., compared to a solvent control) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual.

[0317] In some embodiments, an individual's body weight is reduced by about 1% or more (e.g., compared to a solvent control) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, an individual's body weight is reduced by about 2.5% or more (e.g., compared to a solvent control) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, an individual's body weight is reduced by about 5% or more (e.g., compared to a solvent control) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, an individual's body weight is reduced by about 10% or more (e.g., compared to a solvent control) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the change in body weight is measured at least one day after administration of the compound. In some embodiments, the change in body weight is measured two or more days after administration of the compound. In some embodiments, the change in body weight is measured three or more days after administration of the compound. In some embodiments, the change in body weight is measured four or more days after administration of the compound. In some embodiments, the change in body weight is measured 5 or more days after administration of the compound.

[0318] In some embodiments, plasma chemistry markers are substantially different after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to an individual. In some embodiments, the plasma chemistry markers BUN, Cl, PHOS, Na, and / or the BUN / CREA ratio are substantially different after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to an individual. In some embodiments, the plasma chemistry markers ALB, ALP, ALT, AST, BCARB, Ca, CHOL, CPK, CREA, DBIL, GGT, GLOB, GLU, IBIL, K, LDH, TBIL, and TPRO are not substantially different after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to an individual.

[0319] In some embodiments, an individual's body weight is reduced by about 1% to about 10% (e.g., compared to a solvent control) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, an individual's body weight is reduced by about 1% to about 5% (e.g., compared to a solvent control) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual.

[0320] In some embodiments, a compound described herein (e.g., Compound 1) is safe (e.g., in humans) (see, e.g., Example 1). In some embodiments, a compound described herein (e.g., Compound 1) is well-tolerated (e.g., in humans) (see, e.g., Example 1). In some embodiments, a compound described herein (e.g., Compound 1) is safe and well-tolerated (e.g., in humans) (see, e.g., Example 1). In some embodiments, a compound described herein (e.g., Compound 1) has a pharmacodynamic profile with submaximal partial agonism consistent with a mixed agonist-antagonist of the V1a receptor.

[0321] In some examples, a compound described herein (e.g., Compound 1) is tested in a Phase 1, double-blind, placebo-controlled, dose-group randomized study to investigate the safety, tolerability, and pharmacokinetic and pharmacodynamic (PD) profile of the compound administered to healthy adults aged 18 to 45 years. In some examples, the study included two treatment periods: Period 1 (a 6-hour intravenous [IV] infusion of compound or placebo over a dose range of 0.1 to 0.9 mg) and Period 2 (a single subcutaneous [SC] injection of 0.1, 0.3 mg of compound, or placebo daily for 5 consecutive days). In some examples, Period 1 included 32 men and women. In some examples, 8 men and 5 women continued into Period 2. In some examples, AUC and C were measured, such as after IV administration. max Exposure, as measured by T, was roughly dose proportional over the dose range tested. In some instances, such as after SC administration, T maxThe terminal half-life (t) of a compound described herein (e.g., Compound 1) was 0.3 hours, exposure was more than proportional, bioavailability was 18%, and there was no apparent accumulation after repeated dosing. In some examples, the terminal half-life (t 1 / 2 ) were approximately 1.5 hours and 1.0 hours after IV and SC administration, respectively, indicating, for example, that absorption is not rate-limiting relative to elimination after SC administration. In some instances, for subjects treated with a compound described herein (e.g., Compound 1), diastolic blood pressure (BP) and, to a lesser extent, systolic blood pressure (BP) increased in all dose groups, while pulse rate decreased. In some instances, the overall change in mean arterial pressure (MAP) after IV and SC administration was similar to the change in diastolic BP. In some instances, absolute changes in cardiac output by echocardiography appeared dose-dependent, with mean decreases of 3% to 12% after 0.9 mg IV administration and individual decreases of ≦20% to 25% across any dose. In some instances, adverse events (AEs) included abdominal pain and diarrhea; laboratory tests were negative for mesenteric ischemia, and no cases of mesenteric ischemia were reported. In some instances, AEs were treatment-related, generally mild or moderate in severity, and attributed to expected pharmacological effects.

[0322] In some embodiments, the individual's diastolic blood pressure is increased (e.g., compared to a pre-treatment baseline measurement) after administration of a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1). In some embodiments, the individual's diastolic blood pressure is increased (e.g., compared to a pre-treatment baseline measurement) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1).

[0323] In some embodiments, the individual's systolic blood pressure is increased (e.g., compared to a pre-treatment baseline measurement) after administration of a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1). In some embodiments, the individual's diastolic blood pressure is increased (e.g., compared to a pre-treatment baseline measurement) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1).

[0324] In some embodiments, the individual's diastolic and / or systolic blood pressure is increased in a dose-dependent manner (e.g., compared to a pre-treatment baseline measurement) after administration of a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1). In some embodiments, the individual's diastolic and / or systolic blood pressure is increased in a dose-dependent manner (e.g., compared to a pre-treatment baseline measurement) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1).

[0325] In some embodiments, the compounds provided herein have a maximum therapeutic range concentration. In some embodiments, the maximum therapeutic range concentration includes an increase in concentration that does not result in a dose-dependent increase in blood pressure, such as diastolic blood pressure, systolic blood treatment, and / or MAP. In some embodiments, the compounds provided herein have a non-linear dose-dependence, such as exceeding the maximum therapeutic range concentration. In some embodiments, the dose-dependent increase in blood pressure, such as diastolic blood pressure, systolic blood treatment, and / or MAP, includes the maximum therapeutic range concentration. In some embodiments, dose-dependent includes a situation where the effect increases with dose, at least for a certain dose range. For example, a higher dose may result in no dose-dependent increase or a less dose-dependent increase.

[0326] In some embodiments, MAP is calculated from measurements of systolic and diastolic blood pressure. In some embodiments, MAP is calculated when considering pressure during a single cardiac cycle. In some embodiments, MAP is 1 / 3 (systolic pressure - diastolic pressure) + diastolic pressure.

[0327] In some embodiments, the individual's pulse rate is decreased (e.g., compared to baseline measurements before treatment) after administration of a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1). In some embodiments, the individual's peripheral blood flow is decreased (e.g., compared to baseline measurements before treatment) after administration of a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1). In some embodiments, the individual's pulse rate and peripheral blood flow are decreased (e.g., compared to baseline measurements before treatment) after administration of a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1).

[0328] In some embodiments, administration of a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1), to an individual (e.g., as described herein) improves systemic hemodynamics in the individual. In some embodiments, subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1), to an individual (e.g., as described herein) improves systemic hemodynamics in the individual.

[0329] In some embodiments, administration of a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1), to an individual (e.g., as described herein) reduces water retention in the individual. In some embodiments, administration of a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1), to an individual (e.g., as described herein) reduces water overload in the individual. In some embodiments, administration of a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1), to an individual (e.g., as described herein) reduces water retention and overload in the individual. In some embodiments, subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1), to an individual (e.g., as described herein) reduces water retention in the individual. In some embodiments, subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1), to an individual (e.g., as described herein) reduces water overload in the individual. In some embodiments, subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1) to an individual (e.g., as described herein) reduces water retention and overload in the individual.

[0330] In some embodiments, administration (e.g., subcutaneously) of a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1) to an individual (e.g., described herein) reduces serum creatinine (sCr) in the individual (e.g., compared to a baseline measurement before treatment). In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1) is administered (e.g., subcutaneously) to an individual (e.g., described herein) at least until the individual has an sCr value of 1.5 milligrams (mg) per deciliter (dL) or less. In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1) is administered (e.g., subcutaneously) to an individual (e.g., described herein) at least until the individual's sCr value returns to normal (e.g., baseline).

[0331] In some examples, intravenous (iv) administration of a compound described herein (e.g., Compound 1) results in a terminal half-life of about 1.5 hours with a clearance and distribution volume of about 13 L / h and about 15-20 L, respectively. In some examples, the t after subcutaneous (sc) administration of a compound described herein (e.g., Compound 1) is max is about 0.3 hours with a terminal half-life of about 1 hour (e.g., without any accumulation after repeated administration). In some examples, the bioavailability of a compound described herein (e.g., Compound 1) after subcutaneous (sc) administration is about 18%.

[0332] In some examples, the compounds described herein (e.g., Compound 1) exhibit AUC and C max In some instances, compounds described herein (e.g., Compound 1) have greater than proportional increases in exposure after sc administration. In some instances, compounds described herein (e.g., Compound 1) have higher exposure in women than in men, such as after both iv infusion and subcutaneous injection.

[0333] In some examples, a compound described herein (e.g., Compound 1) metabolizes to the metabolite M1 (see Figure 14). M1 has a structure that is the free form of the circled structure in Figure 14. In some embodiments, M1 is a full (V1A) agonist. In some embodiments, M1 has a molecular weight of 1405.68 g / mol. In some embodiments, M1 is a C 60 H 98 N 19 O 16 S2 + M1 has the chemical formula: M1 is (substantially) less active (with respect to V1a) than Compound 1. Specifically, M1 is about 10 times less active than Compound 1 with respect to V1a.

[0334] In some examples, M1 is found in the plasma of an individual to whom Compound 1 is administered, such as in a single subject after iv administration. In some examples, M1 is found in all subjects studied, such as in all subjects studied, at concentrations equivalent to Compound 1 after sc administration. In some examples, a compound described herein (e.g., Compound 1) is metabolized (e.g., to M1) during transport to the circulation after sc injection. As discussed herein above, the full agonists described herein are known to be toxic and cause (serious) adverse events when administered subcutaneously. Therefore, when a compound described herein is administered by subcutaneous (bolus) injection, the formation of a full agonist (e.g., M1) is undesirable, such as when used for the purposes described herein.

[0335] In some instances, the dose-independent increase in diastolic blood pressure, and to a lesser extent, systolic blood pressure, is more pronounced (e.g., accompanied by a reflex decrease in pulse rate) after sc injection compared to iv infusion of a compound described herein (e.g., Compound 1). In some instances, peripheral blood flow is decreased after intravenous and subcutaneous administration of a compound described herein (e.g., Compound 1).

[0336] In some examples, an individual receiving a dose of a compound described herein (e.g., Compound 1) has an adverse event (AE) (e.g., treatment-related). In some examples, the AE occurs at the beginning of the sc treatment period. In some examples, there are more AEs after sc administration compared to iv administration. In some examples, there are more AEs in females compared to males. In some examples, the AE is mild or moderate in intensity. In some examples, the AE is severe in intensity. In some examples, the severe AE is a mild elevation of troponin I.

[0337] In some examples, compounds described herein (e.g., Compound 1) induce a reversible increase in diastole. In some examples, compounds described herein (e.g., Compound 1) induce a reversible increase in systole. In some examples, compounds described herein (e.g., Compound 1) induce a reversible increase in MAP. In some examples, compounds described herein (e.g., Compound 1) induce a reversible increase in diastole and MAP. In some examples, compounds described herein (e.g., Compound 1) induced a decrease in heart rate and cardiac output. In some examples, evaluation of ECG, clinical chemistry, hematology, hemostasis, and urinalysis parameters did not raise any safety concerns for compounds described herein (e.g., Compound 1).

[0338] In some examples, such as when administered as a single IV infusion, the compounds described herein (e.g., Compound 1) are safe and well tolerated (e.g., in both men and women) at doses of about 0.9 mg or less. In some examples, the sc maximum tolerated dose (MTD) is about 0.1 mg of a compound described herein (e.g., Compound 1).

[0339] In some examples, pharmacokinetic parameters for a compound described herein (e.g., Compound 1) (e.g., in plasma for 0.1-0.9 mg iv dose groups) provide dose proportionality. In some examples, pharmacokinetic parameters for a compound described herein (e.g., Compound 1) (e.g., in plasma for 0.1-0.9 mg iv dose groups) provide dose-independent PK parameters that are comparable between dose groups (see Example 1). In some examples, males eliminate a compound described herein (e.g., Compound 1) at a higher rate than females. In some examples, males administered a compound described herein (e.g., Compound 1) have a lower C of the compound than females. maxIn some examples, males administered a compound described herein (e.g., Compound 1) have a lower AUC of the compound than females. In some examples, males administered a compound described herein (e.g., Compound 1) have a lower C of the compound than females. max and AUC.

[0340] In some instances, such as after sc administration of a compound described herein (e.g., Compound 1), max is consistent between the first and fifth doses. In some instances, such as after sc administration of a compound described herein (e.g., Compound 1), t 1 / 2 is consistent between the first and fifth doses. In some instances, such as after sc administration of a compound described herein (e.g., Compound 1), t max and t 1 / 2 is consistent between the first and fifth doses. In some examples, such as after sc administration of a compound described herein (e.g., Compound 1), the AUC is variable between the first and fifth doses. In some examples, such as after sc administration of a compound described herein (e.g., Compound 1), the C max is variable between the first and fifth doses. In some examples, AUC and C are measured, such as after sc administration of a compound described herein (e.g., Compound 1). max is variable between the first dose and the fifth dose. In some instances, AUC and C max Dose proportionality for the C max (Only with regard to).

[0341] In some examples, the terminal half-life of a compound described herein (e.g., Compound 1) is about 1.5 hours after intravenous administration. In some examples, the terminal half-life of a compound described herein (e.g., Compound 1) is about 1 hour after subcutaneous administration. In some examples, the terminal half-life of a compound described herein (e.g., Compound 1) is comparable in males and females (e.g., similar in both males and females, e.g., C after subcutaneous administration). max (Suggesting that absorption is not rate-limiting for elimination after sc administration, as also supported by the short time to elimination, about 0.3 hours.) In some examples, the bioavailability of a compound described herein (e.g., Compound 1) is about 18%. In some examples, metabolite formation after sc administration (e.g., resulting in comparable concentrations of metabolite and compound) provides a bioavailability of about 18%. In some examples, the percentage of unchanged excreted dose in urine is about <10% after iv administration. In some examples, the percentage of unchanged excreted dose of a compound described herein (e.g., Compound 1) in urine is about <5% after sc administration. In some examples, the percentage of unchanged excreted dose of a compound described herein (e.g., Compound 1) in urine is consistent across the entire dose range (e.g., of the study provided in Example 1).

[0342] The presence of metabolite M1 (full agonist) in plasma after subcutaneous administration (but only at very low concentrations (<1% of Compound 1) after intravenous administration) demonstrates that Compound 1 is metabolized somewhere along the pathway between the subcutaneous tissue and the systemic circulation. In some instances, the half-life of M1 is longer than that for Compound 1 after iv and sc administration. In some instances, the half-life of Compound 1 is shorter after sc administration compared to iv administration (e.g., about 2 hours and 4 hours, respectively). In some instances, the compounds described herein (e.g., Compound 1) are metabolized in the kidney.

[0343] In some examples, the pharmacodynamic effects of a compound described herein (e.g., Compound 1) on blood pressure and heart rate are as expected for a vasopressin V1a-specific agonist. In some examples, administration of a compound described herein (e.g., Compound 1) to an individual results in an increase in the individual's diastolic blood pressure. In some examples, administration of a compound described herein (e.g., Compound 1) to an individual results in an increase in the individual's systolic blood pressure. In some examples, administration of a compound described herein (e.g., Compound 1) to an individual results in an increase in the individual's MAP. In some examples, administration of a compound described herein (e.g., Compound 1) to an individual results in a decrease in the individual's pulse rate. In some examples, administration of a compound described herein (e.g., Compound 1) to an individual results in a decrease in the individual's peripheral blood flow. In some examples, the effects on blood pressure and heart rate are not dose-dependent (e.g., the changes seen in the lowest dose group were approximately the same as those seen in the higher dose groups). In some instances, sc injection resulted in more pronounced PD effects compared to the same dose given iv (e.g., approximately 50% lower C after sc administration). max Nevertheless, in some instances, the active metabolite M1 (e.g., a full (V1a) agonist) in plasma after sc administration contributes (significantly) to the total (e.g., local and / or systemic) V1a pressor effect, such as in individuals who have a (serious) adverse event after a compound described herein is administered by subcutaneous (bolus) injection. In some instances, increased M1 formation, such as after subcutaneous (bolus) injection, results in a substantial decrease in the (systemic) delivery of Compound 1, resulting in undesirable effects (e.g., due to reduced delivery of the active agent (e.g., an M1 or mixed V1a agonist-antagonist described herein) and / or increased amounts of vasoconstriction, which may increase the risk of developing ischemia, cyanosis, pain, inflammation, and / or necrosis).

[0344] In some examples, safety evaluation of a compound described herein (e.g., Compound 1) resulted in an improved profile compared to other (e.g., non-selective) vasopressin receptor agonists described herein. In some examples, absolute changes in mean cardiac output are dose-dependent. In some examples, relative changes in mean cardiac output are comparable between doses (e.g., well removed from placebo). In some examples, individual decreases in cardiac output are approximately 20-25% (e.g., as observed in all active treatment groups, including the placebo group, after both iv and sc administration). In some examples, decreases in cardiac output are secondary to decreases in heart rate. In some examples, ECG evaluation did not reveal any effects of a compound described herein (e.g., Compound 1). In some examples, clinical laboratory parameters did not reveal any signs of cardiac or mesenteric ischemia (e.g., or negative effects on the liver or kidneys).

[0345] In some instances, adverse events in individuals receiving (e.g., intravenously or subcutaneously) a partial agonist described herein (e.g., Compound 1) were comparable to the pharmacodynamic pressor effects of a compound described herein (e.g., Compound 1 or vasopressin). For example, subcutaneous administration of a compound described herein (e.g., Compound 1) resulted in (substantially) more AEs than intravenous administration (see Example 1). Furthermore, the frequency of AEs after subcutaneous administration of a compound described herein (e.g., Compound 1) decreased over 5 days of treatment. For example, in some instances, sc administration resulted in approximately 0.5-fold more AEs per dose on Day 1 than iv administration (e.g., 35 subjects received doses of 0.45 mg or more intravenously, although only 3 subjects received 0.3 mg sc). Furthermore, sc administration of a partial agonist described herein (e.g., Compound 1) resulted in approximately 3-fold more AEs per dose than iv administration of the same compound (see Example 1). (1) M1 (a full (V1a) agonist) is formed after subcutaneous administration of Compound 1; (2) full vasopressin agonists are known to be toxic and cause adverse events; (3) Compound 1 and M1 are present in approximately equimolar concentrations after subcutaneous administration of M1; and (4) exposure to Compound 1 after sc administration (C max Given that the V1a (by V1a and AUC) was lower than after iv infusion, the presence of M1 (but not Compound 1) in plasma after subcutaneous administration contributes to the total V1a pressor effect and (e.g., exaggerated) pharmacological effect and / or AE profile after subcutaneous administration of Compound 1.

[0346] Furthermore, given that the presence of the vasopressin receptor full agonist M1 contributed to an increased number of vasoconstriction-related AEs compared to much higher concentrations of Compound 1, this further demonstrates that Compound 1 is a partial agonist and / or mixed agonist-antagonist (combined with the similar pharmacodynamic and adverse effects of Compound 1 across a wide concentration range). Furthermore, the observations from the studies in Example 1 also demonstrate that the mechanism of action of mixed agonist-antagonists places an upper limit on their (local vasoconstriction) effects in individuals (and limits such effects to levels below the maximal possible level). Further supporting this explanation, studies with the V1A receptor full agonist terlipressin demonstrated greater blood pressure increases than those provided in Example 1 (e.g., further supporting that the maximum pharmacodynamic effect of Compound 1 is "capped" and that Compound 1 is a V1A receptor partial agonist and / or mixed agonist-antagonist).

[0347] In some instances, the pharmacological effects of the compounds described herein (e.g., Compound 1) are due to vasopressin V1a-receptor agonism. In some instances, the lack of any effect on diuresis and homeostasis demonstrates a high degree of specificity for the V1a-receptor (e.g., resulting in a desirable pharmacological profile).

[0348] In some examples, the terminal half-life of a compound described herein (eg, Compound 1) is about 1.5 hours (after iv administration).

[0349] In some examples, the total clearance of a compound described herein (eg, Compound 1) is about 13 L / h (after iv administration).

[0350] In some examples, the terminal half-life of a compound described herein (e.g., Compound 1) is about 1 hour (after sc administration). In some examples, the terminal half-life of a compound described herein (e.g., Compound 1) is about 1 hour (after sc administration). maxis about 0.3 hours (after sc administration). In some examples, the bioavailability of a compound described herein (e.g., Compound 1) is about 18% (without any appreciable accumulation of a compound described herein (e.g., Compound 1), such as after repeated subcutaneous administration).

[0351] In some examples, compounds described herein (e.g., Compound 1) (e.g., AUC and C max The increased exposure of the compound described herein (e.g., Compound 1) to the steroid hormone agonist (SEQ ID NO: 1) is shown by the AUC and C max is roughly proportional to

[0352] In some examples, the compounds described herein (e.g., Compound 1) (AUC and C max Exposure to IL-16 (via IL-16) is higher in females than in males following intravenous infusion of a compound described herein (e.g., Compound 1).

[0353] In some examples, administration of a compound described herein (e.g., Compound 1) resulted in an increase in diastolic blood pressure in an individual receiving the compound. In some examples, administration of a compound described herein (e.g., Compound 1) resulted in an increase in systolic blood pressure in an individual receiving the compound. In some examples, administration of a compound described herein (e.g., Compound 1) resulted in an increase in MAP in an individual receiving the compound. In some examples, administration of a compound described herein (e.g., Compound 1) resulted in a reflex decrease in pulse rate in an individual receiving the compound (e.g., in a clear dose-dependent manner).

[0354] In some instances, peripheral blood flow was reduced following intravenous and subcutaneous administration of compounds described herein (eg, Compound 1).

[0355] In some examples, such as during subcutaneous administration of a compound described herein (e.g., Compound 1), the active metabolite M1 (a full (V1a) agonist) is produced, such as at concentrations equivalent to Compound 1.

[0356] In some embodiments, compounds described herein (e.g., mixed V1AR agonist-antagonists such as Compound 1), such as those described in the study provided in Example 6, reduce portal venous pressure (PP) (following subcutaneous administration) without excessive vasoconstriction across a wide dose range (e.g., from 10 μg / kg to 500 μg / kg of Compound 1) (see Figures 33 and 35). In some embodiments, compounds described herein (e.g., mixed V1AR agonist-antagonists such as Compound 1), such as those described in the study provided in Example 6, reduce PP (following subcutaneous administration) across a wide dose range (e.g., from 10 μg / kg to 500 μg / kg of Compound 1) (see Figures 33 and 35).

[0357] In some embodiments, the methods provided herein further comprise evaluating a biological sample (e.g., of an individual). In some embodiments, the methods further comprise evaluating the individual's biological sample for a biomarker, such as the biomarkers described in Example 6. In some embodiments, the biomarker (e.g., the amount or level of the biomarker) is compared to a control or standard (e.g., the amount or level of the biomarker).

[0358] In some embodiments, biomarkers described herein, such as those described in Example 6, are assessed at a first time point and a second time point. In some embodiments, the second time point is used to determine a responsiveness or efficacy, such as that of a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1). In some embodiments, the second time point is an endpoint. In some examples, the endpoint is used to determine the amount or level of the biomarker sufficient to achieve the desired responsiveness or efficacy of a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1). In some embodiments, the methods provided herein further include administering to the individual a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) at least until the level or amount of the biomarker (in the individual) reaches the endpoint. In some embodiments, the method includes continuing to administer the compound after the level or amount of the biomarker (in the individual) reaches the endpoint.

[0359] In some embodiments, the level or amount of a biomarker described herein, such as a biomarker described in Example 6, is higher (e.g., at least 5% higher, at least 15% higher, at least 25% higher, at least 35% higher, at least 45% higher, at least 55% higher, at least 65% higher, at least 75% higher, at least 85% higher, at least 95% higher, or more) at the second time point compared to the first time point.

[0360] In some embodiments, the level or amount of a biomarker described herein, such as a biomarker described in Example 6, is lower (e.g., up to 95% lower, up to 85% lower, up to 75% lower, up to 65% lower, up to 55% lower, up to 45% lower, up to 35% lower, up to 25% lower, up to 15% lower, up to 5% lower, or more) at the second time point compared to the first time point.

[0361] In some examples, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) affects (e.g., increases or decreases) the level of a biomarker described herein, such as a biomarker described in Example 5 or Example 6. In some embodiments, the biomarker described herein is selected from the group consisting of mean arterial pressure (MAP), (plasma) aldosterone, (plasma) renin, ascites volume, body weight, urine volume, (net) water balance, urinary sodium, urinary potassium, portal pressure, cardiac output, systemic vascular resistance, BUN, BUN / CREA, PHOS, spleen weight, skin blood flow (SBF), blood lactate concentration, heart rate, systolic arterial pressure, diastolic arterial pressure, and blood pH. In some embodiments, the biomarker described herein is MAP. In some embodiments, the biomarker described herein is aldosterone. In some embodiments, the biomarker described herein is renin. In some embodiments, the biomarker described herein is ascites volume. In some embodiments, the biomarker described herein is body weight. In some embodiments, the biomarker described herein is urine volume. In some embodiments, the biomarker described herein is net water balance. In some embodiments, the biomarker described herein is urinary sodium. In some embodiments, the biomarker described herein is urinary potassium. In some embodiments, the biomarker described herein is spleen weight. In some embodiments, the biomarker described herein is systolic arterial pressure. In some embodiments, the biomarker described herein is diastolic arterial pressure. In some embodiments, the biomarker described herein is heart rate. In some embodiments, the biomarker described herein is portal vein pressure. In some embodiments, the biomarker described herein is skin blood flow (SBF). In some embodiments, the biomarker described herein is blood lactate concentration. In some embodiments, the biomarker described herein is blood pH.In some embodiments, the biomarker described herein is an increase in glomerular filtration rate. In some embodiments, the biomarker described herein is an increase in renal blood flow.

[0362] In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1), such as those described in Example 6, reduces hyperaldosteronism in an individual (e.g., in need thereof). In some embodiments, a compound provided herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) reduces aldosterone (e.g., serum) in an individual (e.g., in need thereof). In some embodiments, a compound provided herein reduces aldosterone (e.g., serum) by at least 20% (e.g., at least 30%, at least 40%, at least 50%, at least 60%) in an individual (e.g., in need thereof). In some embodiments, a compound provided herein reduces aldosterone (e.g., serum) by 90% or less (e.g., 80% or less, 70% or less, 60% or less) in an individual (e.g., in need thereof). In some embodiments, the compounds provided herein reduce serum aldosterone in an individual (e.g., in need thereof) by more than 50% (e.g., compared to a control (e.g., vehicle) and / or the first time point).

[0363] In some instances, a reduction in portal hypertension and / or hyperaldosteronism results in a diuretic and natriuretic effect (see Example 6). In some embodiments, the diuretic and natriuretic effect is associated with (e.g., improvement in) ascites (e.g., overall) flow, such as after 3 days of sc treatment with a compound described herein.

[0364] In some embodiments, a compound provided herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) reduces ascites volume in an individual (e.g., in need thereof), such as after 5 days of treatment as described in Example 6. In some embodiments, a compound provided herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) reduces ascites volume in an individual (e.g., in need thereof) by at least 30% (e.g., at least 40%, at least 50%, at least 60%, at least 70%, at least 80%). In some embodiments, a compound provided herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) reduces ascites volume in an individual (e.g., in need thereof) by 95% or less (e.g., 90% or less, 85% or less, 80% or less, 75% or less). In some embodiments, a compound provided herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) reduces ascites volume in an individual (e.g., in need thereof) by about 30% to about 95%. In some embodiments, a compound provided herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) reduces ascites volume in an individual (e.g., in need thereof) by about 67%. In some embodiments, a compound provided herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) reduces ascites volume in an individual (e.g., in need thereof) by about 80%. In some embodiments, the reduction in ascites volume is compared to a control (e.g., vehicle) and / or the first time point.

[0365] In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) increases urine volume (excretion) in an individual (e.g., in need thereof) (see Example 6). In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) increases urinary sodium (excretion) in an individual (e.g., in need thereof) (see Example 6). In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) increases urine volume and urinary sodium excretion in an individual (e.g., in need thereof), such as during the first 24 hours of treatment (see Example 6). In some examples, the increase in urine volume and urinary sodium excretion results in (complete) elimination of ascites fluid accumulated in the peritoneal cavity in an individual (e.g., in need thereof). In some embodiments, the increase in urine volume and urinary sodium excretion results in a decrease in ascites fluid volume in an individual (e.g., in need thereof). In some embodiments, urine volume and / or urinary sodium excretion is increased in an individual (eg, in need thereof) within 24 hours of treatment.

[0366] In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) increases urine volume as described in Example 6. In some embodiments, urine volume is compared to (and greater than) a basal measurement, such as that described in Example 6. In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) increases urine volume by at least 20% (e.g., at least 30%, at least 40%, at least 50%, at least 60%, at least 70%). In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) increases urine volume by about 75%. In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) increases urine volume by at least 100% (at least 150%, at least 200%, at least 250%, at least 300%, at least 350%). In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) increases urine volume by about 430%. In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) increases urine volume by up to 750% (e.g., up to 500%, up to 400%, up to 300%). In some embodiments, urine volume increases in an individual (e.g., in need) within the first 4 hours of treatment. In some embodiments, urine volume increases in an individual (e.g., in need) after 1 day of treatment.

[0367] In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) provides a positive net fluid balance in an individual (e.g., in need), such as that described in Example 6. In some embodiments, the urine output of an individual (e.g., in need) is greater than the fluid intake.

[0368] In some embodiments, a compound provided herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) increases urinary sodium excretion and / or urinary potassium excretion in an individual (e.g., in need thereof), such as those described in Example 6. In some embodiments, a compound provided herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) increases urinary sodium excretion by at least 20% (e.g., at least 100%, at least 250%, at least 500%, at least 750%). In some embodiments, a compound provided herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) increases urinary sodium excretion by up to 1000% (e.g., up to 750%, up to 500%, up to 250%, up to 100%). In some embodiments, a compound provided herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) increases urinary sodium excretion by about 600%. In some embodiments, a compound provided herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) increases urinary potassium by at least 10% (e.g., at least 20%, at least 30%, at least 40%, at least 50%). In some embodiments, a compound provided herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) increases urinary potassium by up to 100% (e.g., up to 75%, up to 50%, up to 40%, up to 30%). In some embodiments, a compound provided herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) increases urinary potassium by about 20%. In some embodiments, urinary sodium excretion and / or urinary potassium excretion are compared to (and greater than) basal measurements. In some embodiments, urinary sodium excretion and / or urinary potassium excretion are increased in an individual (e.g., in need) within the first 4 hours of treatment. In some embodiments, urinary sodium excretion and / or urinary potassium excretion is increased in an individual (eg, in need thereof) after one day of treatment.

[0369] In some embodiments, a compound provided herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) reduces urinary potassium excretion in an individual (e.g., in need thereof), such as those described in Example 6. In some embodiments, a compound provided herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) reduces urinary potassium excretion by at least 10% (e.g., at least 20%, at least 30%, at least 40%, at least 50%). In some embodiments, a compound provided herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) reduces urinary potassium excretion by up to 100% (e.g., up to 75%, up to 50%, up to 40%, up to 30%). In some embodiments, a compound provided herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) reduces urinary potassium excretion by about 20%. In some embodiments, urinary potassium excretion is compared to (and greater than) a basal measurement.

[0370] In some embodiments, urinary sodium excretion increases in an individual (e.g., in need thereof), such as within the first 4 hours of treatment, and urinary potassium excretion decreases in an individual (e.g., in need thereof), such as after 5 hours or more of treatment.

[0371] In some embodiments, a compound provided herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) reduces body weight in an individual (e.g., in need thereof), such as that provided in Example 6. In some embodiments, a compound provided herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) reduces the body weight of an individual (e.g., in need thereof) by at least 5% (e.g., at least 7%, at least 9%, at least 11%). In some embodiments, a compound provided herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) reduces the body weight of an individual (e.g., in need thereof) by up to 15%, up to 13%, up to 11%, or up to 9%. In some embodiments, a compound provided herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) reduces the body weight of an individual (e.g., in need thereof) by about 14%. In some embodiments, the individual's body weight is compared to (and less than) a baseline measurement. In some embodiments, the weight of an individual (eg, in need thereof) is reduced after about 1 day or more, such as 3 days, of treatment.

[0372] In some embodiments, a compound provided herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) reduces spleen weight, such as that described in Example 6. In some embodiments, a compound provided herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) reduces the spleen weight of an individual (e.g., in need thereof) by at least 2% (at least 4%, at least 8%, at least 12%, at least 15%). In some embodiments, a compound provided herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) reduces the spleen weight of an individual (e.g., in need thereof) by up to 20% (e.g., up to 18%, up to 16%, up to 14%). In some embodiments, a compound provided herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) reduces the spleen weight of an individual (e.g., in need thereof) by about 16%. In some embodiments, the individual's spleen weight is compared to (and less than) a baseline measurement. In some embodiments, the spleen weight of an individual (e.g., in need thereof) is reduced after about 1 day or more of treatment, such as after 5 days of treatment.

[0373] In some embodiments, a compound provided herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) reduces creatinine levels in an individual (e.g., in need thereof), such as those described in Example 6. In some embodiments, a compound provided herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) reduces creatinine levels in an individual (e.g., in need thereof) by at least 30% (e.g., at least 40%, at least 50%, at least 60%, at least 70%). In some embodiments, a compound provided herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) reduces creatinine levels in an individual (e.g., in need thereof) by up to 80% (e.g., up to 70%, up to 60%, up to 50%, up to 40%). In some embodiments, a compound provided herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) reduces creatinine levels by about 50%. In some embodiments, the creatinine level in an individual (e.g., in need thereof) is reduced by about 80%. In some embodiments, the creatine level of the individual is compared to (and lower than) a baseline measurement. In some embodiments, the creatine level of the individual (e.g., in need thereof) is reduced about 1 day or 1 hour after treatment, such as about 5-25 hours after treatment.

[0374] In some embodiments, a compound provided herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) increases urinary creatinine levels in an individual (e.g., in need thereof), such as those described in Example 6. In some embodiments, a compound provided herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) increases urinary creatinine levels in an individual (e.g., in need thereof) by at least 30% (e.g., at least 40%, at least 50%, at least 60%, at least 70%). In some embodiments, a compound provided herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) increases urinary creatinine levels in an individual (e.g., in need thereof) by up to 80% (e.g., up to 70%, up to 60%, up to 50%, up to 40%). In some embodiments, a compound provided herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) increases urinary creatinine levels by about 50%. In some embodiments, the urinary creatinine level in an individual (e.g., in need thereof) is increased by about 80%. In some embodiments, the urinary creatine level of the individual is compared to (and lower than) a baseline measurement. In some embodiments, the urinary creatine level of the individual (e.g., in need thereof) is increased about 1 day or 1 hour after treatment, such as about 5-25 hours after treatment.

[0375] In some embodiments, a compound provided herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) reduces urinary creatinine levels in an individual (e.g., in need thereof), such as those described in Example 6. In some embodiments, a compound provided herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) reduces urinary creatinine levels in an individual (e.g., in need thereof) by at least 30% (e.g., at least 40%, at least 50%, at least 60%, at least 70%). In some embodiments, a compound provided herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) reduces urinary creatinine levels in an individual (e.g., in need thereof) by up to 80% (e.g., up to 70%, up to 60%, up to 50%, up to 40%). In some embodiments, a compound provided herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) reduces urinary creatinine levels by about 50%. In some embodiments, the urinary creatinine level in an individual (e.g., in need thereof) is reduced by about 80%. In some embodiments, the individual's urinary creatine level is compared to (and lower than) a baseline measurement. In some embodiments, the urinary creatine level of an individual (e.g., in need thereof) is reduced about 1 day or 1 hour after treatment, such as about 5-25 hours after treatment.

[0376] In some examples, a diuretic and / or natriuretic effect is identified in an individual within the first 24 hours of treatment, such as after subcutaneous administration of a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1), as described in the study provided in Example 6. In some examples, a diuretic and / or natriuretic effect is not identified in an individual after the first 24 hours of treatment, such as after subcutaneous administration of a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1), as described in the study provided in Example 6. In some embodiments, a return to baseline levels in urine volume and sodium excretion is observed 24 hours after treatment with a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1). In some examples, a return to baseline levels in urine volume and sodium excretion is an indication that excess fluid is no longer present in the individual's peritoneal cavity (available for removal). In some instances, there is minimal or no fluid overload or sodium or water retention following administration of the compounds described herein, such as indicating the lack of V2 receptor activity of the compounds provided herein, such as mixed V1aR agonist-antagonists (e.g., Compound 1).

[0377] In some examples, hyponatremia is a potential risk observed during treatment with vasopressin receptor agonists such as terlipressin or desmopressin. In some embodiments, subcutaneous administration of a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) does not cause hyponatremia, despite a significant increase in urinary sodium excretion after the first administration (e.g., compared to vehicle-treated subjects). In some embodiments, repeated administration of a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) over a 5-day period does not cause hyponatremia. In some examples, hyponatremia is defined in rats as a blood sodium level of less than 120 mEq / L.

[0378] In some embodiments, administration of a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) provides beneficial effects on factors associated with renal sodium and water retention, such as without side effects or nonspecific toxicity. In some embodiments, administration of a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) provides submaximal effects on vasoconstriction, such as by reducing the risk of excessive vasoconstriction, thereby offering the dual benefits of improved therapeutic efficacy and safety.

[0379] In some embodiments, the compounds described herein (e.g., mixed V1AR agonist-antagonists such as Compound 1) reduce portal hypertension in an individual (e.g., in need thereof). In some embodiments, the compounds described herein (e.g., mixed V1AR agonist-antagonists such as Compound 1) reduce portal pressure in an individual (e.g., in need thereof) by at least 0.1 mmHg (e.g., at least 0.5 mmHg, at least 1 mmHg, at least 2 mmHg, at least 3 mmHg, at least 4 mmHg). In some embodiments, the compounds described herein (e.g., mixed V1AR agonist-antagonists such as Compound 1) reduce portal pressure in an individual (e.g., in need thereof) by up to 5 mmHg (e.g., up to 4 mmHg, up to 3 mmHg, up to 2 mmHg, up to 1 mmHg).

[0380] In some embodiments, such as those described in the study provided in Example 6, compounds described herein (e.g., mixed V1AR agonist-antagonists such as Compound 1) increase mean arterial pressure (MAP) (following subcutaneous administration) over a wide dose range (e.g., 10 μg / kg to 500 μg / kg of Compound 1) (see Figure 34). In some embodiments, such as those described in the study provided in Example 6, the increase in MAP reaches a peak plateau or upper therapeutic limit (e.g., an increase in MAP of about 10 to about 15 mmHg) (see Figure 34). In some embodiments, such as those described in the study provided in Example 6, the increase in MAP reaches a peak plateau or upper therapeutic limit (e.g., an increase in MAP of about 10 to about 15 mmHg) with a concomitant decrease in PP (e.g., about 2 to about 14 mmHg) (see Figure 34). In some instances, even after a five-fold increase in dose (e.g., 100 μg / kg or 500 μg / kg of Compound 1), the compounds described herein do not produce any significant further changes in effects such as increased MAP (see Figure 34).

[0381] In another example, administration of a fully non-selective (V2, V1a) receptor agonist such as terlipressin results in a significantly higher increase in MAP (and above the therapeutic range of 10-15 mmHg) despite a reduction in PP similar to that for compounds described herein (e.g., mixed V1AR agonist-antagonists such as Compound 1) (see Figure 34).

[0382] In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) increases mean arterial pressure, systolic arterial pressure, and diastolic arterial pressure in an individual (e.g., a mammal), such as after subcutaneous administration (see, e.g., Figures 41A-C). In some examples, the occurrence and amplitude of the maximum increase in blood pressure is related to the dose of a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) in an individual (e.g., a mammal), such as after subcutaneous administration. In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) increases mean arterial pressure (MAP) in an individual (e.g., a mammal) by at least about 10 mmHg (e.g., at least 15 mmHg, at least 20 mmHg, at least 30 mmHg, at least 40 mmHg), such as after subcutaneous administration (see, e.g., Figure 43A). In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) increases mean arterial pressure (MAP) in an individual (e.g., in need thereof) by up to about 50 mmHg (e.g., up to 40 mmHg, up to 30 mmHg, up to 20 mmHg, up to 10 mmHg), such as after subcutaneous administration. In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) increases mean arterial pressure (MAP) in an individual (e.g., a mammal) by about 10 mmHg to about 50 mmHg, such as after subcutaneous administration. In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) increases mean arterial pressure (MAP) in an individual (e.g., a mammal) by about 20 mmHg, such as after subcutaneous administration. In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) increases mean arterial pressure (MAP) in an individual (e.g., a mammal) by about 40 mmHg, such as after subcutaneous administration.In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) increases mean arterial pressure (MAP) in an individual (e.g., a mammal) by about 25 mmHg, such as after subcutaneous administration. In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) increases mean arterial pressure (MAP) in an individual (e.g., a mammal) for at least 75 minutes (e.g., at least 150 minutes, at least 300 minutes), such as after subcutaneous administration, and maintains the increase. In some examples, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) produces a change in mean arterial pressure (MAP) in an individual (e.g., a mammal) that is statistically different from vehicle, such as after subcutaneous administration. In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) increases MAP in an individual (e.g., a mammal), such as after subcutaneous administration, and MAP does not return to baseline values.

[0383] In some embodiments, a full antagonist such as terlipressin increases mean arterial pressure (MAP) in an individual (e.g., a mammal) (see, e.g., Figure 43B). In some embodiments, a full antagonist such as terlipressin increases mean arterial pressure (MAP), and the effect is maintained only for a short period of time, such as less than 90 minutes (e.g., within 30, 75, or 90 minutes) after intravenous administration (see, e.g., Figure 43B). In some embodiments, a full antagonist such as terlipressin produces a transient effect on MAP (see, e.g., Figure 43B). In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) produces an increase in MAP over a 50-fold dose range in an individual (e.g., a mammal), which in some instances may be the maximal effect on arterial pressure.

[0384] In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) reduces heart rate in an individual (e.g., a mammal), such as after subcutaneous administration (see Figure 41D). In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) reduces heart rate in an individual (e.g., a mammal), such as after subcutaneous administration, by at least 2% (e.g., at least 5%, at least 10%, at least 15%) (see Figure 41D). In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) reduces heart rate in an individual (e.g., a mammal), such as after subcutaneous administration, by up to 20% (e.g., up to 15%, up to 10%, up to 5%) (see Figure 41D). In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) reduces heart rate by about 5% in an individual (e.g., a mammal), such as after subcutaneous administration (see, e.g., Figure 41D). In some examples, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) produces a change in MAP that correlates with a measurable decrease in heart rate in an individual (e.g., a mammal), such as after subcutaneous administration (see, e.g., Figures 41D, 43A). In some examples, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) alters systolic and diastolic blood pressure, such as after subcutaneous administration, that correlates with a change in MAP in an individual (e.g., a mammal) (see, e.g., Figures 41A-C).

[0385] In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) has a terminal half-life (t) of at least 50 minutes (e.g., at least 70 minutes, at least 90 minutes, at least 110 minutes, at least 130 minutes) in an individual (e.g., a mammal), such as after subcutaneous administration. 1 / 2termIn some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) has a terminal half-life (t) of up to 150 minutes (e.g., up to 130 minutes, up to 110 minutes, up to 90 minutes, up to 70 minutes) in an individual (e.g., a mammal), such as after subcutaneous injection. 1 / 2term In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) has a terminal half-life (t) of about 50 to about 150 minutes in an individual (e.g., a mammal), such as after subcutaneous injection. 1 / 2term In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) has a terminal half-life (t) of about 110 minutes in an individual (e.g., a mammal), such as after subcutaneous injection. 1 / 2term In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) has an elimination half-life (t) of at least 1 minute (e.g., at least 5 minutes, at least 10 minutes, at least 15 minutes, at least 20 minutes) in an individual (e.g., a mammal), such as after intravenous administration. 1 / 2elim In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) has an elimination half-life (t) of up to 60 minutes (e.g., up to 40 minutes, up to 20 minutes, up to 10 minutes) in an individual (e.g., a mammal). 1 / 2elim In some embodiments, the compounds described herein (e.g., mixed V1AR agonist-antagonists such as Compound 1) have an elimination half-life (t) of about 1 minute to about 40 minutes in an individual (e.g., a mammal). 1 / 2elim In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) has an elimination half-life (t) of about 20 minutes in an individual (e.g., a mammal). 1 / 2elim In some embodiments, the compound has a terminal half-life (t 1 / 2term ) is the elimination half-life (t 1 / 2elim ) longer.

[0386] In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) has a bioavailability in an individual (e.g., a mammal) of at least 40% (e.g., at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%), such as after subcutaneous administration. In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) has a bioavailability in an individual (e.g., a mammal) of up to 75% (e.g., up to 70%, up to 60%, up to 50%, up to 40%). In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) has a bioavailability in an individual (e.g., a mammal) of about 40% to about 70%. In some embodiments, a compound described herein (eg, a mixed V1AR agonist-antagonist such as a compound) has a bioavailability in an individual (eg, a mammal) of about 60%.

[0387] In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) has a clearance rate in an individual (e.g., a mammal) similar to the glomerular filtration rate (e.g., 5-15 mL / min / kg), such as after subcutaneous administration. In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) has a filtration rate of at least 5 mL / min / kg (e.g., at least 7 mL / min / kg, at least 10 mL / min / kg, at least 13 mL / min / kg). In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) has a filtration rate of up to 25 mL / min / kg (e.g., up to 22 mL / min / kg, up to 18 mL / min / kg, up to 15 mL / min / kg). In some embodiments, the compounds described herein (e.g., mixed V1AR agonist-antagonists such as Compound 1) have a filtration rate of about 20 mL / min / kg. In some embodiments, the compounds described herein (e.g., mixed V1AR agonist-antagonists such as Compound 1) have a filtration rate of about 10 mL / min / kg.

[0388] In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) reduces skin blood flow in an individual (e.g., a mammal), such as after intravenous administration (see, e.g., Figure 40A). In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) reduces skin blood flow in an individual (e.g., a mammal) by up to 60% (e.g., up to 55%, up to 50%, up to 45%, up to 40%). In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) reduces skin blood flow in an individual (e.g., a mammal) by at least 10% (e.g., at least 20%, at least 30%, at least 40%, at least 50%). In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) reduces cutaneous blood flow in an individual (e.g., a mammal) by about 20% to about 60%. In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) reduces cutaneous blood flow in an individual (e.g., a mammal) by about 40%. In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) reduces cutaneous blood flow in an individual (e.g., a mammal) less than vasopressin reduces cutaneous blood flow in an individual (e.g., a mammal), such as after intravenous administration (see, e.g., Figure 40A).In some examples, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) reduces skin blood flow in an individual (e.g., a mammal) by about 40% after intravenous administration, and vasopressin reduces skin blood flow in an individual (e.g., a mammal) by about 90% after intravenous administration, demonstrating that a mixed V1AR agonist-antagonist described herein, such as Compound 1, is more suitable for intravenous administration than a fully non-selective (V2, V1a) agonist (e.g., vasopressin or terlipressin), for example, by reducing (significant) injection site reactions (e.g., local vasoconstriction) that prevent the drug from being suitable for systemic delivery. In some examples, the smaller reduction in skin blood flow by a compound provided herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) compared to vasopressin demonstrates less local vasoconstriction compared to vasopressin.

[0389] In some examples, elevated serum lactate levels are a clinical marker for anaerobic metabolism and tissue hypoxia and are used as a surrogate marker for the development of vasoconstriction and tissue ischemia. In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) does not significantly increase blood lactate levels in an individual, such as after intravenous administration (see, e.g., Figure 40B). In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) does not significantly increase blood lactate levels in an individual, such as after intravenous administration, while a similar dose of vasopressin significantly increases blood lactate levels in an individual (see, e.g., Figures 40B-C). In some examples, vasopressin increases blood lactate levels by at least twofold (e.g., threefold, fourfold) in an individual, such as after intravenous administration (see, e.g., Figure 40B).

[0390] In some embodiments, compounds described herein (e.g., mixed V1AR agonist-antagonists such as Compound 1) reduce plasma concentrations (e.g., linearly) (see, e.g., Figures 39A-B, 42A-B).

[0391] In some embodiments, the compounds described herein (e.g., mixed V1AR agonist-antagonists such as Compound 1) increase blood pH in an individual, such as after intravenous administration. In some embodiments, the compounds described herein (e.g., mixed V1AR agonist-antagonists such as Compound 1) decrease blood pH in an individual, such as after intravenous administration.

[0392] In some examples, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) reduces the initial apparent volume of the central compartment (V) in an individual (e.g., mammal) of at least 20 mL / kg (e.g., at least 40 mg / kg, at least 60 mg / kg, at least 80 mg / kg, at least 100 mg / kg), such as after intravenous administration. c In some examples, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) reduces the initial apparent volume of the central compartment (V) in an individual (e.g., a mammal) at up to 150 mg / kg (e.g., up to 130 mg / kg, up to 110 mg / kg, up to 90 mg / kg), such as after intravenous administration. c ) results.

[0393] In some examples, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) has a steady-state volume of distribution (V) in an individual (e.g., a mammal) of at least 120 mL / kg (e.g., at least 130 mg / kg, at least 140 mg / kg, at least 150 mg / kg), such as after intravenous administration. ssIn some examples, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) provides a steady-state volume of distribution (V) in an individual (e.g., a mammal) of up to 200 mL / kg (e.g., up to 180 mg / kg, up to 160 mg / kg, up to 140 mg / kg), such as after intravenous administration. ss ) results.

[0394] In some examples, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) may provide a peak plasma concentration (C) per unit dose in an individual (e.g., a mammal) of at least 200 ng / mL per mg / kg (e.g., at least 300 ng / mL per mg / kg, at least 500 ng / mL per mg / kg, at least 600 ng / mL per mg / kg, at least 700 ng / mL per mg / kg), such as after subcutaneous administration. max In some examples, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) provides a peak plasma concentration (C) per unit dose in an individual (e.g., a mammal) of up to 1000 ng / mL per mg / kg (e.g., up to 900 ng / mL per mg / kg, up to 700 ng / mL per mg / kg, up to 500 ng / mL per mg / kg, up to 400 ng / mL per mg / kg), such as after subcutaneous administration. max In some examples, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) provides a time point of peak plasma concentration (T) in an individual (e.g., a mammal) of at least 5 minutes (e.g., at least 10 minutes, at least 20 minutes, at least 30 minutes), such as after subcutaneous administration. max In some examples, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) provides a time point of peak plasma concentration (T) in an individual (e.g., a mammal) of up to 60 minutes (e.g., up to 50 minutes, up to 40 minutes, up to 30 minutes, up to 20 minutes), such as after subcutaneous administration. max ) results.

[0395] In some examples, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) provides an area under the curve (AUC) per unit dose in an individual (e.g., a mammal) of at least 40,000 min·ng / mL per mg / kg (e.g., at least 45,000 min·ng / mL per mg / kg, at least 50,000 min·ng / mL per mg / kg, at least 55,000 min·ng / mL per mg / kg, or at least 60,000 min·ng / mL per mg / kg), such as after subcutaneous administration. In some examples, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) provides an area under the curve (AUC) per unit dose in an individual (e.g., a mammal) of up to 70,000 min·ng / mL per mg / kg (e.g., 65,000 min·ng / mL per mg / kg, 60,000 min·ng / mL per mg / kg, 55,000 min·ng / mL per mg / kg, 50,000 min·ng / mL per mg / kg), such as after subcutaneous administration.

[0396] In some examples, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) provides an apparent total body clearance (CL / F) in an individual (e.g., a mammal) of at least 10 mL / min / kg (e.g., at least 12 mL / min / kg, at least 15 mL / min / kg, at least 18 mL / min / kg), such as after subcutaneous administration. In some examples, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) provides an apparent total body clearance (CL / F) in an individual (e.g., a mammal) of at most 30 mL / min / kg (e.g., at most 28 mL / min / kg, at most 25 mL / min / kg, at most 22 mL / min / kg, at most 20 mL / min / kg), such as after subcutaneous administration.

[0397] In some embodiments, provided herein is a method of treating a complication of end-stage liver disease, such as ascites (e.g., refractory ascites), in an individual (e.g., in need thereof), comprising administering to the individual a therapeutically effective amount of a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate salt).

[0398] In some embodiments, the individual described herein has cirrhosis portal hypertension. In some embodiments, the individual described herein has end-stage liver disease (ESLD). In some embodiments, the individual described herein has ascites. In some embodiments, the individual described herein has refractory ascites. In some embodiments, the individual described herein has developed ascites as a complication of ESLD. In some embodiments, the individual described herein has developed refractory ascites as a complication of ESLD.

[0399] In some embodiments, the compounds described herein (e.g., Compound 1) provide a significantly improved therapeutic index (e.g., resulting from a lower maximum vasoconstriction and a lower risk of tissue hypoxia), such as when compared to full (V1A) receptor agonists. In some embodiments, the compounds described herein (e.g., Compound 1) provide approximately half the maximum vasoconstriction provided by full agonists, without any concomitant signs of ischemia, etc. In some embodiments, the compounds described herein (e.g., Compound 1) are (clinically) effective vasoconstrictors (e.g., with a favorable benefit / risk profile, such as low or no organ toxicity).

[0400] In some embodiments, provided herein are methods for treating end-stage liver disease (ESLD) in an individual (e.g., in need thereof), comprising administering to the individual a therapeutically effective amount of a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate salt).

[0401] In some embodiments, provided herein are methods for treating a complication of ESLD in an individual (e.g., in need thereof), comprising administering to the individual a therapeutically effective amount of a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate).

[0402] In some embodiments, provided herein are methods of treating ascites in an individual (e.g., in need thereof), comprising administering to the individual a therapeutically effective amount of a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate salt).

[0403] In some embodiments, the individual has a form of ascites that is difficult to treat. In some embodiments, the individual has recurrent ascites. In some embodiments, the individual has unresponsive ascites. In some embodiments, the individual has partially responsive ascites. In some embodiments, the individual has treatment-resistant ascites. In some embodiments, the individual has treatment-unresponsive ascites. In some embodiments, the individual has diuretic-resistant ascites. In some embodiments, the individual has diuretic-refractory ascites.

[0404] In some embodiments, provided herein are methods of treating refractory ascites in an individual (e.g., in need thereof), comprising administering to the individual a therapeutically effective amount of a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate salt).

[0405] In some embodiments, provided herein are methods for treating ascites in an individual, such as an individual who has developed ascites as a complication of cirrhosis, comprising administering to the individual a therapeutically effective amount of a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate).

[0406] In some embodiments, provided herein are methods for treating acute hepatorenal syndrome-acute kidney injury (HRS-AKI) in an individual, such as an individual who has developed HRS-AKI as a complication of cirrhosis, comprising administering to the individual a therapeutically effective amount of a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate).

[0407] In some embodiments, the individual has end-stage liver disease (ESLD). In some embodiments, the individual has ascites as a complication of end-stage liver disease (ESLD). In some embodiments, the individual has developed refractory ascites as a complication of end-stage liver disease (ESLD).

[0408] In some embodiments, the individual has (e.g., decompensated) cirrhosis. In some embodiments, the individual has decompensated cirrhosis. In some embodiments, the individual has decompensated cirrhosis with ascites.

[0409] In some embodiments, a therapeutically effective amount of a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate) is about 5 μg to about 55 μg. In some embodiments, a therapeutically effective amount of a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate) is about 8 μg to about 50 μg. In some embodiments, a therapeutically effective amount of a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate) is about 20 μg to about 35 μg. In some embodiments, a therapeutically effective amount of a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate) is about 25 μg to about 35 μg. In some embodiments, a therapeutically effective amount of a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate) is about 30 μg. In some embodiments, a therapeutically effective amount of a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate salt) is administered over a period of time, such as over several hours (e.g., up to 24 hours continuously), for several days (e.g., up to 10 days).

[0410] In some embodiments, a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate) is administered to an individual intravenously. In some embodiments, Compound 1, or a pharmaceutically acceptable salt (e.g., acetate) is administered to an individual by intravenous infusion.

[0411] In some embodiments, a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate) is administered subcutaneously to an individual. In some embodiments, Compound 1, or a pharmaceutically acceptable salt (e.g., acetate) is administered to an individual by subcutaneous injection.

[0412] In some embodiments, the therapeutically effective amount of a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate) is about 5 μg / hour or greater. In some embodiments, the therapeutically effective amount of a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate) is about 55 μg / hour or less. In some embodiments, the therapeutically effective amount of a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate) is about 5 μg / hour to about 55 μg / hour. In some embodiments, the therapeutically effective amount of a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate) is about 8 μg / hour to about 50 μg / hour. In some embodiments, the therapeutically effective amount of a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate) is about 20 μg / hour to about 35 μg / hour. In some embodiments, the therapeutically effective amount of a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate) is about 25 μg / hour to about 35 μg / hour. In some embodiments, the therapeutically effective amount of a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate) is about 30 μg / hour.

[0413] In some embodiments, a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate) is administered to the individual on days 1 and 2. In some embodiments, a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate) is administered to the individual (e.g., subcutaneously) one or more days after day 1. In some embodiments, the individual receives an initial (e.g., intravenous infusion) dose of a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate) on day 1. In some embodiments, the individual receives an initial (e.g., intravenous infusion) dose of a comp...

Claims

1. A method of treating end-stage liver disease (ESLD) or a symptom (e.g., a complication) thereof in an individual (e.g., in need thereof), comprising subcutaneously injecting the individual (e.g., in need thereof) with a composition comprising an (effective) amount of a compound, wherein the compound is a mixed vasopressin receptor 1A (V1AR) agonist-antagonist.

2. 2. The method of claim 1, wherein the mixed vasopressin receptor 1A (V1AR) agonist-antagonist is selective for V1AR over V2R.

3. The method of claim 1 or 2, wherein the mixed vasopressin receptor 1A (V1AR) agonist-antagonist has no V2R activity, such as at therapeutic concentrations.

4. The method of any one of claims 1 to 3, wherein the compound comprises a first portion having agonist activity and a second portion having antagonist activity.

5. The compound has the structure represented by Formula I: D1-L-D2 Formula I or a pharmaceutically acceptable salt thereof (In the formula, D1 is a vasopressin receptor 1A (V1AR) agonist; D2 is a V1AR antagonist; and L is a linker. The method according to any one of claims 1 to 4, comprising:

6. A method of treating end-stage liver disease (ESLD) or a symptom (e.g., a complication) thereof in an individual (e.g., in need thereof), comprising administering to the individual (e.g., in need thereof) an (effective) amount of a compound having a structure represented by Formula I: D1-L-D2 Formula I or a pharmaceutically acceptable salt thereof (In the formula, D1 is a vasopressin receptor 1A (V1AR) agonist; D2 is a V1AR antagonist; and L is a linker. A method comprising subcutaneously injecting a composition comprising:

7. 7. The method of claim 6, wherein D1 is selective for V1AR over V2R.

8. 8. The method of claim 6 or 7, wherein D1 is or comprises a (e.g., cyclic) peptide.

9. The method of any one of claims 6 to 8, wherein D1 is or comprises a cyclic nanopeptide.

10. D1 has the following structure: 【Chemical 1】 10. The method according to any one of claims 6 to 9, comprising or comprising:

11. The method of any one of claims 6 to 10, wherein D2 is or comprises a (e.g. linear) peptide.

12. The method of any one of claims 6 to 11, wherein D2 is a linear polypeptide comprising about 7 or more amino acid residues.

13. D2 has the following structure: 【Chemistry 2】 13. The method according to any one of claims 6 to 12, comprising or comprising:

14. The method of any one of claims 6 to 13, wherein L is a non-hydrolyzable linker.

15. 14. The method of any one of claims 6 to 13, wherein L comprises one or more linker groups, each linker group independently selected from the group consisting of substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl.

16. The method of any one of claims 6 to 15, wherein L is a bond, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.

17. The method of any one of claims 6 to 16, wherein L is or comprises a substituted or unsubstituted heteroalkyl.

18. 18. The method of any one of claims 6-17, wherein L is heteroalkyl (e.g., alkylamine) substituted with one or more substituents, each substituent independently selected from the group consisting of oxo, amino, and substituted heteroalkyl (e.g., alkylamine substituted with oxo).

19. 19. The method of any one of claims 6 to 18, wherein L is or comprises one or more (e.g. modified) amino acid residues.

20. L has the following structure: 【Chemistry 3】 20. The method of any one of claims 6 to 19, comprising or comprising:

21. The method of any one of claims 6 to 20, wherein the compound is Compound 1, or a pharmaceutically acceptable salt thereof.

22. A method for treating end-stage liver disease (ESLD) or a symptom (e.g., a complication) thereof in an individual (e.g., in need thereof), comprising subcutaneously injecting to said individual (e.g., in need thereof) a composition comprising an (effective) amount of Compound 1, or a pharmaceutically acceptable salt thereof.

23. The method of any one of claims 1 to 22, wherein the composition further comprises a liquid medium or solvent (e.g., water or an aqueous medium).

24. 24. The method of any one of claims 1 to 23, wherein the method further comprises attaching a subcutaneous infusion device to the skin of the individual, the subcutaneous infusion device comprising a chamber body and a hollow tube body, the composition configured within the chamber body, the hollow tube body comprising a first opening and a second opening, the first opening being in fluid contact with the chamber body and the second opening being configured subcutaneously within the individual after attaching the subcutaneous infusion device to the skin.

25. 25. The method of claim 24, wherein the subcutaneous infusion device further comprises a pump configured to subcutaneously infuse the composition into the individual at a constant or variable rate.

26. A method of treating end-stage liver disease (ESLD) or a symptom (e.g., a complication) thereof in an individual (e.g., in need thereof), comprising subcutaneously administering to said individual (e.g., in need thereof) a composition comprising an (effective) amount of a compound, wherein said compound is a mixed vasopressin receptor 1A (V1AR) agonist-antagonist.

27. A method of treating end-stage liver disease (ESLD) or a symptom (e.g., a complication) thereof in an individual (e.g., in need thereof), comprising administering to the individual (e.g., in need thereof) an (effective) amount of a compound having a structure represented by Formula I: D1-L-D2 Formula I or a pharmaceutically acceptable salt thereof (In the formula, D1 is a vasopressin receptor 1A (V1AR) agonist; D2 is a V1AR antagonist; and L is a linker. A method comprising subcutaneously administering a composition comprising:

28. A method for treating end-stage liver disease (ESLD) or a symptom (e.g., a complication) thereof in an individual (e.g., in need thereof), comprising subcutaneously administering to the individual (e.g., in need thereof) an (effective) amount of a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof.

29. 29. The method of any one of claims 1 to 28, wherein less than 50% of the compound of Formula I is degraded (e.g., subcutaneously) when the composition is administered subcutaneously to the individual (e.g., by subcutaneous (bolus) injection or subcutaneous infusion).

30. 30. The method of any one of claims 1 to 29, wherein less than 30% of the compound of formula I is degraded (e.g., subcutaneously) when the composition is administered subcutaneously to the individual (e.g., by subcutaneous (bolus) injection or subcutaneous infusion).

31. 31. The method of any one of claims 1 to 30, wherein when the composition is administered subcutaneously to the individual (e.g., by subcutaneous (bolus) injection or subcutaneous infusion), less than 50% of the compound of formula I degrades (e.g., subcutaneously) to form M1.

32. 32. The method of any one of claims 1 to 31, wherein when the composition is administered subcutaneously to the individual (e.g., by subcutaneous (bolus) injection or subcutaneous infusion), less than 30% of the compound of formula I degrades (e.g., subcutaneously) to form M1.

33. 33. The method of any one of claims 1 to 32, wherein when the composition is injected subcutaneously into the individual, less M1 is formed compared to administration of an otherwise identical composition administered by subcutaneous (bolus) injection.

34. 34. The method of any one of claims 1 to 33, wherein when the composition is injected subcutaneously into the individual, less M1 is formed systemically compared to administration of an otherwise identical composition administered by subcutaneous (bolus) injection.

35. 35. The method of any one of claims 1 to 34, wherein when the composition is injected subcutaneously into the individual, less M1 is formed locally (at the injection / infusion site) compared to administration of an otherwise identical composition administered by subcutaneous (bolus) injection.

36. 36. The method of any one of claims 1 to 35, wherein subcutaneous injection of the composition into the individual improves tolerability (e.g., based on reduced M1 formation) compared to subcutaneous (bolus) injection.

37. 37. The method of any one of claims 1 to 36, wherein the composition is subcutaneously injected into the individual to reduce undesired systemic events (e.g., undesired vasoconstriction resulting in ischemia, etc.), reduce undesired administration site events (e.g., local site vasoconstriction resulting in administration site ischemia, etc.), or reduce both.

38. 38. The method of any one of claims 1 to 37, wherein the composition is subcutaneously infused into the individual for a continuous period of at least 1 hour.

39. 39. The method of any one of claims 1-38, wherein the composition is infused subcutaneously into the individual at a rate of about 0.005 milliliters per hour (mL / hr) to about 1 mL / hr for the administration period.

40. The method of any one of claims 1 to 39, wherein the composition comprises a buffering agent.

41. 41. The method of claim 40, wherein the buffer is selected from the group consisting of acetate buffer, succinate buffer, and citrate buffer.

42. 42. The method of any one of claims 1 to 41, wherein the composition comprises a buffering agent at a concentration of from about 1 millimolar (mM) to about 1 molar (M).

43. 43. The method of any one of claims 1 to 42, wherein the composition comprises a buffering agent at a concentration of about 5 mM to about 250 mM.

44. 44. The method of any one of claims 1 to 43, wherein the composition comprises a buffering agent at a concentration of about 5 mM to about 25 mM.

45. 44. The method of any one of claims 1 to 43, wherein the composition comprises a buffering agent at a concentration of about 50 mM to about 250 mM.

46. 46. ​​The method of any one of claims 1 to 45, wherein the composition has a pH of from about 4 to about 8.

47. 47. The method of any one of claims 1 to 46, wherein the composition has a pH of from about 4 to about 6.

48. 48. The method of any one of claims 1 to 47, wherein the composition has a pH of about 4.5 to about 5.

49. 49. The method of any one of claims 1-48, wherein the compound is administered to the individual (e.g., continuously) in an amount of from about 0.001 milligrams (mg) to about 100 mg, such as over a period of one or more days.

50. 50. The method of any one of claims 1-49, wherein the composition comprises the compound at a concentration of about 0.001 milligram per milliliter (mg / mL) to about 100 mg / mL.

51. 51. The method of any one of claims 1 to 50, wherein the composition comprises the compound at a concentration of about 0.1 mg / mL to about 100 mg / mL.

52. 52. The method of any one of claims 1 to 51, wherein the composition comprises the compound at a concentration of about 1 mg / mL to about 10 mg / mL.

53. The method of any one of claims 1 to 52, wherein the composition further comprises a preservative.

54. 54. The method of claim 53, wherein the preservative is present in an amount of about 1 mg / mL to about 20 mg / mL.

55. 55. The method of any one of claims 1 to 54, wherein the composition further comprises a solubilizing agent.

56. 33. The method of claim 32, wherein the solubilizing agent is present in an amount of about 1 mg / mL to about 250 mg / mL (e.g., about 60-80 mg / mL).

57. 57. The method of any one of claims 1 to 56, wherein said compound is administered (continuously) to said individual in need thereof at a dose of about 0.1 mg / day to about 100 mg / day.

58. 1. A method of reducing (the incidence of) local vasoconstriction, such as (injection site) ischemia, in an individual in need thereof, comprising administering to said individual in need thereof a compound having a structure represented by Formula I, or a pharmaceutically acceptable salt thereof: D1-L-D2 Formula I or a pharmaceutically acceptable salt thereof, D1 is a vasopressin receptor 1A (V1AR) agonist; D2 is a V1AR antagonist; and L is a linker. A method comprising subcutaneously injecting a composition comprising:

59. 1. A method of treating end-stage liver disease (ESLD) in an individual in need thereof, comprising administering to said individual in need thereof a compound having a structure represented by Formula I, or a pharmaceutically acceptable salt thereof: D1-L-D2 Formula I or a pharmaceutically acceptable salt thereof (In the formula, D1 is a vasopressin receptor 1A (V1AR) agonist; D2 is a V1AR antagonist; and L is a linker. subcutaneously injecting a composition comprising A method wherein less than 50% of said compound of formula I is degraded (eg, subcutaneously).

60. 60. The method of any one of claims 1 to 59, wherein the individual's urine output (e.g. within the first 24 hours, such as within the first 4 hours) is (significantly) increased (e.g. compared to a solvent control) following subcutaneous administration to said individual of a compound of any one of claims 1 to 59, or a pharmaceutically acceptable salt thereof.

61. 61. The method of any one of claims 1 to 60, wherein the individual's urine output is increased by about 25% or more, 50% or more, 100% or more, 200% or more, 300% or more, 400% or more, or 500% or more (e.g., compared to a solvent control) following subcutaneous administration to the individual of a compound of any one of claims 1 to 60, or a pharmaceutically acceptable salt thereof.

62. 62. The method of any one of claims 1-61, wherein the individual's urine output is about 50% or more or 100% or more greater at least one day (e.g., three or more days) after subcutaneous administration of the compound of any one of claims 1-61, or a pharmaceutically acceptable salt thereof, to the individual.

63. 63. The method of any one of claims 1 to 62, wherein the individual's urinary sodium (excretion) is (significantly) increased (e.g. compared to a solvent control) following subcutaneous administration to the individual of a compound of any one of claims 1 to 62, or a pharmaceutically acceptable salt thereof.

64. 64. The method of any one of claims 1 to 63, wherein the individual's urinary sodium and / or urinary potassium (excretion) is increased by about 100% or more, 250% or more, 500% or more, 750% or more, 1000% or more, 1500% or more, or 2000% or more (e.g., compared to a vehicle control, such as within the first 4 hours of treatment) following subcutaneous administration to the individual of a compound of any one of claims 1 to 63, or a pharmaceutically acceptable salt thereof.

65. 65. The method of any one of claims 1 to 64, wherein the amount of ascites fluid in said individual is (significantly) reduced (e.g. compared to a solvent control) following subcutaneous administration to said individual of a compound of any one of claims 1 to 64, or a pharmaceutically acceptable salt thereof.

66. 66. The method of any one of claims 1 to 65, wherein the amount of ascites fluid in the individual is reduced by about 25% or more, 50% or more, 100% or more, about 200% or more, or about 300% or more (e.g., compared to a vehicle control, such as when measured 3 days after treatment) following subcutaneous administration to the individual of a compound of any one of claims 1 to 65, or a pharmaceutically acceptable salt thereof.

67. 67. The method of any one of claims 1 to 66, wherein the body weight of the individual is (significantly) reduced (e.g. compared to a solvent control) following subcutaneous administration to the individual of a compound of any one of claims 1 to 66, or a pharmaceutically acceptable salt thereof.

68. 68. The method of any one of claims 1 to 67, wherein the body weight of the individual is reduced by about 1% or more, 2.5% or more, 5% or more, or 10% or more (e.g., compared to a solvent control) following subcutaneous administration to the individual of a compound of any one of claims 1 to 67, or a pharmaceutically acceptable salt thereof.

69. 69. The method of any one of claims 1 to 68, wherein the individual's body weight is reduced by at least about 1%, at least about 2.5%, at least about 5%, or at least about 10% at least one day (e.g., three or more days (e.g., five days)) after subcutaneous administration of the compound of any one of claims 1 to 68, or a pharmaceutically acceptable salt thereof, to the individual.

70. 70. The method of any one of claims 1 to 69, wherein the mean arterial pressure (MAP) of the individual is increased (e.g., compared to a baseline measurement before treatment) following subcutaneous administration to the individual of a compound of any one of claims 1 to 69, or a pharmaceutically acceptable salt thereof.

71. 71. The method of any one of claims 1 to 70, wherein the individual's MAP is increased by about 1% to about 10% (e.g., compared to a baseline measurement before treatment) following administration to the individual of a compound of any one of claims 1 to 70, or a pharmaceutically acceptable salt thereof.

72. 72. The method of any one of claims 1 to 71, wherein the MAP of the individual is increased in a dose-dependent manner following administration to the individual of a compound of any one of claims 1 to 71, or a pharmaceutically acceptable salt thereof.

73. 73. The method of any one of claims 1 to 72, wherein (subcutaneous) administration to said individual of a compound of any one of claims 1 to 72, or a pharmaceutically acceptable salt thereof, improves systemic hemodynamics in said individual.

74. 74. The method of any one of claims 1 to 73, wherein (subcutaneous) administration to said individual of a compound according to any one of claims 1 to 73, or a pharmaceutically acceptable salt thereof, reduces water retention and / or fluid overload in said individual.

75. 75. The method of any one of claims 1 to 74, wherein the method comprises administering to the individual on a first day and a second day (e.g., the second day is one or more days after the first day) a compound of any one of claims 1 to 74, or a pharmaceutically acceptable salt thereof.

76. 76. The method of any one of claims 1 to 75, wherein the method further comprises administering (subcutaneously) to said individual a compound of any one of claims 1 to 75, or a pharmaceutically acceptable salt thereof, one or more days after said first day.

77. 77. The method of any one of claims 1 to 76, wherein the method comprises administering (subcutaneously) to the individual a compound of any one of claims 1 to 76, or a pharmaceutically acceptable salt thereof, daily for two or more days (e.g. after the first day).

78. 78. The method of any one of claims 1 to 77, wherein the method further comprises administering (subcutaneously) to the individual a compound of any one of claims 1 to 77, or a pharmaceutically acceptable salt thereof, on consecutive days after the first day.

79. 79. The method of any one of claims 1 to 78, wherein the method comprises administering (subcutaneously) to the individual a compound of any one of claims 1 to 78, or a pharmaceutically acceptable salt thereof, on multiple days.

80. 80. The method of any one of claims 1 to 79, wherein the individual receives repeated subcutaneous injections of a compound of any one of claims 1 to 79, or a pharmaceutically acceptable salt thereof.

81. 81. The method of any one of claims 1 to 80, wherein the method comprises subcutaneously administering to the individual a compound of any one of claims 1 to 80, or a pharmaceutically acceptable salt thereof, once or twice daily (e.g., on two or more consecutive days).

82. 82. The method of any one of claims 1 to 81, wherein the method comprises administering to the individual a compound of any one of claims 1 to 81, or a pharmaceutically acceptable salt thereof, by subcutaneous bolus injection.

83. 83. The method of any one of claims 1 to 82, wherein the method comprises administering to the individual by (e.g. continuous) subcutaneous infusion of a compound of any one of claims 1 to 82, or a pharmaceutically acceptable salt thereof.

84. 84. The method of any one of claims 1 to 83, wherein the method comprises administering (e.g., subcutaneously) to the individual a compound of any one of claims 1 to 83, or a pharmaceutically acceptable salt thereof, in an amount of from about 0.01 milligram (mg) per day to about 100 mg per day (e.g., from about 0.01 milligram (mg) per day to about 10 mg per day (e.g., from about 0.01 mg / day to about 1 mg / day)).

85. 85. The method of any one of claims 1 to 84, wherein the individual has end-stage liver disease (ESLD).

86. 86. The method of any one of claims 1 to 85, wherein the individual has ascites.

87. 87. The method of any one of claims 1 to 86, wherein the individual has refractory ascites.

88. 88. The method of any one of claims 1 to 87, wherein the individual develops (refractory) ascites as a complication of ESLD.

89. 89. The method of any one of claims 1-88, wherein the method further comprises decreasing serum creatinine (sCr) in the individual (e.g., compared to a pre-treatment baseline measurement).

90. 90. The method of any one of claims 1 to 89, wherein the method comprises administering to the individual a compound of any one of claims 1 to 89, or a pharmaceutically acceptable salt thereof, at least until the individual has an sCr value of 1.5 milligrams (mg) per deciliter (dL) or less.

91. 91. The method of any one of claims 1 to 90, wherein the individual has improved renal function after administration of the compound of any one of claims 1 to 90, or a pharmaceutically acceptable salt thereof.

92. 60. The method of any one of claims 1, 6, 22, 26-28, 58, and 59, wherein the method comprises any one of the elements of claims 2-5, 7-21, 23-25, 29-57, and 60-91.

93. A pharmaceutical composition comprising an effective amount of a compound, or a pharmaceutically acceptable salt thereof, wherein the compound is a mixed vasopressin receptor 1A (V1AR) agonist-antagonist, and the composition is formulated for subcutaneous administration.

94. The compound has the structure represented by Formula I: D1-L-D2 Formula I or a pharmaceutically acceptable salt thereof (In the formula, D1 is a vasopressin receptor 1A (V1AR) agonist; D2 is a V1AR antagonist; and L is a linker.

56. The composition of claim 55, having:

95. 57. The composition of claim 55 or 56, wherein the compound is Compound 1.

96. an effective amount of a compound having a structure represented by Formula I: D1-L-D2 Formula I or a pharmaceutically acceptable salt thereof (In the formula, D1 is a vasopressin receptor 1A (V1AR) agonist; D2 is a V1AR antagonist; and L is a linker. A pharmaceutical composition comprising: A pharmaceutical composition, wherein the composition is formulated for subcutaneous administration.

97. A pharmaceutical composition comprising an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, wherein the composition is formulated for subcutaneous administration.

98. 98. The composition of any one of claims 1 to 97, wherein the composition is suitable for systemic delivery of an active agent, such as Compound 1.

99. A compound having a structure represented by Formula I, or a pharmaceutically acceptable salt thereof: D1-L-D2 Formula I or a pharmaceutically acceptable salt thereof (In the formula, D1 is a vasopressin receptor 1A (V1AR) agonist; D2 is a V1AR antagonist; and L is a linker. Including, A subcutaneous formulation in which less than 50% of the compound of formula I is degraded (eg, subcutaneously).

100. A compound having a structure represented by Formula I, or a pharmaceutically acceptable salt thereof: D1-L-D2 Formula I or a pharmaceutically acceptable salt thereof (In the formula, D1 is a vasopressin receptor 1A (V1AR) agonist; D2 is a V1AR antagonist; and L is a linker. A subcutaneous formulation comprising: A subcutaneous formulation, wherein the formulation has a concentration of the compound of Formula I from about 0.1 mg / mL to about 100 mg / mL.

101. a. A compound having a structure represented by Formula I, or a pharmaceutically acceptable salt thereof: D1-L-D2 Formula I (In the formula, D1 is a vasopressin receptor 1A (V1AR) agonist; D2 is a V1AR antagonist; and L is a linker, and b. A subcutaneous formulation comprising a buffer at a concentration of about 1 millimolar (mM) to about 1 M.

102. 102. The subcutaneous formulation of any one of claims 99 to 101, further comprising a preservative.

103. a. A compound having a structure represented by Formula I, or a pharmaceutically acceptable salt thereof: D1-L-D2 Formula I (In the formula, D1 is a vasopressin receptor 1A (V1AR) agonist; D2 is a V1AR antagonist; and L is a linker, and b. Subcutaneous formulations containing preservatives.

104. a. A compound having a structure represented by Formula I, or a pharmaceutically acceptable salt thereof: D1-L-D2 Formula I (In the formula, D1 is a vasopressin receptor 1A (V1AR) agonist; D2 is a V1AR antagonist; and L is a linker, and b. A subcutaneous formulation containing a solubilizing agent.

105. 105. The subcutaneous formulation of any one of claims 99 to 104, further comprising a preservative (e.g., m-cresol) at a concentration of about 1 mg / mL to about 100 mg / mL.

106. 106. The subcutaneous formulation of any one of claims 99-105, further comprising a solubilizing agent (e.g., cyclodextrin) in an amount of about 1 mg / mL to about 250 mg / mL (e.g., about 60-80 mg / mL).

107. 107. The subcutaneous formulation of any one of claims 99 to 106, wherein the compound of formula I is not susceptible to degradation, such as in the subcutaneous layer of an individual to whom the formulation is administered subcutaneously.

108. 108. The subcutaneous formulation of any one of claims 99-107, wherein less than 50% of the compound of formula I degrades (e.g., in the vial and / or subcutaneously), such as over a period of about 1 or 2 days.

109. 109. The subcutaneous formulation of any one of claims 99-108, wherein the compound of formula I is present in the formulation at a concentration of from about 0.1 mg / mL to about 100 mg / mL.

110. 110. The subcutaneous formulation of any one of claims 99-109, wherein the compound of formula I is present in the formulation at a concentration of from about 1 mg / mL to about 50 mg / mL.

111. 110. The subcutaneous formulation of any one of claims 99-109, further comprising a buffering agent at a concentration of about 1 millimolar (mM) to about 1 M.

112. 112. The subcutaneous formulation of any one of claims 99 to 111, further comprising a buffering agent having a pKa of about 3.0 to about 6.0, such as at 25°C.

113. 113. The subcutaneous formulation of claim 111 or 112, wherein the buffering agent is selected from the group consisting of acetate, citrate, succinate, and phosphate.

114. 114. The subcutaneous formulation of any one of claims 99-113, having a pH sufficient to inhibit (e.g., inactivate or inactivate) proteases (e.g., trypsin), such as in the subcutaneous layer of an individual to whom the formulation is administered subcutaneously.

115. 115. The subcutaneous formulation of any one of claims 99 to 114, having a pH of about 4 to about 5 (e.g., 4.5).

116. 116. The subcutaneous formulation of any one of claims 99 to 115, having an ionic strength of about 5 mM to about 200 mM (e.g., about 10 mM to about 100 mM).

117. 117. The subcutaneous formulation of any one of claims 99 to 116, wherein the pH of the subcutaneous formulation does not (substantially) change when administered subcutaneously to an individual (e.g. by subcutaneous (bolus) injection or subcutaneous infusion).

118. 1. A system for treating end-stage liver disease (ESLD), comprising: (a) a composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof; and (b) a system comprising a device configured, when placed on the skin of an individual, to provide subcutaneous infusion of the composition into the individual.

119. The system of claim 118, wherein the system includes an adhesive for (e.g., reversibly) attaching the (subcutaneous injection) device to the surface of the skin of the individual.

120. 120. The system of claim 118 or 119, wherein the system comprises a chamber body and a hollow tube body, and the composition is configured within the chamber body.

121. The system of any one of claims 118 to 120, wherein the hollow tube body includes a first opening and a second opening.

122. The system of any one of claims 118 to 121, wherein the first opening is in fluid contact with the chamber body.

123. A system according to any one of claims 118 to 122, wherein the second opening is configured subcutaneously within the individual after the subcutaneous infusion device is attached to the skin of the individual.

124. 124. The system of any one of claims 118 to 123, wherein the (subcutaneous infusion) device further comprises a pump configured to subcutaneously infuse the composition into the individual at a constant or variable rate.

125. 125. The system of any one of claims 118 to 124, wherein the system is configured to provide (continuously) the composition to the individual for a period of about 24 hours or more.

126. 126. The system of any one of claims 118 to 125, wherein the device is configured to receive a vial and / or cartridge of the composition.

127. The system of any one of claims 118 to 126, wherein the device is a subcutaneous infusion device (e.g., a pump).

128. A system according to any one of claims 118 to 127, wherein the composition is a composition or formulation according to any one of claims 1 to 127.

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