Hybrid vasopressin receptor agonist-antagonist for treatment of end-stage liver disease and related complications thereof

Abstract

Provided herein are compositions, such as suitable for subcutaneous administration, and methods for treating ascites in a subject using a hybrid V1A receptor agonist-antagonist.

Description

[0001] Cross - Reference to Related Applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 378,014, filed on September 30, 2022, U.S. Provisional Application No. 63 / 432,976, filed on December 15, 2022, and U.S. Provisional Application No. 63 / 471,713, filed on June 7, 2023, each of which is hereby incorporated by reference in its entirety. Background Art

[0003] Complications of end - stage liver disease result in approximately one million deaths per year. Patients with end - stage liver disease often develop portal hypertension. Ascites represents the most common decompensated event and is associated with a high risk of developing additional complications including bacterial infection and acute kidney injury (AKI). Summary of the Invention

[0004] The management of decompensated cirrhosis typically involves the use of vasoconstrictors that are full vasopressin 1a receptor (V1AR) agonists. Full (vasopressin V2 receptor (V2R), V1AR) agonists reduce portal venous pressure by increasing splanchnic arteriolar vasoconstriction, thereby redistributing blood volume into the systemic circulation, which in turn can lead to an increase in glomerular filtration rate and improved renal perfusion. However, (non - selective) full (V2R, V1AR) agonists (e.g., those having only an agonist moiety without an antagonist moiety) may cause undesirable events such as undesirable systemic events like vasoconstriction leading to 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 leading to ischemia at the administration site; or both (e.g., when administered subcutaneously). Such events may preclude the use of such compounds in an outpatient setting (e.g., home use), such as limiting their use to intravenous administration and short - term application in a hospital setting under close expert monitoring (e.g., thus being unsuitable for chronic diseases and outpatient settings). In addition, given the risk profile of full (V2R, V1AR) agonists, careful titration and monitoring are generally required to prevent the occurrence of critical adverse events (AEs) (such as those related to tissue hypoxia and ischemia caused by excessive vasoconstriction).

[0005] In addition, it is difficult to increase the mean arterial pressure (MAP) by 10 - 15 mmHg (which is strongly associated with the reversal of HRS - AKI) using a (non - selective) full (V1AR, V2R) agonist such as vasopressin. In some cases, achieving and / or maintaining a 10 - 15 mmHg increase in MAP is the treatment goal of current therapies. Due to the pharmacokinetics of the vasopressin system and the very steep concentration - response curve, it may be more likely to be under - dosed (and lose clinical efficacy) or cause excessive vasoconstriction, which can lead to serious, potentially life - threatening adverse events (AEs). Secondly, individuals with decompensated cirrhosis may already have high endogenous vasopressin levels, which promote water retention through V2 - mediated antidiuresis. Clinical vasopressin agonists are primarily V2 agonists and secondarily act as V1a agonists at pharmacological concentrations. The inherent V2 activity may lead to an adverse event profile associated with fluid overload and respiratory complications of clinical vasopressin agonists.

[0006] In some embodiments, compounds selective for the V1a receptor (e.g., mixed agonist - antagonists) are provided herein. In some embodiments, the compounds achieve and maintain a (target) level of vasoconstriction and avoid fluid retention, such as through a uniform dosing profile. In some cases, the compounds have a reduced (critical) adverse event incidence and improved clinical efficacy (e.g., compared to clinical vasopressin agonists). In some cases, it is not necessary to titrate the compounds, such as to achieve a reduced (critical) adverse event incidence and improved clinical efficacy (e.g., compared to clinical vasopressin agonists). In some cases, the compounds described herein (e.g., mixed V1a agonist - antagonists) are administered at higher doses (compared to the necessary dose) and effectively achieve maximal efficacy. In contrast, administering a relatively high dose of a non - selective full (V2, V1a) agonist such as terlipressin may become toxic and lead to (critical) adverse events.

[0007] In some cases, after administering to an individual described herein a composition comprising a compound described herein (e.g., a mixed V1a agonist - antagonist such as Compound 1) by subcutaneous administration (e.g., subcutaneous infusion or subcutaneous (bolus) injection), the compound is delivered (e.g., systemically) to the individual. In some cases, after administering to an individual described herein a composition comprising a compound described herein (e.g., a mixed V1a agonist - antagonist such as Compound 1) by subcutaneous administration (e.g., subcutaneous infusion or subcutaneous (bolus) injection), the compound provides a systemic effect in the individual, such as the regulation of mean arterial pressure (MAP).

[0008] In some cases, the compounds described herein (e.g., mixed V1a agonist-antagonists such as Compound 1) are metabolized to full vasopressin agonists, such as when administered subcutaneously. In some cases, the formation of full vasopressin agonists is associated with a higher risk of adverse events in an individual, such as after subcutaneous (bolus) injection of a mixed V1a agonist-antagonist. In some cases, the adverse events are systemic events, local administration site events, or both. In some embodiments, the adverse events are associated with excessive vasoconstriction. In some cases, the full vasopressin agonists have partial activity (compared to the mixed V1a agonist-antagonists). In some cases, subcutaneous administration of the mixed V1a agonist-antagonists described herein (e.g., by subcutaneous (bolus) injection) provides an overproduction of full vasopressin agonists (e.g., in the subcutaneous space of an individual). The overproduction of full vasopressin agonists (e.g., in the subcutaneous space of an individual) is undesirable, for example because less of the parent compound (e.g., the mixed V1a agonist-antagonist described herein such as Compound 1) is delivered systemically, thereby increasing the risk of undesirable (systemic) events (e.g., toxicities associated with excessive (local and / or systemic) vasoconstriction) (such as caused by full agonism of the V1a receptor by the full vasopressin agonist). Additional challenges caused by the overproduction of full vasopressin agonists (e.g., in the subcutaneous space of an individual) after administration of the compositions described herein include reduced efficacy, increased side effects, and / or difficulty in controlling (e.g., titrating) to achieve efficacy. As Figure 32 shown, full agonism of one or more vasopressin receptors may induce critical side effects and / or may be lethal.

[0009] In some embodiments, methods and formulations are described herein for reducing the formation of a full vasopressin agonist (e.g., M1), such as following subcutaneous (bolus) injection of a mixed V1a agonist - antagonist (e.g., compound 1) described herein. In some embodiments, reducing the formation of a full vasopressin agonist (e.g., M1), such as following subcutaneous administration of a mixed V1a agonist - antagonist described herein, reduces the risk that an individual will experience an unwanted (systemic) event (e.g., toxicity associated with excessive (local and / or systemic) vasoconstriction) (such as caused by full agonism of the V1a receptor by the full vasopressin agonist). In some embodiments, reducing the formation of a full vasopressin agonist (e.g., M1), such as following subcutaneous administration of a mixed V1a agonist - antagonist described herein, increases the effectiveness of the treatment described herein (e.g., the mixed V1a agonist - antagonist), reduces side effects (e.g., associated with overproduction of the full agonist), and / or improves the efficacy control (e.g., titration) of the treatment described herein (e.g., the mixed V1a agonist - antagonist). 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 concentration). 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 concentration), such as in vitro and in vivo (e.g., following subcutaneous administration). 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 concentration), such as in vitro and in vivo (e.g., following subcutaneous administration). In some embodiments, such as when the composition described herein is administered at a relatively slow administration rate, subcutaneous infusion of a mixed V1a agonist - antagonist and increasing its concentration in the composition reduces metabolite (M1) formation (e.g., as measured systemically, such as by serum / plasma concentration), such as in vitro and in vivo (e.g., following subcutaneous administration). In some embodiments, any combination of subcutaneous infusion, increased buffer concentration of the composition, and increased drug concentration in the composition reduces metabolite (M1) formation following subcutaneous administration. In some embodiments, subcutaneous infusion of the compounds described herein, increasing the buffer concentration of the composition described herein, and / or increasing the drug concentration in the composition described herein improves the systemic delivery of the mixed agonist - antagonist described herein.

[0010] In some embodiments, the present disclosure provides compounds (e.g., mixed V1AR receptor agonists - 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 within a wide dose range (such as 10 μg / kg to 500 μg / kg).

[0011] In some embodiments, the present disclosure provides compounds (e.g., mixed V1a receptor agonists - antagonists such as Compound 1) that increase 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, such as a peak plateau of about +10 to +15 mmHg (e.g., even at doses as high as 100 to 500 μg / kg). In contrast, administration of a fully non - selective (V2, V1a) receptor agonist (such as terlipressin) described herein at a similarly high dose provides a significantly higher increase in MAP, such as well beyond the therapeutic window of +10 to +15 mmHg. Such a large increase in MAP can significantly increase the likelihood of (critical) side effects (in the treated individual).

[0012] In some embodiments, the compounds described herein (e.g., mixed V1AR receptor agonists - antagonists such as Compound 1) reach a therapeutic ceiling (e.g., when administered subcutaneously) such that even after increasing the dose of the compound (e.g., to a dose as high as 100 to 500 μg / kg), the effect (e.g., increasing MAP) is not (significantly) altered (e.g., increased or decreased).

[0013] In some cases, increasing the dose of the compounds described herein (e.g., fully non - selective (V2R, V1AR) receptor agonists such as terlipressin) does provide a (significant) change (e.g., increase) in the effect (e.g., MAP). In some cases, increasing the dose of the compounds described herein (e.g., fully non - selective (V2, V1AR) receptor agonists such as terlipressin) continues to push the effect (e.g., MAP) to levels that may be harmful and / or may cause (severe) side effects in the individual receiving the compound.

[0014] In some cases, increasing the dose of the hybrid V1a agonist-antagonist described herein (such as Compound 1) does not continue to increase the MAP of an individual (e.g., even at doses up to 100 to 500 μg / kg), while increasing the dose of a fully non-selective (V2, V1a) agonist (such as terlipressin) does continue to increase the MAP of an individual. In some cases, the hybrid agonist-antagonist described herein (such as Compound 1) can be safely administered subcutaneously to treat ESLD or its symptoms and / or complications, such as without the individual experiencing (critical) side effects and / or the risk of an effect (such as MAP) developing to a dangerous or harmful level. In some cases, the therapeutic window (and safety profile) of the hybrid V1AR agonist-antagonist described herein (such as Compound 1) is significantly improved compared to a V1AR agonist (e.g., which does not contain a separate V1AR antagonist moiety) (such as terlipressin).

[0015] In some embodiments, the compounds described herein have an agonist moiety (e.g., D1). In some embodiments, the compounds described herein have an antagonist moiety (e.g., D2). In some embodiments, the compounds described herein have an agonist moiety (e.g., D1) and an antagonist moiety (e.g., D2). In some embodiments, the antagonist moiety (e.g., D2) has no (agonist) activity or has significantly lower (agonist) activity than the agonist moiety (e.g., D1), such as having at least about 1.5x lower agonist activity than the agonist moiety (e.g., D1), at least about 2x lower agonist activity than the agonist moiety (e.g., D1), at least about 3x lower agonist activity than the agonist moiety (e.g., D1), 5x lower agonist activity than the agonist moiety (e.g., D1), at least about 10x lower agonist activity than the agonist moiety (e.g., D1), or at least about 100x lower agonist activity than the agonist moiety (e.g., D1). In some embodiments, the agonism and / or antagonism is agonism and / or antagonism of V1AR.

[0016] 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, administration (subcutaneously) of the compounds described herein (e.g., mixed V1a agonist - antagonists such as Compound 1) is non - toxic (at therapeutic levels), e.g., even at doses up to 100 to 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, such as at therapeutic doses. In some embodiments, the compounds described herein (e.g., mixed V1a agonist - antagonists such as Compound 1) are suitable for subcutaneous administration. In some embodiments, the compounds described herein (e.g., mixed V1a agonist - antagonists such as Compound 1) increase the mean arterial pressure (MAP) of an individual receiving one or more (subcutaneously administered) doses of the compound. In some embodiments, the compounds described herein (e.g., mixed V1a agonist - antagonists such as Compound 1) decrease the portal venous pressure (PP) of an individual receiving one or more (subcutaneously administered) doses of the compound. In some embodiments, the compounds described herein (e.g., mixed V1a agonist - antagonists such as Compound 1) increase the MAP and decrease the PP of an individual receiving one or more (subcutaneously administered) doses of the compound. In some embodiments, such as after subcutaneous administration of the compounds described herein (e.g., mixed V1a agonist - antagonists such as Compound 1), the change in MAP tends to plateau or reach a therapeutic maximum after a period of time (e.g., after about 10 minutes). In some cases, such as after subcutaneous administration of the compounds described herein (e.g., full non - selective (V2, V1a) agonists such as terlipressin), the MAP rapidly increases and reaches a peak after a period of time (e.g., after about 20 minutes). In some embodiments, such as after subcutaneous administration of the compounds described herein (e.g., mixed V1a agonist - antagonists such as Compound 1), the change in PP tends to plateau. In some embodiments, such as after subcutaneous administration of the compounds described herein (e.g., mixed V1a agonist - antagonists such as Compound 1), the changes in MAP and PP tend to plateau or reach a therapeutic maximum after a period of time (e.g., after about 10 minutes).

[0017] 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 reducing portal venous pressure and improving renal excretion of excess sodium and water (e.g., thereby reducing the need for paracentesis and improving the quality of life of the patient).

[0018] 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 pooling of blood in the splanchnic circulation, leakage of fluid into the abdomen and surrounding organs (ascites), and a decrease in arterial pressure. In some cases, such as in decompensated cirrhosis, these hemodynamic changes can lead to systemic complications including ascites, such as refractory ascites.

[0019] In some cases, the treatment paradigm focuses on restoring blood pressure, portal pressure, and splanchnic pressure to levels that will restore renal function. In some cases, treatment success is measured by increasing the mean arterial pressure (MAP) by 10 to 20 mmHg relative to baseline at presentation (e.g., because this is associated with improved renal function and / or hemodynamic parameters). Unfortunately, available vasoactive agents have limited efficacy or pose critical risks of excessive vasoconstriction, fluid overload, or critical respiratory adverse events.

[0020] In some cases, the compounds described herein (e.g., Compound 1) are vasoconstrictors that selectively target the vasopressin V1a molecule as a mixed agonist - antagonist. In some cases, the agonist domain of the compounds described herein (e.g., Compound 1) causes vasoconstriction of the desired splanchnic vasculature (e.g., thereby reducing portal blood flow and pressure and / or improving the individual's systemic hemodynamics). In some cases, the antagonist domain of the compounds described herein (e.g., Compound 1) prevents full activation of the V1a - mediated vasoconstrictor effects that drive safety concerns with other agents. In some cases, such as at therapeutic concentrations, the compounds described herein (e.g., Compound 1) do not activate the vasopressin V2 receptor (e.g., which causes unwanted water retention).

[0021] In some embodiments, the compounds described herein (e.g., mixed V1A agonist - antagonists such as Compound 1) can be used to treat ESLD (or manifestations thereof), decompensated cirrhosis, and / or its complications (or symptoms) such as resistant ascites, refractory ascites, or post - paracentesis induced circulatory dysfunction.

[0022] In some cases, the hybrid V1A agonist-antagonist provided herein is used to treat an individual (e.g., in need thereof) with ESLD or its complications (e.g., refractory ascites). In some cases, the hybrid V1A agonist-antagonist provided herein is used to treat an individual (e.g., in need thereof) with ESLD or its complications (e.g., refractory ascites) without (significant) injection site reactions (e.g., local vasoconstriction), such as at the subcutaneous injection site. In some cases, the hybrid V1A agonist-antagonist is suitable for systemic delivery, such as provided that the agonist-antagonist properties of the hybrid V1A agonist-antagonist prevent (significant) injection site reactions (e.g., local vasoconstriction), such as at the subcutaneous injection site. In some cases, the hybrid V1A agonist-antagonist provided herein does not have (functional) vasopressin 2 (V2) receptor activity, such as at therapeutic concentrations. In some embodiments, the hybrid V1A receptor agonist-antagonist is Compound 1.

[0023] 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, prolonging life, such as by treating its associated symptoms and / or complications (e.g., ascites and hepatic decompensation events).

[0024] In some cases, the hybrid V1A agonist-antagonist provided herein increases mean arterial pressure (MAP). In some cases, the hybrid V1A agonist-antagonist provided herein increases MAP without (significant) injection site reactions (e.g., local vasoconstriction), such as at the subcutaneous injection site.

[0025] In some cases, the hybrid V1A agonist-antagonist provided herein reduces portal venous pressure, such as by increasing splanchnic arteriolar vasoconstriction.

[0026] In some embodiments, the hybrid V1A agonist-antagonist provided herein is used to treat complications of ESLD (e.g., cirrhotic portal hypertension), such as ascites (e.g., ascites refractory to treatment). In some embodiments, the hybrid V1A agonist-antagonist provided herein is used to treat complications of ESLD (e.g., cirrhotic portal hypertension), such as refractory ascites.

[0027] In some embodiments, Compound 1 is used to treat complications of ESLD (e.g., cirrhotic portal hypertension), such as ascites. In some embodiments, Compound 1 is used to treat complications of ESLD (e.g., cirrhotic portal hypertension), such as refractory ascites.

[0028] In some instances, the hybrid V1A agonist-antagonists provided herein (e.g., compound 1) provide a significantly improved therapeutic index (e.g., caused by lower maximal vasoconstrictor effects and lower risk of tissue hypoxia), such as when compared to a completely non-selective (V2, V1A) receptor agonist. In some instances, the hybrid V1A agonist-antagonists provided herein (e.g., compound 1) provide approximately half of the maximal vasoconstriction produced by a full agonist, such as without any accompanying signs of ischemia. In some instances, the hybrid V1A agonist-antagonists provided herein (e.g., compound 1) (such as when administered subcutaneously) are (clinically) effective vasoconstrictors, such as having low to no local toxicity. In some instances, the hybrid V1A agonist-antagonists provided herein (e.g., compound 1) are (clinically) effective vasoconstrictors (e.g., having a favorable benefit / risk profile (e.g., when administered subcutaneously), such as having low to no local toxicity). In some instances, the hybrid V1A agonist-antagonists provided herein (e.g., compound 1) provide sufficient splanchnic vasoconstriction to reduce elevated portal venous pressure while minimizing the risk of excessive vasoconstriction in other vascular beds with associated adverse events (such as mesenteric ischemia).

[0029] In some embodiments, provided herein are methods of treating end-stage liver disease (ESLD) or its signs or symptoms (e.g., complications) in an individual (e.g., in need thereof), the methods comprising subcutaneously administering to the individual (e.g., in need thereof) a (therapeutically) effective amount of a compound that is a hybrid vasopressin receptor 1A (V1AR) agonist-antagonist.

[0030] In some embodiments, provided herein are methods of treating end-stage liver disease (ESLD) or its symptoms (e.g., complications) in an individual (e.g., in need thereof), the methods comprising subcutaneously infusing into the individual (e.g., in need thereof) a composition comprising a (therapeutically) effective amount of a compound that is a hybrid vasopressin receptor 1A (V1AR) agonist-antagonist.

[0031] In some embodiments, provided herein are methods of treating end-stage liver disease (ESLD) or its symptoms (e.g., complications) in an individual (e.g., in need thereof), the methods comprising subcutaneously injecting into the individual (e.g., in need thereof) a composition comprising a (therapeutically) effective amount of a compound that is a hybrid vasopressin receptor 1A (V1AR) agonist-antagonist.

[0032] In some embodiments, the hybrid vasopressin receptor 1A (V1AR) agonist-antagonist is more selective for V1AR than for V2R. In some embodiments, the hybrid vasopressin receptor 1A (V1AR) agonist-antagonist has no V2R activity, such as at therapeutic concentrations.

[0033] In some embodiments, the compound comprises a first moiety having agonist activity and a second moiety having antagonist activity.

[0034] In some embodiments, the modulation of the mean arterial pressure (MAP) of an individual comprises increasing the MAP by at least 5% relative to baseline. In some embodiments, the modulation of the mean arterial pressure (MAP) of an individual comprises increasing the MAP by at least 5 mmHg (e.g., 5 mmHg or more or 10 mmHg or more) relative to baseline.

[0035] In some embodiments, the compound has a structure represented by Formula I:

[0036] D1-L-D2

[0037] Formula I

[0038] or a pharmaceutically acceptable salt thereof,

[0039] wherein:

[0040] D1 is a vasopressin receptor 1A (V1AR) agonist;

[0041] D2 is a V1AR antagonist; and

[0042] L is a linker.

[0043] In some embodiments, provided herein is a method of treating end-stage liver disease (ESLD) or its signs or symptoms (e.g., complications) in an individual (e.g., in need thereof), the method comprising subcutaneously administering to the individual (e.g., in need thereof) a therapeutically effective amount of a compound having a structure represented by Formula I:

[0044] D1-L-D2

[0045] Formula I

[0046] or a pharmaceutically acceptable salt thereof,

[0047] wherein:

[0048] D1 is a vasopressin receptor 1A (V1AR) agonist;

[0049] D2 is a V1AR antagonist; and

[0050] L is a linker.

[0051] In some embodiments, provided herein is a method of treating end-stage liver disease (ESLD) or its signs or symptoms (e.g., complications) in an individual (e.g., in need thereof), the method comprising subcutaneously infusing into the individual (e.g., in need thereof) a composition comprising a therapeutically effective amount of a compound having a structure represented by Formula I:

[0052] D1-L-D2

[0053] Formula I

[0054] or a pharmaceutically acceptable salt thereof,

[0055] wherein:

[0056] D1 is a vasopressin receptor 1A (V1AR) agonist;

[0057] D2 is a V1AR antagonist; and

[0058] L is a linker.

[0059] In some embodiments, D1 is more selective for V1AR than for V2R.

[0060] In some embodiments, D1 is or comprises (e.g., cyclic) peptide. In some embodiments, D1 is or comprises a cyclic nonapeptide. In some embodiments, D1 has or comprises the following structure:

[0061]

[0062] In some embodiments, D1 has or comprises the following structure:

[0063]

[0064] In some embodiments, D2 is or comprises (e.g., linear) peptide. In some embodiments, D2 is a linear polypeptide comprising about seven or more amino acid residues. In some embodiments, D2 has or comprises the following structure:

[0065]

[0066] In some embodiments, D2 has or comprises the following structure:

[0067]

[0068] 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, a substituted or unsubstituted alkyl, or a 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., alkylamine), each substituent independently selected from the group consisting of oxo, amino, and substituted heteroalkyl (e.g., 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 or comprises the following structure:

[0069]

[0070] In some embodiments, L has or comprises the following structure:

[0071]

[0072] In some embodiments, the compound is Compound 1 or a pharmaceutically acceptable salt thereof.

[0073] In some embodiments, provided herein is a method of treating end-stage liver disease (ESLD) or a sign or symptom thereof (e.g., a complication) in an individual (e.g., in need thereof), the method comprising subcutaneously administering to the individual (e.g., in need thereof) a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof.

[0074] In some embodiments, provided herein is a method of treating end-stage liver disease (ESLD) or a sign or symptom thereof (e.g., a complication) in an individual (e.g., in need thereof), the method comprising subcutaneously infusing into the individual (e.g., in need thereof) a composition comprising a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof.

[0075] 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, the method comprising subcutaneously infusing into the individual in need thereof a composition comprising a compound having a structure represented by Formula I or a pharmaceutically acceptable salt thereof.

[0076] In some embodiments, the composition further comprises a liquid vehicle or solvent (e.g., water or an aqueous vehicle).

[0077] In some embodiments, the method further includes attaching a subcutaneous infusion device to the skin of an individual, the subcutaneous infusion device including a cavity and a hollow tube, the composition being configured within the cavity, the hollow tube including a first opening and a second opening, the first opening being in fluid communication with the cavity, and after attaching the subcutaneous infusion device to the skin, the second opening being subcutaneously disposed within the individual.

[0078] In some embodiments, the subcutaneous infusion device further includes a pump configured to infuse the composition subcutaneously into the individual at a constant or varying rate.

[0079] In some embodiments, relative to subcutaneous (bolus) injection, infusing the composition subcutaneously into the individual improves tolerance (e.g., based on a reduction in M1 overproduction, such as subcutaneous). In some embodiments, infusing the composition subcutaneously into the individual reduces undesired systemic events (e.g., undesired vasoconstriction, such as leading to ischemia), reduces undesired site-of-administration events (e.g., local site vasoconstriction, such as leading to site-of-administration ischemia), or both.

[0080] In some embodiments, provided herein is a method of treating end-stage liver disease (ESLD) in an individual in need thereof, the method including subcutaneously infusing into 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 degrades (e.g., subcutaneously).

[0081] In some embodiments, provided herein is a method of treating end-stage liver disease (ESLD) in an individual in need thereof, the method including subcutaneously injecting into 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 degrades (e.g., subcutaneously).

[0082] In some embodiments, such as when administering the composition 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, such as when administering the composition 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, such as when administering the composition 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, such as when administering the composition 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, such as when administering the composition by subcutaneous infusion to an individual, less M1 is formed relative to the administration of an otherwise identical composition administered by subcutaneous (bolus) injection. In some embodiments, such as when administering the composition by subcutaneous infusion to an individual, less M1 is formed systemically relative to the administration of an otherwise identical composition administered by subcutaneous (bolus) injection. In some embodiments, such as when administering the composition by subcutaneous infusion to an individual, less M1 is formed locally (at the injection / infusion site) relative to the administration of an otherwise identical composition administered by subcutaneous (bolus) injection.

[0083] In some embodiments, the composition is continuously subcutaneously infused into an individual for at least one hour. In some embodiments, the composition is subcutaneously infused into an individual at a rate of about 0.005 milliliters per hour (mL / h) to about 1 mL / h for the duration of the administration period.

[0084] In some embodiments, the compound is administered to an individual (e.g., continuously) in an amount of about 0.001 milligrams (mg) to about 100 mg, such as over a period of one or more days.

[0085] 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.

[0086] 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.

[0087] In some embodiments, the composition further comprises a preservative. In some embodiments, the preservative is present in an amount of about 1 mg / mL to about 20 mg / mL.

[0088] In some embodiments, the composition further comprises a solubilizer. In some embodiments, the solubilizer is present in an amount of about 1 mg / mL to about 100 mg / mL (e.g., about 60 - 80 mg / mL).

[0089] In some embodiments, the composition comprises a buffer. In some embodiments, the buffer is selected from the group consisting of acetate buffer, succinate buffer, and citrate buffer. In some embodiments, the composition comprises a buffer at a concentration of about 1 millimolar (mM) to about 1 molar (M). In some embodiments, the composition comprises a buffer at a concentration of about 5 mM to about 250 mM. In some embodiments, the composition comprises a buffer at a concentration of about 5 mM to about 25 mM. In some embodiments, the composition comprises a buffer at a concentration of about 50 mM to about 250 mM.

[0090] 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.

[0091] In some embodiments, after subcutaneous administration of the compound or a pharmaceutically acceptable salt thereof described herein to an individual (e.g., within the first 24 hours, such as within the first 4 hours), the urine volume of the individual (significantly) increases (e.g., compared to a vehicle control). In some embodiments, after subcutaneous administration of the compound or a pharmaceutically acceptable salt thereof described herein to an individual, the urine volume of the individual increases 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 vehicle control). In some embodiments, at least one day (e.g., 3 days or longer) after subcutaneous administration of the compound or a pharmaceutically acceptable salt thereof described herein to an individual, the urine volume of the individual is about 50% or more or 100% or more higher.

[0092] In some embodiments, the parameters described herein, such as urine volume, are measured at the time described in the examples (such as 4 hours or more after administration of the compound described herein to an individual).

[0093] In some embodiments, after subcutaneous administration of the compound or a pharmaceutically acceptable salt thereof described herein to an individual, the urinary sodium (excretion) of the individual (significantly) increases (e.g., compared to a vehicle control). In some embodiments, after subcutaneous administration of the compound or a pharmaceutically acceptable salt thereof described herein to an individual, the urinary sodium and / or urinary potassium (excretion) of the individual increases 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).

[0094] In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the amount of ascites in the individual is (significantly) reduced (e.g., compared to a vehicle control). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the amount of ascites 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).

[0095] In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the body weight of the individual is (significantly) reduced (e.g., compared to a vehicle control). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the body weight of the individual is reduced by about 1% or more, 2.5% or more, 5% or more, or about 10% or more (e.g., compared to a vehicle control). In some embodiments, at least one day (e.g., 3 days or longer (e.g., 5 days)) after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the body weight of the individual is reduced by at least about 1%, at least about 2.5%, at least about 5%, or at least about 10%.

[0096] In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the mean arterial pressure (MAP) of the individual is increased (e.g., compared to a baseline measurement before treatment). In some embodiments, after administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the MAP of the individual is increased by about 1% to about 10% (e.g., compared to a baseline measurement before treatment). In some embodiments, after administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the MAP of the individual increases in a dose-dependent manner.

[0097] In some embodiments, after administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the diastolic blood pressure of the individual is increased (e.g., compared to a baseline measurement before treatment).

[0098] In some embodiments, after administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the systolic blood pressure of the individual is increased (e.g., compared to a baseline measurement before treatment).

[0099] In some embodiments, after administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the diastolic blood pressure and / or the systolic blood pressure of the individual increases in a dose-dependent manner.

[0100] In some embodiments, after administering a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the pulse rate and / or peripheral blood flow of the individual decreases.

[0101] In some embodiments, administering (subcutaneously) a compound or a pharmaceutically acceptable salt thereof described herein to an individual improves the systemic hemodynamics of the individual.

[0102] In some embodiments, administering (subcutaneously) a compound or a pharmaceutically acceptable salt thereof described herein to an individual reduces fluid retention and / or overload in the individual.

[0103] In some embodiments, the method includes administering a compound or a pharmaceutically acceptable salt thereof described herein to an individual on the first day and the second day (e.g., the second day is one or more days after the first day). In some embodiments, the method further includes administering (subcutaneously) a compound or a pharmaceutically acceptable salt thereof described herein to an individual one or more days after the first day. In some embodiments, the method includes administering (subcutaneously) a compound or a pharmaceutically acceptable salt thereof described herein to an individual daily for two or more days (e.g., after the first day). In some embodiments, the method further includes administering (subcutaneously) a compound or a compound or a pharmaceutically acceptable salt thereof described herein to an individual on consecutive days after the first day. In some embodiments, the method includes administering (subcutaneously) a compound or a pharmaceutically acceptable salt thereof described herein to an individual for multiple days.

[0104] In some embodiments, the compound or a pharmaceutically acceptable salt thereof described herein is administered subcutaneously to an individual multiple times, such as over a period of several days. In some embodiments, the compound is administered continuously to an individual, such as over a period of several days.

[0105] In some embodiments, the individual receives repeated subcutaneous injections of a compound or a pharmaceutically acceptable salt thereof described herein.

[0106] In some embodiments, the method includes administering (subcutaneously) a compound or a pharmaceutically acceptable salt thereof described herein to an individual once or twice daily (e.g., for two or more consecutive days).

[0107] In some embodiments, the method will include administering (by bolus injection) a compound or a pharmaceutically acceptable salt thereof described herein to an individual, such as where the compound is administered to the individual as a single dose (e.g., all at once).

[0108] In some embodiments, the method includes administering (subcutaneously) a compound or a pharmaceutically acceptable salt thereof described herein to an individual by subcutaneous infusion. In some embodiments, the method includes administering (subcutaneously) a compound or a pharmaceutically acceptable salt thereof described herein to an individual by continuous subcutaneous infusion.

[0109] In some embodiments, the method comprises administering to an individual (e.g., subcutaneously) a compound or a pharmaceutically acceptable salt thereof described herein in an amount of from about 0.01 milligram (mg) / day to about 100 mg / day (e.g., from about 0.01 mg / day to about 10 mg / day (e.g., from about 0.01 mg / day to about 1 mg / day)).

[0110] In some embodiments, the individual has end-stage liver disease (ESLD).

[0111] In some embodiments, the individual has ascites. In some embodiments, the individual has refractory ascites.

[0112] In some embodiments, the individual has developed (refractory) ascites as a complication of ESLD.

[0113] In some embodiments, the method further comprises reducing the serum creatinine (sCr) (value) of the individual (e.g., compared to a pre-treatment baseline measurement). In some embodiments, the method comprises administering to the individual a compound or a pharmaceutically acceptable salt thereof described herein, at least until the individual has an sCr value of 1.5 milligrams (mg) / deciliter (dL) or less. In some embodiments, a compound or a pharmaceutically acceptable salt thereof described herein (e.g., Compound 1) is administered to the individual (e.g., as described herein) (e.g., subcutaneously), at least until the sCr value of the individual returns to normal (e.g., baseline).

[0114] In some embodiments, after administering a compound described herein, such as after completion of a treatment regimen, the individual has an improvement in renal function.

[0115] In some embodiments, provided herein is 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.

[0116] In some embodiments, the compound has a structure represented by Formula I:

[0117] D1-L-D2

[0118] Formula I

[0119] or a pharmaceutically acceptable salt thereof,

[0120] wherein:

[0121] D1 is a vasopressin receptor 1A (V1AR) agonist;

[0122] D2 is a V1AR antagonist; and

[0123] L is a linker.

[0124] In some embodiments, the compound is Compound 1.

[0125] In some embodiments, provided herein is a pharmaceutical composition comprising an effective amount of a compound having a structure represented by Formula I:

[0126] D1-L-D2

[0127] Formula I

[0128] or a pharmaceutically acceptable salt thereof,

[0129] wherein:

[0130] D1 is a vasopressin receptor 1A (V1AR) agonist;

[0131] D2 is a V1AR antagonist; and

[0132] L is a linker,

[0133] 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.

[0134] In some embodiments, the composition is suitable for an administration route other than intravenous administration, such as subcutaneous administration.

[0135] In some embodiments, the composition is suitable for systemic delivery of an active agent, such as Compound 1.

[0136] In some embodiments, provided is a pharmaceutical composition comprising an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof, and the composition is formulated for subcutaneous administration.

[0137] In some embodiments, the compound is Compound 1.

[0138] In some embodiments, the composition is suitable for systemic delivery of an active agent, such as Compound 1.

[0139] In some embodiments, provided herein is a subcutaneous formulation 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).

[0140] In some embodiments, provided herein is a subcutaneous formulation comprising a compound having a structure represented by Formula I or a pharmaceutically acceptable salt thereof, and the formulation has a concentration of the compound of Formula I of about 0.1 mg / mL to about 100 mg / mL.

[0141] In some embodiments, provided herein are subcutaneous formulations that comprise a compound having a structure represented by Formula I or a pharmaceutically acceptable salt thereof and a buffer at a concentration of from about 1 millimolar (mM) to about 1 M.

[0142] In some embodiments, the formulation comprises a buffer at a concentration of from about 1 mM to about 1 M. In some embodiments, the buffer has a pKa of from about 3.0 to about 6.0, such as at 25 °C. In some embodiments, the buffer is selected from the group consisting of acetate, citrate, succinate, and phosphate.

[0143] In some embodiments, the formulation has a pH sufficient to inhibit a protease (e.g., trypsin) (e.g., inactivate or deactivate it), 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 from about 4 to about 5 (e.g., about 4.5).

[0144] In some embodiments, when administered subcutaneously to an individual (e.g., by subcutaneous (bolus) injection or subcutaneous infusion), the pH of the subcutaneous formulation does not change (significantly).

[0145] In some embodiments, the formulation has an ionic strength of from about 5 mM to about 200 mM (e.g., from about 10 mM to about 100 mM).

[0146] In some embodiments, the subcutaneous formulation further comprises a preservative.

[0147] In some embodiments, provided herein are subcutaneous formulations that comprise a compound having a structure represented by Formula I or a pharmaceutically acceptable salt thereof and a preservative.

[0148] In some embodiments, the preservative is any suitable preservative, such as m-cresol. In some embodiments, the formulation comprises the preservative (e.g., m-cresol) at a concentration of from about 1 mg / mL to about 100 mg / mL.

[0149] In some embodiments, provided herein are subcutaneous formulations that comprise a compound having a structure represented by Formula I or a pharmaceutically acceptable salt thereof and a solubilizer.

[0150] In some embodiments, the solubilizer is any suitable solubilizer, such as cyclodextrin. In some embodiments, the formulation comprises the solubilizer (e.g., cyclodextrin) at a concentration of from about 1 mg / mL to about 100 mg / mL (e.g., about 60 - 80 mg / mL).

[0151] In some embodiments, the compound of Formula I is less prone to degradation, such as in the subcutaneous layer of an individual to whom the formulation is administered subcutaneously.

[0152] In some embodiments, less than 50% of the compound of formula I degrades (e.g., in a vial and / or subcutaneously), such as over a period of about one day or more (e.g., about one day, about two days, or longer).

[0153] 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.

[0154] In some instances, the dual V1A agonist - antagonist provided herein (e.g., compound 1) is administered in the form of an acetate salt.

[0155] In some instances, the dual V1A agonist - antagonist provided herein (e.g., compound 1) is administered in a form described in any of the examples provided herein (such as any one of Examples 1 - 6).

[0156] In some embodiments, provided herein is a system for treating end - stage liver disease (ESLD), the system comprising a composition that includes 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 the device is positioned on the skin of the individual.

[0157] In some embodiments, the system includes an adhesive body for (subcutaneously) securing the device to the skin surface of the individual (e.g., reversibly). In some embodiments, the system includes a cavity and a hollow tube body, and the composition is configured within the cavity. In some embodiments, the hollow tube body includes a first opening and a second opening. In some embodiments, the first opening is in fluid communication with the cavity. In some embodiments, after the subcutaneous infusion device is secured to the skin of the individual, the second opening is subcutaneously disposed within the individual.

[0158] In some embodiments, the (subcutaneous infusion) device further includes a pump configured to subcutaneously infuse the composition to the individual at a constant or varying rate.

[0159] In some embodiments, the system is configured to continuously provide the composition to the individual over a period of about 24 hours or more.

[0160] In some embodiments, the device is configured to receive a vial and / or a cartridge of the composition.

[0161] In some embodiments, the device is a subcutaneous infusion device (e.g., a pump). BRIEF DESCRIPTION OF THE DRAWINGS

[0162] 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 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 "Figure" and "FIG."):

[0163] Figure 1 Shows the study design described in Example 1 for each subject in Phase 1 (intravenous infusion) and Phase 2 (subcutaneous injection).

[0164] Figure 2 Shows the time course of compound 1 concentration after intravenous administration, Phase 1.

[0165] Figure 3A Shows the time course of compound 1 concentration after the first subcutaneous administration, Phase 2.

[0166] Figure 3B Shows the time course of compound 1 concentration after the fifth subcutaneous administration, Phase 2.

[0167] Figure 4A Shows the diastolic blood pressure (mean) of the intravenous infusion.

[0168] Figure 4B Shows the diastolic blood pressure (percent mean change) of the intravenous infusion.

[0169] Figure 5A Shows the diastolic blood pressure (mean) of the repeated subcutaneous injections.

[0170] Figure 5B Shows the diastolic blood pressure (percent mean change) of the repeated subcutaneous injections.

[0171] Figure 6A Shows the systolic blood pressure (mean) of the intravenous infusion.

[0172] Figure 6B Shows the systolic blood pressure (percent mean change) of the intravenous infusion.

[0173] Figure 7A Shows the systolic blood pressure (mean) of the subcutaneous injection.

[0174] Figure 7B Shows the systolic blood pressure (percent mean change) of the subcutaneous injection.

[0175] Figure 8A Shows the change in mean arterial pressure over time (percent mean change in mean arterial pressure relative to baseline after intravenous infusion).

[0176] Figure 8BShows the change in mean arterial pressure over time (mean percentage change in mean arterial pressure relative to baseline after repeated subcutaneous injections).

[0177] Figure 9A Shows the pulse rate (mean value) after intravenous infusion.

[0178] Figure 9B Shows the pulse rate (mean percentage change) after intravenous infusion.

[0179] Figure 10A Shows the pulse rate (mean value) after subcutaneous injection.

[0180] Figure 10B Shows the pulse rate (mean percentage change) after subcutaneous injection.

[0181] Figure 11 Shows the amount of Compound 1 excreted intact in urine after intravenous infusion.

[0182] Figure 12A Shows the amount of Compound 1 excreted after the 1st subcutaneous injection.

[0183] Figure 12B Shows the amount of Compound 1 excreted after the 5th subcutaneous injection.

[0184] Figure 13A Shows the average plasma concentration of metabolite M1 after the 1st subcutaneous injection of Compound 1.

[0185] Figure 13B Shows the average plasma concentration of metabolite M1 after the 5th subcutaneous injection of Compound 1.

[0186] Figure 14 Shows the structure of M1 (circled) relative to Compound 1.

[0187] Figure 15 Shows the time course of urine volume after subcutaneous administration of Compound 1.

[0188] Figure 16 Shows the time course of urinary sodium excretion after subcutaneous administration of Compound 1.

[0189] Figure 17 Shows the time course of body weight after subcutaneous administration of Compound 1.

[0190] Figure 18 Shows the time course of urine volume after intravenous administration of Compound 1.

[0191] Figure 19 Shows the time course of urinary sodium excretion after intravenous administration of Compound 1.

[0192] Figure 20 Shows the time course of glomerular filtration rate after intravenous administration of Compound 1.

[0193] Figure 21 Shows the time course of portal vein pressure after intravenous administration of Compound 1.

[0194] Figure 22 Shows the time course of cardiac output after intravenous administration of Compound 1.

[0195] Figure 23 Shows the time course of mean arterial pressure after intravenous administration of Compound 1.

[0196] Figure 24 Shows the time course of systemic vascular resistance after intravenous administration of Compound 1.

[0197] Figure 25 Shows the effect on body weight after subcutaneous administration of Compound 1.

[0198] Figure 26A Shows the effect on urine volume measured 4 hours after subcutaneous administration of Compound 1.

[0199] Figure 26B Shows the effect on urine volume measured 5 to 24 hours after subcutaneous administration of Compound 1.

[0200] Figure 26C Shows the effect on urine volume measured 24 hours after subcutaneous administration of Compound 1.

[0201] Figure 27 Shows the effect on net fluid balance measured 24 hours after subcutaneous administration of Compound 1.

[0202] Figure 28A Shows the effect on urinary sodium measured 4 hours after subcutaneous administration of Compound 1.

[0203] Figure 28B Shows the effect on urinary sodium measured 5 to 24 hours after subcutaneous administration of Compound 1.

[0204] Figure 28C Shows the effect on urinary potassium measured 4 hours after subcutaneous administration of Compound 1.

[0205] Figure 28D Shows the effect on urinary potassium measured 5 to 24 hours after subcutaneous administration of Compound 1.

[0206] Figure 28E Shows the effect on urinary creatinine measured 4 hours after subcutaneous administration of Compound 1.

[0207] Figure 28FShows the effect on urinary creatinine measured 5 to 24 hours after subcutaneous administration of Compound 1.

[0208] Figure 29 Shows the effect on the volume of ascites after subcutaneous administration of Compound 1.

[0209] Figure 30 Shows the effect on spleen weight after subcutaneous administration of Compound 1.

[0210] Figure 31A Shows the effect on BUN after subcutaneous administration of Compound 1.

[0211] Figure 31B Shows the effect on Cl after subcutaneous administration of Compound 1.

[0212] Figure 31C Shows the effect on PHOS after subcutaneous administration of Compound 1.

[0213] Figure 31D Shows the effect on Na after subcutaneous administration of Compound 1.

[0214] Figure 31E Shows the effect on BUN / CREA after subcutaneous administration of Compound 1.

[0215] Figure 32 Shows exemplary dose - response curves for full agonists, partial agonists, and weak agonists. Figure 32 Generally shows that a wider therapeutic window for vasoconstriction can be achieved with Curve 2 compared to Curve 1 or 3. Part A shows the full agonist levels at which vasoconstriction can be lethal. Part A shows the full agonist levels at which vasoconstriction can induce critical side effects.

[0216] Figure 33 Shows the change in portal venous pressure over time (ΔPP) in rats with bile duct ligation (BDL) after subcutaneous administration of different doses of a mixed V1a agonist - antagonist.

[0217] Figure 34 Shows the change in mean arterial pressure over time (ΔMAP) in rats on a methionine / choline - deficient (MCD) diet after subcutaneous administration of a fully non - selective (V2, V1a) agonist and different doses of a mixed V1a agonist - antagonist.

[0218] Figure 35 Shows the change in portal venous pressure over time (ΔPP) in rats on a methionine / choline - deficient (MCD) diet after subcutaneous administration of a fully non - selective (V2, V1a) agonist and different doses of a mixed V1a agonist - antagonist.

[0219] Figure 36 Exemplary dose - response curves showing the maximal possible effects of a fully non - selective (V2, V1a) agonist and a mixed V1a agonist - antagonist on the human V1a (hV1a) receptor are presented.

[0220] Figure 37 Exemplary dose - response curves showing the maximal possible effects of a mixed V1a agonist - antagonist on the human V1a (hV1a) receptor and the human V2 (hV2) receptor are presented.

[0221] Figure 38 Exemplary dose - response curves showing the contractility of human mesenteric resistance arteries in response to a mixed V1a agonist - antagonist are presented.

[0222] Figure 39A The normalized plasma concentration - time curve of compound 1 after intravenous administration (10 mg / kg) in an individual (e.g., a mammal) is shown.

[0223] Figure 39B The normalized plasma concentration - time curve of compound 1 after subcutaneous administration (1.0 mg / kg) in an individual (e.g., a mammal) is shown.

[0224] Figure 40A The dose - response (baseline %) of compound 1, vasopressin, and vehicle on skin blood flow (SBF) in an individual (e.g., a mammal) after intravenous administration is shown.

[0225] Figure 40B The dose - response of compound 1, vasopressin, and vehicle on blood lactate concentration (mM) in an individual (e.g., a mammal) after intravenous administration is shown.

[0226] Figure 40C The comparison of blood lactate concentration in an individual (e.g., a mammal) after administration of vehicle, compound 1, or vasopressin (AVP) is shown.

[0227] Figure 41A The mean arterial pressure (MAP) in an individual (e.g., a mammal) after subcutaneous administration of compound 1 is shown.

[0228] Figure 41B The arterial systolic blood pressure in an individual (e.g., a mammal) after subcutaneous administration of compound 1 is shown.

[0229] Figure 41C The arterial diastolic blood pressure in an individual (e.g., a mammal) after subcutaneous administration of compound 1 is shown.

[0230] Figure 41D The heart rate in an individual (e.g., a mammal) after subcutaneous administration of compound 1 is shown.

[0231] Figure 42A Shows the time curve of the normalized plasma concentration (ng / mL) of Compound 1 after intravenous bolus administration (0.05 mg / kg) in an individual (e.g., a mammal).

[0232] Figure 42B Shows the time curve of the normalized plasma concentration of Compound 1 after subcutaneous bolus administration (0.5 mg / kg) in an individual (e.g., a mammal).

[0233] Figure 43A Shows the change (ΔMAP) in mean arterial pressure relative to baseline within 480 minutes after administration of Compound 1 in an individual (e.g., a mammal).

[0234] Figure 43B Shows the change (ΔMAP) in mean arterial pressure relative to baseline within 480 minutes after administration of terlipressin in an individual (e.g., a mammal).

[0235] Figure 44 Shows that after intravenous (IV) infusion, little metabolism of Compound 1 occurred in healthy humans (inset A), and after subcutaneous (bolus) injection, the concentrations of Compound 1 and M1 were approximately equimolar in healthy humans (inset B).

[0236] Figure 45 Shows that little metabolism of Compound 1 occurred in minipigs after subcutaneous (SC) infusion of relatively low (insets A and B) and high (insets C and D) doses of Compound 1.

[0237] Figure 46 Depicts Figure 45 the Compound 1 / M1 ratios for insets A and B of

[0238] Figure 47 Shows that little metabolism of Compound 1 occurred in minipigs after relatively slow subcutaneous (SC) infusion of relatively low (insets A and B) and high (insets C and D) doses of Compound 1.

[0239] Figure 48 Depicts Figure 47 the Compound 1 / M1 ratios for insets A - D of Detailed Description

[0240] Certain Definitions

[0241] As used herein and in the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes reference to one or more cells (or cell populations) known to those of ordinary skill in the art and their equivalents, and the like. When ranges are used herein for physical properties (such as molecular weight) or chemical properties (such as chemical formula), all combinations and sub-combinations of the ranges and specific embodiments therein are intended to be included. When referring to a number or numerical range, the term "about" means that the recited number or numerical range is an approximation within experimental variability (or within statistical experimental error), and 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 disclosure of the number itself. The term "comprising" (and related terms such as "comprise", "comprises", "having", or "including") is not intended to exclude that in certain other embodiments (e.g., embodiments of any substance composition, composition, method, or process described herein), it may "consist of the described features" or "consist essentially of the described features".

[0242] As used herein, the terms "treat", "treating", or "treatment" include reducing, attenuating, alleviating, ameliorating, managing, relieving, or mitigating symptoms associated with a disease, disease state, disorder, or indication (e.g., as provided herein) in a chronic or acute treatment scenario. In addition, treatment of a disease or disease state described herein includes disclosure of treating such disease, disease state, disorder, or indication with such compounds or compositions.

[0243] As used herein, the term "modulate" or "modulating" refers to a change in a biological, chemical, and / or biochemical reaction (such as a physiological reaction) in an individual. In some instances, the change is an increase in the biological, chemical, and / or biochemical reaction of the individual. In some instances, the change is a decrease in the biological, chemical, and / or biochemical reaction of the individual. In some instances, the change is observed after administration of a compound described herein to an individual (e.g., immediately, 30 min or longer, 1 hour or longer, 6 hours or longer, 12 hours or longer, 24 hours or longer, or 1 week or longer).

[0244] As used herein, the term "adverse event" or "AE" refers to an untoward medical event in an individual (such as an individual participating in a clinical trial). In some cases, an AE is an adverse and / or unanticipated sign, symptom, or disease (such as temporally related to the use of an investigational medicinal product (IMP)), whether or not considered to be caused by the IMP. For example, an AE can include accidental injury, the cause of any change in medication (drug and / or dose), the cause of any medical, nursing, or pharmaceutical consultation, or the cause of hospitalization or surgery, as well as over-dosing and medication errors with or without clinical consequences. In some cases, an AE is expected based on the pharmacological action of the IMP. In some cases, an AE is an abnormal laboratory test, a vital sign, or a physical or gynecological examination finding evaluated by the investigator as clinically significant. In some cases, a pre-treatment adverse event is any untoward medical event that occurs or is observed between signing the informed consent form and the first administration of the IMP. In some cases, an adverse event occurring during treatment is an AE that occurs after administration of the IMP and within the residual drug effect time, or a pre-treatment adverse event or pre-existing medical condition that deteriorates in intensity after administration of the IMP and within the residual drug effect time. In some cases, the residual drug effect time is the estimated time period after administration of the IMP during which the effect of the product is still considered to be present based on PK, PD, or other substance characteristics. In some cases, the residual drug effect is 5 times the terminal half-life. In some cases, the terminal half-life of Compound 1 is about 1.5 - 2 hours. In some cases, the residual drug effect is within the time between the last assessment in Phase 1 and the follow-up visit in Phase 2 (as described in the examples below). In some cases, an adverse event occurring after treatment is an AE that occurs after the residual drug effect time of the IMP (e.g., between the last assessment in Phase 1 and the first administration in Phase 2, and after the follow-up visit in Phase 2).

[0245] "Amino" refers to the -NH2 group.

[0246] "Cyano" refers to the -CN group.

[0247] "Nitro" refers to the -NO2 group.

[0248] "Oxo" refers to the =O group.

[0249] "Hydroxy" refers to the -OH group.

[0250] "Alkyl" generally refers to an acyclic hydrocarbon (e.g., straight-chain or branched) or cycloalkane (e.g., ring) group consisting solely of carbon and hydrogen atoms, such as having from one to fifteen carbon atoms (e.g., C1-C 15(alkyl). Unless otherwise specified, an alkyl group is saturated or unsaturated (e.g., an alkenyl group, which contains at least one carbon-carbon double bond). The disclosure of "alkyl" provided herein is intended to include the independent recitation of "alkyl" unless otherwise specified. The alkyl groups described herein are generally monovalent, but can also be divalent (which can also be described herein as an "alkylene" or "alkylenyl" group). In certain embodiments, the alkyl group contains from one to thirteen carbon atoms (e.g., C1-C 13 (alkyl). In certain embodiments, the alkyl group contains from one to eight carbon atoms (e.g., C1-C8 alkyl). In other embodiments, the alkyl group contains from one to five carbon atoms (e.g., C1-C5 alkyl). In other embodiments, the alkyl group contains from one to four carbon atoms (e.g., C1-C4 alkyl). In other embodiments, the alkyl group contains from one to three carbon atoms (e.g., C1-C3 alkyl). In other embodiments, the alkyl group contains from one to two carbon atoms (e.g., C1-C2 alkyl). In other embodiments, the alkyl group contains one carbon atom (e.g., C1 alkyl). In other embodiments, the alkyl group contains from five to fifteen carbon atoms (e.g., C5-C 15 (alkyl). In other embodiments, the alkyl group contains from five to eight carbon atoms (e.g., C5-C8 alkyl). In other embodiments, the alkyl group contains from two to five carbon atoms (e.g., C2-C5 alkyl). In other embodiments, the alkyl group contains from three to five carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (isopropyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl group is attached to the rest of the molecule by a single bond. Generally, the alkyl groups are each independently substituted or unsubstituted. Each recitation of "alkyl" provided herein (unless otherwise specified) includes a specific and explicit recitation of an unsaturated "alkyl" group. Similarly, unless specifically specified otherwise in the specification, the alkyl group is optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oxime, trimethylsilyl, -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 (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where each R a is independently hydrogen, alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, carbocyclic group (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), carbocyclic alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic group (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl) or heteroaryl alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl).

[0251] "Alkoxy" refers to a group of the formula -O-alkyl bonded through an oxygen atom, where the alkyl is an alkyl chain as defined above.

[0252] "Alkenyl" refers to a straight-chain or branched-chain hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing at least one carbon-carbon double bond and having two to twelve carbon atoms. In certain embodiments, the alkenyl contains two to eight carbon atoms. In other embodiments, the alkenyl contains two to four carbon atoms. The alkenyl is optionally substituted as described for the "alkyl" group.

[0253] "Alkylene" or "alkylene chain" generally refers to a straight-chain or branched-chain divalent alkyl group that connects the remainder of the molecule to a group, such as having one to twelve carbon atoms, for example, methylene, ethylene, propylene, isopropylidene, n-butylene, etc. Unless specifically stated otherwise in the specification, the alkylene chain is optionally substituted as described herein for the alkyl group.

[0254] "Aryl" means a group 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 carbon atoms with one hydrogen and five to eighteen carbon atoms, where at least one ring in the ring system is completely unsaturated, i.e., according to Hückel's theory, it contains a cyclic delocalized system of (4n + 2) π electrons. 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 specifically stated otherwise in the specification, the term "aryl" or the prefix "ar" (such as in "aralkyl") is intended to include aryl groups optionally substituted with one or more substituents independently selected from the following: alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclic, optionally substituted carbocyclic alkyl, optionally substituted heterocyclic, optionally substituted heterocyclic alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl alkyl, -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 -O-R 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 (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -Rb -S(O) t N(R a )2 (where t is 1 or 2), wherein each R a is independently hydrogen, alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), cycloalkylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic group (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), each R b is 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 wherein each of the above substituents is unsubstituted unless otherwise indicated.

[0255] "Aralkyl" or "aryl-alkyl" refers to a group of the formula -R c -aryl, wherein R c is an alkylene chain as defined above, such as methylene, ethylene, etc. The alkylene chain portion of the aralkyl group is optionally substituted as described above for alkylene chains. The aryl portion of the aralkyl group is optionally substituted as described above for aryl groups.

[0256] "Carbocyclic group" or "cycloalkyl group" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms, which includes fused or bridged ring systems and has three to fifteen carbon atoms. In certain embodiments, the carbocyclic group contains three to ten carbon atoms. In other embodiments, the carbocyclic group contains five to seven carbon atoms. The carbocyclic group is attached to the rest of the molecule by a single bond. The carbocyclic group or cycloalkyl group is saturated (i.e., contains only single C-C bonds) or unsaturated (i.e., contains one or more double or triple bonds). Examples of saturated cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The unsaturated carbocyclic group is also referred to as "cycloalkenyl". Examples of monocyclic cycloalkenyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclic groups include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptyl), norbornenyl, decahydronaphthyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, etc. Unless otherwise specifically stated in the specification, the term "carbocyclic group" is intended to include carbocyclic groups optionally substituted with one or more substituents independently selected from the following: alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thiocarbonyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclic group, optionally substituted carbocyclic alkyl, optionally substituted heterocyclic group, optionally substituted heterocyclic alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl alkyl, -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 -O-R 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 (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2(where t is 1 or 2), where each R a is independently hydrogen, alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), cycloalkylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), arylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic group (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic group alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), each R b is 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 where each of the above substituents is unsubstituted unless otherwise indicated.

[0257] "Carbocyclic alkyl" means a group of the formula -R c -carbocyclic, where R c is an alkylene chain as defined above. The alkylene chain and the carbocyclic group are optionally substituted as defined above.

[0258] "Carbocyclic alkenyl" means a group of the formula -R c -carbocyclic, where R c is an alkenylene chain as defined above. The alkenylene chain and the carbocyclic group are optionally substituted as defined above.

[0259] "Carbocyclic alkoxy" means a group of the formula -O-R c -carbocyclic bonded through an oxygen atom, where R c is an alkylene chain as defined above. The alkylene chain and the carbocyclic group are optionally substituted as defined above.

[0260] "Halogen" or "halo" means a fluoro, bromo, chloro or iodo substituent.

[0261] "Halogenated alkyl" refers to an alkyl group as defined above that is substituted with one or more halogen groups as defined above, such as trifluoromethyl, dichloromethyl, chloromethyl, etc. In some embodiments, the halogenated alkyl is a fluoroalkyl, such as trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the fluoroalkyl group is optionally substituted as defined above for alkyl groups.

[0262] The term "heteroalkyl" refers to an alkyl group as defined above, wherein one or more backbone carbon atoms of the alkyl are replaced by heteroatoms (with an appropriate number of substituents or valences - for example, -CH2- can be replaced by -NH- or -O-). For example, each substituted carbon atom is independently replaced by a heteroatom, such as where carbon is replaced by nitrogen, oxygen, sulfur, or other suitable heteroatoms. In some cases, each substituted carbon atom is independently replaced by oxygen, nitrogen (e.g., -NH-, -N(alkyl)- or -N(aryl)- or having another substituent contemplated herein) or sulfur (e.g., -S-, -S(=O)- or -S(=O)2-). In some embodiments, the heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In some embodiments, the heteroalkyl is attached to the remainder of the molecule at a heteroatom of the heteroalkyl. In some embodiments, the heteroalkyl is a C1-C 18 heteroalkyl. In some embodiments, the heteroalkyl is a C1-C 12 heteroalkyl. In some embodiments, the heteroalkyl is a C1-C6 heteroalkyl. In some embodiments, the heteroalkyl is a C1-C4 heteroalkyl. In some embodiments, the heteroalkyl includes alkylamino, alkylaminoalkyl, aminoalkyl, heterocycloalkyl, heterocycloalkyl, heterocyclic group, and heterocycloalkylalkyl as defined herein. Unless specifically stated otherwise in the specification, heteroalkyl does not include alkoxy as defined herein. Unless specifically stated otherwise in the specification, the heteroalkyl group is optionally substituted as defined above for alkyl groups.

[0263] "Heteroalkylene" refers to a divalent heteroalkyl group as defined above that connects one part of a molecule to another part of the molecule. Unless specifically stated otherwise, the heteroalkylene is optionally substituted as defined above for alkyl groups.

[0264] "Heterocyclic group" refers to a stable 3- to 18-membered non-aromatic ring group containing two to twelve carbon atoms and one to six heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise specifically stated in the specification, the heterocyclic group is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which optionally includes a fused or bridged ring system. The heteroatoms in the heterocyclic group are optionally oxidized. One or more nitrogen atoms (if present) are optionally quaternized. The heterocyclic group is partially or fully saturated. The heterocyclic group 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 cases, the heterocyclic group is saturated. In some cases, the heterocyclic group is saturated and substituted. In some cases, the heterocyclic group is unsaturated. Examples of such heterocyclic groups 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-piperidone, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thioxomorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless otherwise specifically stated in the specification, the term "heterocyclic group" is intended to include heterocyclic groups as defined above that are optionally substituted with one or more substituents selected from the following: alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thiocarbonyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclic group, optionally substituted carbocyclic alkyl, optionally substituted heterocyclic group, optionally substituted heterocyclic alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl alkyl, -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 -O-R c -C(O)N(Ra ) 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 (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2), where each R a is independently hydrogen, alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), cycloalkylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), arylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic group (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), each R b is 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 where each of the above substituents is unsubstituted unless otherwise indicated.

[0265] "N - heterocyclic group" or "N - attached heterocyclic group" means a heterocyclic group as defined above which contains at least one nitrogen and where the point of attachment of the heterocyclic group to the rest of the molecule is through a nitrogen atom in the heterocyclic group. The N - heterocyclic group is optionally substituted as described above for the heterocyclic group. Examples of such N - heterocyclic groups include, but are not limited to, 1 - morpholinyl, 1 - piperidinyl, 1 - piperazinyl, 1 - pyrrolidinyl, pyrazolidinyl, imidazolinyl and imidazolidinyl.

[0266] "C - heterocyclic group" or "C - attached heterocyclic group" means a heterocyclic group as defined above, which contains at least one heteroatom and wherein the point of attachment of the heterocyclic group to the remainder of the molecule is through a carbon atom in the heterocyclic group. The C - heterocyclic group is optionally substituted as described above for heterocyclic groups. Examples of such C - heterocyclic groups include, but are not limited to, 2 - morpholinyl, 2 - piperidinyl or 3 - piperidinyl or 4 - piperidinyl, 2 - piperazinyl, 2 - pyrrolidinyl or 3 - pyrrolidinyl, etc.

[0267] "Heterocyclic alkyl" means a group of the formula -R c -heterocyclic, where R c is an alkylene chain as defined above. If the heterocyclic group is a nitrogen - containing heterocyclic group, the heterocyclic group is optionally attached to the alkyl group at the nitrogen atom. The alkylene chain of the heterocyclic alkyl group is optionally substituted as defined above for alkylene chains. The heterocyclic moiety of the heterocyclic alkyl group is optionally substituted as defined above for heterocyclic groups.

[0268] "Heterocyclic alkoxy" means a group of the formula -O - R c -heterocyclic bonded through an oxygen atom, where R c is an alkylene chain as defined above. If the heterocyclic group is a nitrogen - containing heterocyclic group, the heterocyclic group is optionally attached to the alkyl group at the nitrogen atom. The alkylene chain of the heterocyclic alkoxy group is optionally substituted as defined above for alkylene chains. The heterocyclic moiety of the heterocyclic alkoxy group is optionally substituted as defined above for heterocyclic groups.

[0269] "Heteroaryl" means a group derived from a 3- to 18-membered aromatic ring group containing two to seventeen carbon atoms and one to six heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, a heteroaryl group is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, wherein at least one ring in the ring system is completely unsaturated, i.e., according to Hückel's theory, it contains a system of cyclic delocalized (4n + 2) π electrons. Heteroaryl includes fused or bridged ring systems. One or more heteroatoms in the heteroaryl group are optionally oxidized. One or more nitrogen atoms (if present) are optionally quaternized. The heteroaryl is attached to the remainder of the molecule through any atom of one or more rings.Examples of heteroaryl include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benz[d]thiazolyl, benzothiadiazolyl, benz[b][1,4]dioxazolyl, benz[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, chromenyl, chromenone, benzofuranyl, benzofuranone, benzothienyl (benzothienyl / benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benz[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, dibenzothienyl, furanyl, furanone, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[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, isoquinolinyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridone, 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, 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 otherwise specifically stated in the specification, the term "heteroaryl" is intended to include a heteroaryl group as defined above optionally substituted with one or more substituents selected from: alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thiocarbonyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclic group, optionally substituted carbocyclic alkyl, optionally substituted heterocyclic group, optionally substituted heterocyclic alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl alkyl, -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 -O-R 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 (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2(where t is 1 or 2), where each R aindependently is hydrogen, alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), cycloalkylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), arylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic group (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic group alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), each R b independently is 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 wherein each of the above substituents is unsubstituted unless otherwise indicated.

[0270] “N - heteroaryl” means a heteroaryl group as defined above that contains at least one nitrogen and wherein the point of attachment of the heteroaryl group to the rest of the molecule is through a nitrogen atom in the heteroaryl group. The N - heteroaryl group is optionally substituted as described above for the heteroaryl group.

[0271] “C - heteroaryl” means a heteroaryl group as defined above and wherein the point of attachment of the heteroaryl group to the rest of the molecule is through a carbon atom in the heteroaryl group. The C - heteroaryl group is optionally substituted as described above for the heteroaryl group.

[0272] “heteroarylalkyl” means a group of the formula - R c - heteroaryl, wherein 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 group at the nitrogen atom. The alkylene chain of the heteroarylalkyl group is optionally substituted as defined above for the alkylene chain. The heteroaryl moiety of the heteroarylalkyl group is optionally substituted as defined above for the heteroaryl group.

[0273] “heteroarylalkoxy” means a group of the formula - O - R c - heteroaryl bonded through an oxygen atom, wherein 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 group at the nitrogen atom. The alkylene chain of the heteroarylalkoxy group is optionally substituted as defined above for the alkylene chain. The heteroaryl moiety of the heteroarylalkoxy group is optionally substituted as defined above for the heteroaryl group.

[0274] In some embodiments, the compounds disclosed herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, which are defined as (R)- or (S)- in terms of absolute stereochemistry. Unless otherwise stated, this disclosure is intended to contemplate all stereoisomeric forms of the compounds disclosed herein. When the compounds described herein contain an olefinic double bond and unless otherwise stated, this disclosure is intended to include both E and Z geometric isomers (e.g., cis or trans). Similarly, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included. The term "geometric isomers" refers to the E or Z geometric isomers of an olefinic double bond (e.g., cis or trans). The term "positional isomers" refers to structural isomers around a central ring, such as ortho, meta, and para isomers around a benzene ring.

[0275] Generally, the optionally substituted groups are each independently substituted or unsubstituted. Each recitation of an optionally substituted group provided herein (unless otherwise stated) includes independent and distinct recitations of both the unsubstituted group and the substituted group (e.g., substituted in certain embodiments and unsubstituted in certain other embodiments). Unless otherwise stated, the substituted groups provided herein (e.g., substituted alkyl) are substituted with one or more substituents, each independently selected from the group consisting of halo, cyano, nitro, oxo, thiocarbonyl, imino, oxime, trimethylsilyl, -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 (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where each R aIndependently is hydrogen, alkyl (e.g., optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, carbocyclic group (e.g., optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), carbocyclic alkyl (e.g., optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aryl (e.g., optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (e.g., optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic group (e.g., optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic alkyl (e.g., optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (e.g., optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl) or heteroaryl alkyl (e.g., optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl).

[0276] "Pharmaceutically acceptable salts" include both acid addition salts and base addition salts. Pharmaceutically acceptable salts of any of the pharmacological agents described herein are intended to include any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0277] "Pharmaceutically acceptable acid addition salts" refers to those salts that retain the biological effectiveness and properties of the free base, which are not biologically or otherwise undesirable, and are formed with inorganic acids (such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, etc.). Also included are salts formed with organic acids (such as aliphatic monocarboxylic and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkane diacids, aromatic acids, aliphatic and aromatic sulfonic acids, etc., and including 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, etc.). Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, octanoates, isobutyrates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, etc. Amino acid salts such as arginates, gluconates, and galacturonates are also contemplated (see, for example, Berge S.M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19 (1997)). In some embodiments, the acid addition salts of basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt by methods and techniques familiar to those of ordinary skill in the art.

[0278] "Pharmaceutically acceptable base addition salts" refer to those salts that retain the biological effectiveness and properties of the free acid and are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or organic base to the free acid. In some embodiments, the pharmaceutically acceptable base addition salts are formed with metals or amines such as alkali metals, 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, etc. 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, N-ethylpiperidine, polyamine resins, etc. See Berge et al., supra.

[0279] In some embodiments, the compounds disclosed herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers and other stereoisomeric forms, which are defined as (R)- or (S)- in terms of absolute stereochemistry. Unless otherwise stated, this disclosure is intended to contemplate all stereoisomeric forms of the compounds disclosed herein. When the compounds described herein contain an olefinic double bond and unless otherwise stated, this disclosure is intended to include both E and Z geometric isomers (e.g., cis or trans). Similarly, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included. The term "geometric isomers" refers to the E or Z geometric isomers of an olefinic double bond (e.g., cis or trans). The term "positional isomers" refers to structural isomers around a central ring, such as ortho, meta and para isomers around a benzene ring.

[0280] Systemic hemodynamic complications may indicate cirrhosis and portal hypertension (PHT). Due to increased intrahepatic resistance, an individual may typically experience an elevation in portal pressure (PP). The combination of increased blood flow and elevated intrahepatic resistance may lead to the common manifestations of PHT and decompensated cirrhosis. Clinical PHT may occur when the hepatic venous pressure gradient (HVPG) > 5 mmHg. PHT may then lead to a hyperdynamic state, characterized by reduced splanchnic and systemic vascular resistance, which may further increase portal blood flow. As advanced cirrhosis progresses, splanchnic arteriolar vasodilation may worsen PHT, which may then lead to a further increase in HVPG, further resulting in renal hypoperfusion at 10 mmHg or higher. The kidneys may perceive low perfusion pressure and reduced glomerular filtration rate as volume depletion, which may then activate the renin-angiotensin-aldosterone (RAAS) and vasopressin systems, leading to severe vasoconstriction within the kidneys as well as sodium and water retention. If renal hypoperfusion is severe enough, it may lead to the development of ascites and kidney injury in the form of hepatorenal syndrome - acute kidney injury (HRS-AKI).

[0281] Ascites is a common complication of cirrhosis, and ascites requiring paracentesis is a common liver-related cause of hospitalization. HRS-AKI is a severe complication of cirrhosis; only 50% of patients with HRS-AKI are expected to respond to currently available treatments, and more than half of the patients die within 90 days. However, HRS-AKI is reversible with early intervention.

[0282] Ascites is a critical and rapidly progressive consequence of end-stage liver disease (ESLD), which may lead to acute kidney failure and usually results in death. For example, refractory ascites (which is the end-stage form of ascites) is estimated to affect up to 60,000 - 100,000 individuals (e.g., globally) each year, and is associated with a mortality rate of approximately 50% at 3 years after diagnosis and a 1-year survival rate of less than 50%. With the increasing incidence of (chronic) liver disease, the prevalence of ascites is expected to increase. For more than two decades, there has been no innovation in therapeutic agents for ascites, and there is no FDA-approved treatment for this disease. Therapeutic interventions typically only have a modest effect and / or fail to achieve the goals of reversing kidney failure and prolonging the survival of critically ill patients. Patients are typically managed symptomatically via paracentesis or surgically placed shunts (transjugular intrahepatic portosystemic shunt [TIPS]) to remove ascites. While such treatments can provide symptomatic relief of ascites, they do not improve the underlying circulatory disorder and have no impact on survival. Cirrhosis manifestations may also lead to other complications, such as bleeding esophageal varices, spontaneous bacterial peritonitis, and kidney failure.

[0283] Patients with refractory ascites typically have abnormally high splanchnic blood flow, such as due to excessive hepatic vascular resistance and systemic vasodilation. Vasoconstrictors that constrict the splanchnic vessels can reduce ascites formation by decreasing venous blood flow. Although studies with terlipressin (a non-selective vasopressin receptor full agonist) have demonstrated a reduction in ascites formation, such compounds are limited to continuous (e.g., 24-hour) intravenous infusion, such as due to local vasoconstriction at the injection site, which precludes alternative routes of administration (such as subcutaneous administration).

[0284] The management of HRS-AKI typically focuses on restoring systemic arterial pressure and reducing PHT through splanchnic vasoconstriction, the vasopressin system is the target, and the long-term goal is liver transplantation. Although monitoring and titration are challenging, an increase in vasoconstriction (i.e., mean arterial pressure (MAP)) has been associated with improved hemodynamic parameters. Vasoconstrictors (including terlipressin, norepinephrine, and midodrine / octreotide) have been used as therapies for patients with HRS-AKI, attempting to restore renal perfusion and function. Terlipressin (a vasopressin analogue) plus albumin has been used as first-line therapy for HRS-AKI because it reduces short-term mortality compared to placebo. Albumin is added to increase the circulating volume. Terlipressin is approved by the US Food and Drug Administration for the treatment of adults with HRS with rapid reduction in renal function.

[0285] There are three vasopressin receptors: V1a, V1b, and V2. The V1a receptor is found throughout the circulatory system and regulates vasoconstriction. The V2 receptor regulates water excretion (aquaresis) by exerting an antidiuretic effect at the renal level by mediating water reabsorption in the collecting tubules. The V1b receptor is found in the anterior pituitary 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 activity on the V1a system; significant vasoconstriction occurs only at supra-physiological concentrations. In the case of pharmacological applications, strong vasoconstriction can be achieved in a concentration-dependent manner.

[0286] Arginine vasopressin (AVP) is the endogenous ligand for the vasopressin V1A, V1B, and V2 G protein-coupled receptors (V1AR, V1BR, V2R). The homeostatic functions of the vasopressin system (such as regulating blood osmolality and pressor effects) are mediated by the V2 and V1A receptor subtypes. Activation of the V2 receptor located in the renal collecting ducts plays a role in regulating fluid balance through an antidiuretic effect. Activation of the V1A receptor located on vascular smooth muscle cells provides vasoconstriction and increased arterial pressure.

[0287] Lysine vasopressin (LVP) (the active metabolite of terlipressin) is active on V1a, V1b, and V2 receptors and is a full agonist. Although there is a significant improvement in renal function, the use of terlipressin is associated with critical adverse events, including gastrointestinal disorders, sepsis, and respiratory failure. These adverse effects, which can be attributed to the strength of LVP binding to V1a and off-target effects on V2, may lead to further water retention. As a result of the likelihood of critical side effects, terlipressin carries a black box warning from the US FDA regarding critical or fatal respiratory failure.

[0288] The pressor activity of vasopressin receptor agonists is of clinical interest, 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 may induce severe vasoconstriction and tissue hypoperfusion when used at therapeutic doses. The pharmacological activity of V1AR partial agonists (e.g., compounds with reduced maximal efficacy at the V1A receptor) can be used in a variety of conditions where a modest increase in blood flow and / or blood pressure without hypoperfusion is desired. Such indications include hepatorenal syndrome, refractory ascites, bleeding esophageal varices, anesthesia-induced hypotension, vasodilatory shock, paracentesis-induced circulatory dysfunction, and spontaneous bacterial peritonitis.

[0289] Individuals with cirrhosis often develop a number of clinical complications, among which ascites accumulation is the most important and indicates a poor prognosis. In some cases, ascites formation is caused by the homeostatic activation of the endogenous sodium and water retention system, attempting to counteract circulatory dysfunction (such as occurs in patients with advanced liver disease). In some cases, circulatory dysfunction is characterized by the presence of splanchnic vasodilation and portal hypertension. In some embodiments, the compounds described herein (e.g., Compound 1) have effects on ascites volume, sodium and water excretion, portal hypertension, and systemic hemodynamics after administration of the compound or vehicle to cirrhotic rats with ascites.

[0290] In some embodiments, after intravenous (IV) and / or subcutaneous (SC) administration of a composition comprising a compound described herein (e.g., a hybrid V1a agonist / antagonist such as Compound 1), the compound is systemically delivered in an individual (see Example 1). In some embodiments, after intravenous and / or subcutaneous administration of the compound, the individual has a systemic effect such as a change in MAP. In some embodiments, the compound is administered by intravenous infusion. In some embodiments, the compound is administered by subcutaneous (bolus) injection. Although the systemic effects observed after intravenous infusion and subcutaneous (bolus) injection are comparable, more adverse events were measured in individuals receiving the subcutaneous (bolus) injection composition (see Example 1). Overall, the compound is well tolerated by individuals receiving the composition by intravenous infusion.

[0291] In some cases, after subcutaneous (bolus) injection of a composition comprising a compound described herein (e.g., a hybrid V1a agonist / antagonist such as Compound 1), metabolites are formed (e.g., a large amount of metabolite M1) (e.g., overproduction of M1) (see Figure 44 , small panel B). In some cases, after intravenous infusion of a composition comprising a compound described herein (e.g., a hybrid V1a agonist / antagonist such as Compound 1), very little metabolite is formed (e.g., less than 15% of metabolite M1) (see Figure 44 , small panel A). As discussed herein, it is known that the full vasopressin receptor agonists described herein (e.g., terlipressin) cause (critical) adverse events when administered subcutaneously. Thus, the overproduction of the full agonist (M1) after subcutaneous (bolus) injection provides an explanation for the difference in the tolerance profiles of the composition in healthy individuals after intravenous infusion versus (subcutaneous) bolus injection.

[0292] As described herein, in some cases, metabolite (M1) formation is reduced by subcutaneous infusion of a composition comprising a compound described herein into an individual (see Example 3). Additionally, in some cases, metabolite (M1) formation is reduced by increasing the buffer concentration of a composition comprising a compound described herein (see Example 4). Furthermore, in some cases, 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 cases, metabolite (M1) formation is reduced by any one or a combination of subcutaneous infusion, increasing buffer concentration, and increasing drug concentration.

[0293] In some embodiments, provided herein are methods of treating end-stage liver disease (ESLD) in an individual in need thereof, the methods comprising subcutaneously infusing into 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 a compound of Formula I) degrades. In some embodiments, less than 50% of the compound (such as a compound of Formula I) degrades subcutaneously.

[0294] In some embodiments, the 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, the 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, the 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.

[0295] In some embodiments, such as after subcutaneous (bolus) injection, more than 50% of the parent compound (e.g., Compound 1) degrades (e.g., to form M1). In some embodiments, such as after subcutaneous (bolus) injection, more than 60% of the parent compound (e.g., Compound 1) degrades (e.g., to form M1). In some embodiments, such as after subcutaneous (bolus) injection, more than 70% of the parent compound (e.g., Compound 1) degrades (e.g., to form M1). In some embodiments, such as after subcutaneous (bolus) injection, more than 80% of the parent compound (e.g., Compound 1) degrades (e.g., to form M1).

[0296] In some embodiments, the 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, the 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, the 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.

[0297] In some embodiments, a composition is subcutaneously infused into an individual, and less M1 is formed relative to administration of an otherwise identical composition administered by subcutaneous (bolus) injection.

[0298] In some embodiments, a composition is subcutaneously infused into an individual, and less M1 is formed systemically relative to administration of an otherwise identical composition administered by subcutaneous (bolus) injection.

[0299] In some embodiments, a composition is infused subcutaneously into an individual, and less M1 is formed locally (at the injection / infusion site) relative to the administration of an otherwise identical composition administered by subcutaneous (bolus) injection.

[0300] In some embodiments, subcutaneous infusion of a composition into an individual improves tolerance. In some embodiments, subcutaneous infusion of a composition into an individual improves tolerance relative to subcutaneous (bolus) injection, such as based on a reduction in overproduction of M1, such as subcutaneous.

[0301] In some embodiments, subcutaneous infusion of a composition into an individual reduces unwanted systemic events, such as unwanted vasoconstriction leading to ischemia. In some embodiments, subcutaneous infusion of a composition into an individual reduces unwanted site-of-administration events, such as local site vasoconstriction leading to ischemia at the site of administration. In some embodiments, subcutaneous infusion of a composition into an individual reduces unwanted systemic events and unwanted site-of-administration events.

[0302] In some embodiments, provided herein are methods of reducing (the incidence of) local vasoconstriction in an individual in need thereof. In some embodiments, the method is a method for reducing the incidence of local vasoconstriction in an individual in need thereof. In some embodiments, the method is a method of reducing (the incidence of) ischemia in an individual in need thereof. In some embodiments, the method is a method of reducing (the incidence of) injection site ischemia in an individual in need thereof. In some embodiments, the method comprises subcutaneous infusion into an individual in need thereof of a composition comprising a compound (such as a compound having a structure represented by Formula I) described herein or a pharmaceutically acceptable salt thereof.

[0303] In some cases, a compound (e.g., Compound 1) described herein is used to treat complications of ESLD, such as refractory ascites.

[0304] In some embodiments, provided herein are methods of treating ESLD in an individual (e.g., as described herein), the method comprising subcutaneously administering to the individual (e.g., as described herein) an amount of a compound that is a mixed vasopressin receptor 1A (V1AR) agonist - antagonist. In some embodiments, the amount of the compound is an effective amount of the compound.

[0305] In some embodiments, provided herein are methods of treating symptoms of ELSD in an individual (e.g., as described herein), the method comprising subcutaneously administering to the individual (e.g., as described herein) an amount of a compound that is a mixed vasopressin receptor 1A (V1AR) agonist - antagonist. In some embodiments, the amount of the compound is an effective amount of the compound.

[0306] In some embodiments, provided herein are methods of treating a complication of ELSD in an individual (e.g., as described herein), the method comprising subcutaneously administering to the individual (e.g., as described herein) an amount of a compound that 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.

[0307] In some embodiments, provided herein are methods of treating end - stage liver disease (ESLD) or a symptom thereof (e.g., a complication) in an individual (e.g., in need thereof), the method comprising subcutaneously infusing into the individual (e.g., in need thereof) a composition comprising a (effective) amount of a compound as described herein (such as a mixed vasopressin receptor 1A (V1AR) agonist - antagonist as described herein). In some embodiments, the compound has a structure represented by Formula I. In some embodiments, the compound is Compound 1.

[0308] In some embodiments, the method further comprises securing a subcutaneous infusion device to the skin (e.g., skin surface) of the individual. In some embodiments, the subcutaneous infusion device comprises a cavity and a hollow tube. In some embodiments, the composition is configured within the cavity. In some embodiments, the hollow tube comprises a first opening and a second opening. In some embodiments, the first opening is in fluid communication with the cavity. In some embodiments, after securing the subcutaneous infusion device to the skin, the second opening is subcutaneously disposed within the individual. In some embodiments, the hollow tube is a needle, such as having any gauge suitable for subcutaneous administration (e.g., subcutaneous infusion).

[0309] In some embodiments, the subcutaneous infusion device further includes a pump configured to infuse the composition subcutaneously into an individual at a constant rate. In some embodiments, the subcutaneous infusion device further includes a pump configured to infuse the composition subcutaneously into an individual at a varying rate. In some embodiments, the rate is a flow rate. In some embodiments, the continuous infusion is performed at a flow rate insufficient to provide a stream of the composition. In some embodiments, the continuous infusion is performed at a flow rate that provides a continuous drip to the individual. In some embodiments, the composition is infused subcutaneously into the individual at a rate of about 0.001 milliliters per hour (mL / h) or higher. In some embodiments, the composition is infused subcutaneously into the individual at a rate of about 1 mL / h or lower. In some embodiments, the composition is infused subcutaneously into the individual at a rate of about 0.005 mL / h to about 1 mL / h for a period of administration. In some embodiments, the composition is infused subcutaneously into the individual at a rate of about 0.01 mL / h to about 1 mL / h for a period of administration. In some embodiments, the composition is infused subcutaneously into the individual at a rate of about 0.04 mL / h to about 1 mL / h for a period of administration. In some embodiments, the period of administration lasts at least about one hour. In some embodiments, the period of administration lasts at least about one day. In some embodiments, the period of administration lasts at least about one week. In some embodiments, the period of administration lasts at least about one month. In some embodiments, the period of administration is about one month or longer. In some embodiments, the period of administration is about two months or longer. In some embodiments, the period of administration is about three months or longer. In some embodiments, the period of administration is about four months or longer. In some embodiments, the period of administration is about five months or longer. In some embodiments, the period of administration is about six months or longer. In some embodiments, the period of administration is about nine months or longer. In some embodiments, the period of administration is about twelve months or longer.

[0310] In some embodiments, the composition described herein is infused subcutaneously into an individual for at least one hour. In some embodiments, the composition is infused subcutaneously into an individual for at least one day. In some embodiments, the composition is infused subcutaneously into an individual for at least one week. In some embodiments, the composition is infused subcutaneously into an individual for at least one month.

[0311] In some embodiments, the composition described herein is continuously infused subcutaneously into an individual for at least one hour. In some embodiments, the composition is continuously infused subcutaneously into an individual for at least one day. In some embodiments, the composition is continuously infused subcutaneously into an individual for at least one week. In some embodiments, the composition is continuously infused subcutaneously into an individual for at least one month.

[0312] In some embodiments, the compounds described herein are administered to an individual in an amount of from about 0.001 milligrams (mg) to about 100 mg (e.g., continuously). In some embodiments, the compound is administered to an individual in an amount of from about 0.01 mg to about 50 mg (e.g., continuously). In some embodiments, the compound is administered to an individual in an amount of from about 0.01 mg to about 20 mg (e.g., continuously). In some embodiments, the compound is administered to an individual in an amount of from about 0.01 mg to about 10 mg (e.g., continuously). In some embodiments, the compound is administered to an individual in an amount of from about 0.1 mg to about 1 mg (e.g., continuously). In some embodiments, the compound is administered to an individual in an amount of about 0.2 mg (e.g., continuously). In some embodiments, the composition is administered to an individual over a period of one or more days.

[0313] In some embodiments, the composition described herein comprises a compound at a concentration of about 0.001 milligrams per milliliter (mg / mL) or higher. In some embodiments, the composition comprises a compound at a concentration of about 100 mg / mL or lower. In some embodiments, the composition comprises a compound at a concentration of from about 0.001 mg / mL to about 100 mg / mL. In some embodiments, the composition comprises a compound at a concentration of from about 0.01 mg / mL to about 100 mg / mL. In some embodiments, the composition comprises a compound at a concentration of from about 0.1 mg / mL to about 100 mg / mL. In some embodiments, the composition comprises a compound at a concentration of from about 1 mg / mL to about 100 mg / mL. In some embodiments, the composition comprises a compound at a concentration of from about 0.1 mg / mL to about 50 mg / mL. In some embodiments, the composition comprises a compound at a concentration of from about 1 mg / mL to about 50 mg / mL. In some embodiments, the composition comprises a compound at a concentration of from about 0.1 mg / mL to about 10 mg / mL. In some embodiments, the composition comprises a compound at a concentration of from about 1 mg / mL to about 10 mg / mL.

[0314] In some embodiments, the compounds described herein are administered to the described individual in need thereof at a dose of about 0.1 milligrams (mg) / day. In some embodiments, the compounds described herein are administered to the described individual in need thereof at a dose of about 100 mg / day. In some embodiments, the compounds described herein are administered to the described individual in need thereof at a dose of about 0.1 mg / day to about 100 mg / day. In some embodiments, the compounds described herein are administered to the described individual in need thereof at a dose of about 0.1 mg / day to about 50 mg / day. In some embodiments, the compounds described herein are administered to the described individual in need thereof at a dose of about 1 mg / day to about 50 mg / day. In some embodiments, the compounds described herein are administered to the described individual in need thereof at a dose of about 1 mg / day to about 10 mg / day. In some embodiments, the compounds are administered to the individual continuously.

[0315] In some embodiments, provided herein are methods of modulating an individual's mean arterial pressure (MAP), the methods comprising subcutaneously administering to the individual an effective amount of a compound that 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.

[0316] In some embodiments, after subcutaneously administering the compounds described herein (e.g., compound 1), the MAP of the individual increases (e.g., compared to baseline measurements prior to treatment). In some embodiments, after subcutaneously administering compound 1, the MAP of the individual increases (e.g., compared to baseline measurements prior to treatment).

[0317] In some embodiments, after administration of a compound or a pharmaceutically acceptable salt thereof described herein (e.g., Compound 1), the MAP of an individual increases by about 1% or more (e.g., compared to a pre-treatment baseline measurement). In some embodiments, after administration of a compound or a pharmaceutically acceptable salt thereof described herein (e.g., Compound 1), the MAP of an individual increases by about 5% or more (e.g., compared to a pre-treatment baseline measurement). In some embodiments, after administration of a compound or a pharmaceutically acceptable salt thereof described herein (e.g., Compound 1), the MAP of an individual increases by about 10% or more (e.g., compared to a pre-treatment baseline measurement). In some embodiments, after administration of a compound or a pharmaceutically acceptable salt thereof described herein (e.g., Compound 1), the MAP of an individual increases by about 15% or more (e.g., compared to a pre-treatment baseline measurement). In some embodiments, after administration of a compound or a pharmaceutically acceptable salt thereof described herein (e.g., Compound 1), the MAP of an individual increases by about 20% or more (e.g., compared to a pre-treatment baseline measurement). In some embodiments, after administration of a compound or a pharmaceutically acceptable salt thereof described herein (e.g., Compound 1), the MAP of an individual increases by about 1% to about 20% (e.g., compared to a pre-treatment baseline measurement). In some embodiments, after administration of a compound or a pharmaceutically acceptable salt thereof described herein (e.g., Compound 1), the MAP of an individual increases by about 5% to about 20% (e.g., compared to a pre-treatment baseline measurement). In some embodiments, after administration of a compound or a pharmaceutically acceptable salt thereof described herein (e.g., Compound 1), the MAP of an individual increases by about 10% to about 20% (e.g., compared to a pre-treatment baseline measurement). In some embodiments, after administration of a compound or a pharmaceutically acceptable salt thereof described herein (e.g., Compound 1), the MAP of an individual increases by about 1% to about 10% (e.g., compared to a pre-treatment baseline measurement). In some embodiments, the increase in MAP occurs about one hour or more after administration of the compound or a pharmaceutically acceptable salt thereof to the individual. In some embodiments, the increase in MAP occurs about two hours or more after administration of the compound or a pharmaceutically acceptable salt thereof to the individual. In some embodiments, the increase in MAP occurs about three hours or more after administration of the compound or a pharmaceutically acceptable salt thereof to the individual. In some embodiments, the increase in MAP occurs about four hours or more after administration of the compound or a pharmaceutically acceptable salt thereof to the individual. In some embodiments, the increase in MAP occurs about five hours or more after administration of the compound or a pharmaceutically acceptable salt thereof to the individual. In some embodiments, the increase in MAP occurs about six hours or more after administration of the compound or a pharmaceutically acceptable salt thereof to the individual. In some embodiments, the increase in MAP occurs about twelve hours or more after administration of the compound or a pharmaceutically acceptable salt thereof to the individual.In some embodiments, the increase in MAP occurs about one to twelve hours after administration of the compound or a pharmaceutically acceptable salt thereof to an individual. In some embodiments, the increase in MAP occurs about one to six hours after administration of the compound or a pharmaceutically acceptable salt thereof to an individual. In some embodiments, the increase in MAP occurs about four to six hours after administration of the compound or a pharmaceutically acceptable salt thereof to an individual.

[0318] In some embodiments, after administration of the compound or a pharmaceutically acceptable salt thereof to an individual, the MAP of the individual increases in a dose-dependent manner.

[0319] In some embodiments, the compounds provided herein have a maximum therapeutic concentration. In some embodiments, the maximum therapeutic concentration includes a concentration increase that does not provide a dose-dependent increase in MAP. In some embodiments, the compounds provided herein have a non-linear dose-dependence, such as above the maximum therapeutic concentration. In some embodiments, the dose-dependent increase in MAP includes the maximum therapeutic concentration. In some embodiments, the dose-dependence includes a situation where the effect increases with the dose for at least a certain dose range. For example, a higher dose may not provide or may provide a lower dose-dependent increase.

[0320] In some embodiments, the compounds described herein (e.g., Compound 1) are selective vasopressin V1a receptor partial agonists. In some embodiments, the compounds described herein (e.g., Compound 1) are mixed agonist-antagonists. In some embodiments, the compounds described herein (e.g., Compound 1) are selective for V1AR. In some embodiments, the compounds described herein (e.g., Compound 1) are more selective for V1AR than the vasopressin 2 (V2) receptor (V2R). In some cases, the compounds described herein (e.g., Compound 1) do not have functional V2R activity. In some cases, the compounds described herein (e.g., Compound 1) do not have functional V2R activity at therapeutic concentrations. In some embodiments, the therapeutic concentration is a concentration sufficient to modulate V1AR.

[0321] In some cases, the activity and selectivity of the compounds described herein (e.g., mixed agonist-antagonists such as Compound 1) are shown in Tables 35 and 36. In some cases, the activity and selectivity of the compounds described herein (e.g., mixed agonist-antagonists such as Compound 1) are shown by Figures 36 - 38 shown.

[0322] In some embodiments, the compounds described herein (e.g., compound 1) are more than 10-fold selective for V1AR over V2R. In some embodiments, the compounds described herein (e.g., compound 1) are more than 100-fold selective for V1AR over V2R. In some embodiments, the compounds described herein (e.g., compound 1) are more than 1,000-fold selective for V1AR over V2R. In some embodiments, the compounds described herein (e.g., compound 1) are more than 10,000-fold selective for V1AR over V2R. In some embodiments, the compounds described herein (e.g., compound 1) are inactive against V2R.

[0323] In some embodiments, the compounds described herein (e.g., compound 1) comprise a first moiety having agonist activity. In some embodiments, the compounds described herein (e.g., compound 1) comprise a second moiety having antagonist activity. In some embodiments, the compounds described herein (e.g., compound 1) comprise a first moiety having agonist activity and a second moiety having antagonist activity.

[0324] In some embodiments, the compounds provided herein have a ratio of agonist activity to antagonist activity of from about 90:10 to about 10:90. In some embodiments, the compounds provided herein have a ratio of agonist activity to antagonist activity of about 50:50.

[0325] In some embodiments, an agonist-antagonist refers to a compound having an agonist moiety and an antagonist moiety. In a specific embodiment, the agonist moiety and the antagonist moiety are separate.

[0326] In some embodiments, the V1AR agonist-antagonist has a wider therapeutic window than a V1AR agonist. In some embodiments, the V1AR agonist-antagonist described herein has a selective V1a agonist moiety and a selective V1a antagonist moiety. In some instances, the selective V1a agonist moiety or the selective V1a antagonist moiety binds to V1AR such that the selective V1a agonist moiety and the selective V1a antagonist moiety do not both bind to V1AR simultaneously. In some instances, the V1a antagonist moiety competes with the selective V1a agonist moiety for binding to V1AR. In some instances, V1AR agonism provides the (desired) vasoconstrictive effect. In some instances, V1AR antagonism prevents maximal activation of the V1a pathway.

[0327] In some instances, Figure 32 Curve 1 shows the concentration-response curve of a compound (e.g., a completely non-selective (V2, V1a) agonist such as terlipressin), which provides a lethal level of vasoconstriction (e.g., at relatively high doses, depicted as Figure 32Part A) and / or critical adverse events (e.g., at doses above the therapeutic level and at doses of vasoconstriction below the lethal level, depicted as Figure 32 Part B) in. In some embodiments, the compounds described herein (e.g., fully non-selective (V2, V1a) agonists such as terlipressin) have Figure 32 the concentration-response curve shown in Line 1. In some cases, Figure 32 Line 1 shows that the compounds described herein (e.g., fully non-selective (V2, V1a) agonists such as terlipressin) have a relatively narrow therapeutic window. In some cases, Figure 32 Line 1 shows that at relatively high doses, the compounds described herein (e.g., fully non-selective (V2, V1a) agonists such as terlipressin) provide lethality (depicted as Figure 32 Part A) and / or vasoconstriction at levels associated with critical adverse events (depicted as Figure 32 Part B) (such as elevated lactate and / or vasoconstriction with ischemia).

[0328] In some embodiments, Figure 32 Curve 2 shows the concentration-response curve of a compound having a safe and effective profile (e.g., a mixed V1a agonist-antagonist such as Compound 1). In some embodiments, the compounds described herein (e.g., a mixed V1a agonist-antagonist such as Compound 1) have Figure 32 the concentration-response curve shown in Line 2. In some cases, Figure 32 Line 2 shows that even at high doses, the compounds described herein (e.g., a mixed V1a agonist-antagonist such as Compound 1) have a relatively large therapeutic window. In some cases, Figure 32 Line 2 shows that even at high doses, the compounds described herein (e.g., a mixed V1a agonist-antagonist such as Compound 1) are safe and effective.

[0329] In some cases, Figure 32 Curve 3 shows the concentration-response curve of a compound that does not reach the therapeutic level. In some cases, Figure 32 Curve 3 shows the concentration-response curve of a full agonist or partial agonist (such as a compound having relatively low activity against V1AR).

[0330] In some cases, Figures 32 - 38 it is shown that the compounds described herein (e.g., a mixed V1a agonist-antagonist such as Compound 1) can be safely used (in a large dose range) to treat ESLD or its symptoms and / or complications. In some cases, Figure 32Demonstrate that even at supra - physiological concentrations, the compounds described herein (e.g., mixed V1a agonist - antagonists such as Compound 1) provide maximal effects (e.g., change (increase) in MAP) in an individual (e.g., after subcutaneous administration). In some cases, Figures 32 - 38 Demonstrate that the compounds described herein (e.g., mixed V1a agonist - antagonists such as Compound 1) provide robust effects (e.g., change (increase) in MAP) in an individual (e.g., after subcutaneous administration). In some cases, Figures 32 - 38 Demonstrate that the compounds described herein (e.g., mixed V1a agonist - antagonists such as Compound 1) achieve, maintain, and do not exceed a safe and effective therapeutic effect (e.g., change (increase) in MAP), such as after subcutaneous administration. In some cases, Figures 32 - 38 Demonstrate that the compounds described herein (e.g., mixed V1a agonist - antagonists such as Compound 1) (e.g., after subcutaneous administration) maintain (a safe level of) therapeutic efficacy over an extended period of time (such as for at least 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 70 minutes, 80 minutes, 90 minutes or 100 minutes or longer). In some cases, Figures 32 - 38 Demonstrate that the compounds described herein (e.g., fully non - selective (V2, V1a) agonists such as terlipressin) rapidly reach toxic and potentially harmful concentrations, such as at relatively high doses. In some cases, Figures 32 - 38 Demonstrate that the compounds described herein (e.g., fully non - selective (V2, V1a) agonists such as terlipressin), the effects of the fully non - selective (V2, V1a) agonists rapidly wane, such as dropping below the therapeutic level rapidly after a relatively short period of time (e.g., after about 80 min or longer).

[0331] In some embodiments, the compounds described herein (e.g., Compound 1) modulate (e.g., increase) mean arterial pressure (MAP). In some embodiments, the compounds described herein (e.g., Compound 1) are administered subcutaneously and modulate (e.g., increase) MAP. In some embodiments, the compounds described herein (e.g., Compound 1) are administered subcutaneously and modulate (e.g., increase) MAP without (significant) injection site reactions (e.g., local vasoconstriction), such as at the subcutaneous injection site. In some embodiments, the compounds described herein (e.g., Compound 1) are suitable for subcutaneous administration for treating one or more complications of ESLD, such as refractory ascites.

[0332] In some embodiments, the regulation of an individual's mean arterial pressure (MAP) includes increasing the MAP by at least 5% relative to a baseline (e.g., the level such as before administering a compound described herein (e.g., Compound 1)). In some embodiments, the regulation of an individual's MAP includes increasing the MAP by at least 10% relative to a baseline (e.g., the level such as before administering a compound described herein (e.g., Compound 1)). In some embodiments, the regulation of an individual's MAP includes increasing the MAP by at least 15% relative to a baseline (e.g., the level such as before administering a compound described herein (e.g., Compound 1)). In some embodiments, the baseline is the level before administering a compound described herein (e.g., Compound 1). In some cases, the baseline is the level compared to a control (such as a placebo).

[0333] In some embodiments, the regulation of an individual's mean arterial pressure (MAP) includes increasing the MAP by at most 5% relative to a baseline (e.g., the level such as before administering a compound described herein (e.g., Compound 1)). In some embodiments, the regulation of an individual's MAP includes increasing the MAP by at most 10% relative to a baseline (e.g., the level such as before administering a compound described herein (e.g., Compound 1)). In some embodiments, the regulation of an individual's MAP includes increasing the MAP by at most 15% relative to a baseline (e.g., the level such as before administering a compound described herein (e.g., Compound 1)). In some embodiments, the baseline is the level before administering a compound described herein (e.g., Compound 1). In some cases, the baseline is the level compared to a control (such as a placebo).

[0334] In some embodiments, the regulation of an individual's MAP includes increasing the MAP by at least 5 mmHg relative to a baseline (e.g., the level such as before administering a compound described herein (e.g., Compound 1)). In some embodiments, the regulation of an individual's MAP includes increasing the MAP by 1 mmHg or more relative to a baseline (e.g., the level such as before administering a compound described herein (e.g., Compound 1)). In some embodiments, the regulation of an individual's MAP includes increasing the MAP by 5 mmHg or more relative to a baseline (e.g., the level such as before administering a compound described herein (e.g., Compound 1)). In some embodiments, the regulation of an individual's MAP includes increasing the MAP by 10 mmHg or more relative to a baseline (e.g., the level such as before administering a compound described herein (e.g., Compound 1)). In some embodiments, the regulation of an individual's MAP includes increasing the MAP by about 20 mmHg or more relative to a baseline (e.g., the level such as before administering a compound described herein (e.g., Compound 1)). In some embodiments, the baseline is the level before administering a compound described herein (e.g., Compound 1).

[0335] In some embodiments, provided herein are methods of modulating mean arterial pressure (MAP) in an individual (e.g., as described above), the methods comprising subcutaneously administering to the individual an effective amount of a compound having 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 the individual as a pharmaceutically acceptable salt.

[0336] In some embodiments, the compounds described herein (e.g., Compound 1) have 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 the individual as a pharmaceutically acceptable salt.

[0337] In some embodiments, D1 is selective for V1AR. In some embodiments, D1 is more selective for V1AR than for V2R. In some embodiments, D1 is more than 10-fold more selective for V1AR than for V2R. In some embodiments, D1 is more than 100-fold more selective for V1AR than for V2R. In some embodiments, D1 is more than 1,000-fold more selective for V1AR than for V2R. In some embodiments, D1 is more than 10,000-fold more selective for V1AR than for V2R. In some embodiments, D1 is inactive against V2R.

[0338] 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 cyclononapeptide. In some embodiments, D1 is a cyclononapeptide.

[0339] In some embodiments, D1 has or comprises the following structure:

[0340]

[0341] In some embodiments, D1 has or comprises the following structure:

[0342]

[0343] In some cases, D2 is selective for V1AR. In some embodiments, D2 is more selective for V1AR than for V2R. In some cases, D2 is more than 10-fold more selective for V1AR than for V2R. In some cases, D2 is more than 100-fold more selective for V1AR than for V2R. In some cases, D2 is more than 1,000-fold more selective for V1AR than for V2R. In some cases, D2 is more than 10,000-fold more selective for V1AR than for V2R. In some cases, D2 is inactive against V2R.

[0344] In some embodiments, at least one of D1 and D2 is selective for V1AR. In some embodiments, at least one of D1 and D2 is more selective for V1AR than for V2R.

[0345] 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, it is a linear polypeptide comprising about seven or more amino acid residues. In some embodiments, D2 comprises seven to twelve amino acid residues.

[0346] In some embodiments, D2 has or comprises the following structure:

[0347]

[0348] In some embodiments, D2 has or comprises the following structure:

[0349]

[0350] In some embodiments, L is a non-hydrolyzable linker.

[0351] 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.

[0352] 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, a substituted or unsubstituted alkyl, or a 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, 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 an oxo group.

[0353] In some embodiments, L has or comprises the following structure:

[0354]

[0355] In some embodiments, L has or comprises the following structure:

[0356]

[0357] In some embodiments, the compounds described herein are Compound 1 or a pharmaceutically acceptable salt thereof.

[0358] In some instances, Compound 1 is glycyl-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-L-ε-lysyl)-L-2,4-diaminobutyryl-, cyclo(1→6)-disulfide.

[0359] In some instances, Compound 1 has C 110 H 161 N 31 O 27 S2 as its empirical formula.

[0360] In some instances, Compound 1 has an average molecular weight of 2413.78 u.

[0361] In some instances, the mixed V1A agonist-antagonist provided herein (e.g., Compound 1) is a white to off-white powder.

[0362] In some cases, the hybrid V1A agonist-antagonist provided herein (e.g., Compound 1) has a solubility of at least 10 mg / mL in water.

[0363] In some embodiments, Compound 1 has a structure represented by Formula (I-A):

[0364]

[0365] or a pharmaceutically acceptable salt thereof.

[0366] In some cases, the hybrid V1A agonist-antagonist provided herein (e.g., Compound 1) is a 20-mer monocyclic branched peptide containing natural and non-natural amino acids (such as from non-animal sources). In some cases, the hybrid V1A agonist-antagonist provided herein (e.g., Compound 1) has an S-S bridge between Cys 1 and Cys 6 residues. In some cases, the branched chain is linked through the position 8 side chain amino functional group.

[0367] In some cases, the present invention provides a compound having a structure represented by Formula (I-B):

[0368]

[0369] or a pharmaceutically acceptable salt thereof,

[0370] wherein:

[0371] Dab is 2,4-diaminobutyric acid, D-Tyr(Me) is O-methyl-D-tyrosine, and

[0372] PhAc is phenylacetic acid (e.g., wherein L-2,4-diaminobutyric acid, N-ε-acetyl-L-lysine, L-isoglutamine, and O-methyl-D-tyrosine are non-natural, and the N-terminal moiety is replaced by phenylacetic acid).

[0373] In some cases, the hybrid V1A agonist-antagonist provided herein (e.g., Compound 1) is provided as a pharmaceutically acceptable salt. In some cases, the hybrid V1A agonist-antagonist provided herein (e.g., Compound 1) is provided as an acetate. In some cases, the hybrid V1A agonist-antagonist provided herein (e.g., Compound 1) is administered in the form described in Example 1.

[0374] In some embodiments, the compounds described herein are any of the compounds described in either U.S. Patent No. 9,644,000 or U.S. Patent No. 9,388,214, each of which is incorporated herein by reference in its entirety (specifically for the compounds provided herein).

[0375] In some cases, Compound 1 has the empirical formula C 110 H 161 N 31 O 27 S2(AcOH) z where z is any integer (e.g., from 1 - 100).

[0376] In some embodiments, provided herein are methods of modulating mean arterial pressure (MAP) in an individual (e.g., as described herein), the method comprising subcutaneously administering to the individual an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof.

[0377] In some embodiments, provided herein are pharmaceutical compositions that comprise an amount of a compound or a pharmaceutically acceptable salt thereof (e.g., Compound 1) described herein. 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.

[0378] In some embodiments, provided herein are subcutaneous formulations that comprise a compound described herein (such as a compound having a structure represented by Formula I) or a pharmaceutically acceptable salt thereof.

[0379] 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 subcutaneously to form M1.

[0380] 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 subcutaneously to form M1.

[0381] In some embodiments, the compositions described herein further comprise a liquid vehicle or solvent (e.g., water or an aqueous vehicle).

[0382] In some embodiments, provided herein are subcutaneous formulations having a compound as described herein at a concentration of about 0.001 milligrams (mg) per milliliter (mL) or higher, such as a compound having a structure represented by Formula I. In some embodiments, the subcutaneous formulation has a compound as described herein at a concentration of about 100 mg / mL or lower, such as a compound having a structure represented by Formula I. In some embodiments, the subcutaneous formulation has a compound as described herein at a concentration of about 0.001 mg / mL to 100 mg / mL, such as a compound having a structure represented by Formula I. In some embodiments, the subcutaneous formulation comprises a compound at a concentration of about 0.01 mg / mL to about 100 mg / mL. In some embodiments, the subcutaneous formulation comprises a compound at a concentration of about 0.1 mg / mL to about 100 mg / mL. In some embodiments, the subcutaneous formulation comprises a compound at a concentration of about 1 mg / mL to about 100 mg / mL. In some embodiments, the subcutaneous formulation comprises a compound at a concentration of about 0.1 mg / mL to about 50 mg / mL. In some embodiments, the subcutaneous formulation comprises a compound at a concentration of about 1 mg / mL to about 50 mg / mL. In some embodiments, the subcutaneous formulation comprises a compound at a concentration of about 0.1 mg / mL to about 10 mg / mL. In some embodiments, the subcutaneous formulation comprises a compound at a concentration of about 1 mg / mL to about 10 mg / mL.

[0383] 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 concentration of at least about 0.01 mg / mL of the compound. In some embodiments, the compound is formulated as an aqueous solution having a concentration of at least about 0.1 mg / mL of the compound. In some embodiments, the compound is formulated as an aqueous solution having a concentration of at least about 1 mg / mL of the compound. In some embodiments, the compound is formulated as an aqueous solution having a concentration of at least about 10 mg / mL of the compound. In some embodiments, the compound is formulated as an aqueous solution having a concentration of at most about 50 mg / mL of the compound. In some embodiments, the compound is formulated as an aqueous solution having a concentration of at most about 10 mg / mL of the compound. In some embodiments, the compound is formulated as an aqueous solution having a concentration of at most about 1 mg / mL of the compound. In some embodiments, the compound is formulated as an aqueous solution having a concentration of at most about 0.1 mg / mL of the compound. In some embodiments, the compound is formulated as an aqueous solution having a concentration of at most about 0.01 mg / mL of the compound. In some embodiments, the compound is formulated as an aqueous solution having a concentration of from about 0.01 mg / mL to about 50 mg / mL of the compound. In some embodiments, the compound is formulated as an aqueous solution having a concentration of from about 0.01 mg / mL to about 10 mg / mL of the compound. In some embodiments, the compound is formulated as an aqueous solution having a concentration of from about 1 mg / mL to about 10 mg / mL of the compound. In some embodiments, the composition is formulated with acetate buffer. In some embodiments, the composition is formulated at a pH of 4.5. In some embodiments, the composition is formulated with mannitol.

[0384] In some embodiments, an additive (e.g., a preservative) is added to the composition (e.g., subcutaneously) having a pH of about 3 - 6 (e.g., 4.5) and comprising at least about 1 millimolar (mM) acetate buffer (e.g., from about 5 mM sodium acetate to about 150 mM sodium acetate) and from about 10 milligrams per milliliter (mg / mL) to about 100 mg / mL mannitol (e.g., about 43.6 mg / mL mannitol). In some cases, the additive is a preservative. In some cases, a preservative is added to the composition (e.g., subcutaneously) having a pH of about 4.5 and comprising about 10 mM sodium acetate and about 43.6 mg / mL mannitol.

[0385] In some embodiments, provided herein are compositions comprising Compound 1. In some embodiments, the composition is suitable for subcutaneous administration. In some embodiments, the formulation is 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 formulation is suitable for subcutaneous infusion.

[0386] In some embodiments, the compositions described herein comprise an additive. In some embodiments, the compositions described herein are subcutaneous compositions and comprise an additive. In some embodiments, the additive is selected from the group consisting of preservatives, solubilizers (e.g., cyclodextrins), buffering agents, and chelating agents (e.g., zinc acetate or ethylenediaminetetraacetic acid (EDTA)). In some embodiments, the additive is a preservative.

[0387] In some embodiments, provided herein is a subcutaneous formulation that comprises a compound having a structure represented by Formula I and a preservative.

[0388] In some embodiments, the compositions described herein further comprise a preservative. In some embodiments, the preservative is any suitable preservative such as m-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 more. 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.

[0389] In some cases, even at relatively high concentrations of the preservative, the compositions described herein that contain the preservative do not show a physical interaction (e.g., aggregation) with any of the screened preservatives (e.g., between the preservative and Compound 1).

[0390] In some embodiments, provided herein is a subcutaneous formulation that comprises a compound having a structure represented by Formula I and a solubilizer.

[0391] In some embodiments, the compositions described herein further comprise a solubilizer. In some embodiments, the solubilizer is any suitable solubilizer such as cyclodextrin (e.g., sulfobutyl ether-β-cyclodextrin (SBECD)). In some embodiments, the solubilizer is present in the composition in an amount of about 0.1 mg / mL or more. In some embodiments, the solubilizer is present in the composition in an amount of about 500 mg / mL or less. In some embodiments, the solubilizer is present in the composition in an amount of about 250 mg / mL or less. In some embodiments, the solubilizer is present in the composition in an amount of about 100 mg / mL or less. In some embodiments, the solubilizer is present in the composition in an amount of about 0.1 mg / mL to about 250 mg / mL. In some embodiments, the solubilizer is present in the composition in an amount of about 0.1 mg / mL to about 100 mg / mL. In some embodiments, the solubilizer is present in the composition in an amount of about 1 mg / mL to about 250 mg / mL. In some embodiments, the solubilizer is present in the composition in an amount of about 1 mg / mL to about 100 mg / mL. In some embodiments, the solubilizer is present in the composition in an amount of about 60 mg / mL to about 80 mg / mL.

[0392] In some embodiments, the composition further comprises a buffer. In some embodiments, the buffer has a pKa of about 3.0 to about 6.0, such as at 25 °C. In some embodiments, the buffer is selected from the group consisting of acetate buffer, succinate buffer, phosphate buffer, and citrate buffer. In some embodiments, the composition further comprises acetate buffer. In some embodiments, the acetate buffer is a combination of acetate and acetic acid. In some embodiments, the composition further comprises succinate buffer. In some embodiments, the succinate buffer is a combination of succinate and succinic acid. In some embodiments, the composition further comprises citrate buffer. In some embodiments, the citrate buffer is a combination of citrate and citric acid.

[0393] In some embodiments, provided herein is a subcutaneous formulation that comprises a compound having a structure represented by Formula I and a buffer at a concentration of about 1 millimolar (mM) to about 1 M.

[0394] In some embodiments, the compositions described herein comprise a buffer at a concentration of about 1 millimolar (mM) or higher. In some embodiments, the compositions described herein comprise a buffer at a concentration of about 1 molar (M) or lower. In some embodiments, the compositions described herein comprise a buffer at a concentration of from about 1 mM to about 1 M. In some embodiments, the compositions described herein comprise a buffer at a concentration of from about 1 mM to about 500 mM. In some embodiments, the compositions described herein comprise a buffer at a concentration of from about 1 mM to about 250 mM. In some embodiments, the compositions described herein comprise a buffer at a concentration of from about 50 mM to about 250 mM. In some embodiments, the compositions described herein comprise a buffer at a concentration of from about 50 mM to about 150 mM. In some embodiments, the compositions described herein comprise a buffer at a concentration of about 100 mM. In some embodiments, the compositions described herein comprise a buffer at a concentration of from about 1 mM to about 50 mM. In some embodiments, the compositions described herein comprise a buffer at a concentration of from about 5 mM to about 25 mM. In some embodiments, the compositions described herein comprise a buffer at a concentration of about 10 mM.

[0395] In some embodiments, the compositions described herein have a pH sufficient to inhibit a protease (e.g., trypsin) (e.g., inactivate or deactivate it), such as in the subcutaneous layer of an individual to whom the formulation is administered subcutaneously.

[0396] In some embodiments, the pH of the compositions described herein does not change (significantly) when administered subcutaneously to an individual. In some embodiments, the pH of the compositions described herein does not change (significantly) when administered subcutaneously to an individual by subcutaneous (bolus) injection. In some embodiments, the pH of the compositions described herein does not change (significantly) when administered subcutaneously to an individual by subcutaneous infusion.

[0397] 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 lower, 8 or lower, 7 or lower, 6 or lower, 5 or lower, or 4 or lower. In some embodiments, the compositions described herein have a pH of from about 4 to about 8. In some embodiments, the compositions described herein have a pH of from about 4 to about 6. In some embodiments, the compositions described herein have a pH of from 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.

[0398] In some embodiments, the compositions described herein have an ionic strength of about 1 mM or higher. In some embodiments, the compositions described herein have an ionic strength of about 1 M or lower. 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.

[0399] In some embodiments, the compounds described herein (such as compounds having a structure represented by Formula I) are (e.g., substantially) less susceptible to degradation (e.g., by proteases). In some embodiments, in the subcutaneous layer of an individual to whom a composition comprising the compound is administered subcutaneously, the compounds described herein (such as compounds having a structure represented by Formula I) are (e.g., substantially) less susceptible to degradation (e.g., by proteases).

[0400] 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 longer, two weeks or longer, three weeks or longer, or four weeks or longer). 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 longer, six hours or longer, twelve hours or longer, or twenty-four hours or longer).

[0401] In some embodiments, the 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 the compounds described herein (e.g., Compound 1)) are well tolerated after subcutaneous (e.g., injection or infusion) administration (see Examples 3 and 4).

[0402] In some embodiments, the compositions described herein have a pH and / or buffer (e.g., acetate buffer) concentration sufficient to inhibit, reduce, or eliminate the formation of undesirable metabolites (such as full (V1a) agonists, like M1) of the compounds described herein (e.g., Compound 1). In some instances, compositions containing a relatively high buffer concentration (e.g., 50 mM or more of buffer) extend the amount of time that a local environment (e.g., at or near the injection site) maintains a certain pH (e.g., a pH of about 3 or higher) sufficient to inhibit, reduce, or eliminate the formation of undesirable metabolites (such as full (V1a) agonists, like M1) of the compounds described herein (e.g., Compound 1). In some instances, when (subcutaneously) injected, compositions having an acidic pH (e.g., a pH of 1 to 6) produce undesirable effects, such as a burning sensation, stinging, pain, etc. at the injection site. It is expected that compositions having a relatively acidic pH or a buffer concentration that extends the amount of time that a local environment (e.g., at or near the injection site) maintains a certain (e.g., acidic) pH will prolong such undesirable effects. In contrast, the compositions described herein having a relatively acidic pH (e.g., a pH of 4 or 4.5) and / or a buffer concentration that extends the amount of time that a local environment (e.g., at or near the injection site) maintains a certain (e.g., acidic) pH do not produce (significant) undesirable effects when administered subcutaneously (e.g., by injection or infusion). In some instances, a higher buffer concentration inhibits, reduces, or eliminates the formation of M1 to provide sufficient time for absorption of the compounds described herein, such as due to an extended period of time during which the pH of the local environment after administration is acidic (e.g., 4.5). In some embodiments, the buffer concentration of the compositions provided herein that extends the amount of time that a local environment (e.g., at or near the injection site) maintains a certain (e.g., acidic) pH is about 50 mM or higher. In some embodiments, when administered subcutaneously (e.g., by injection or infusion), the pH of the compositions provided herein sufficient to inhibit, reduce, or eliminate the formation of undesirable metabolites (such as full (V1a) agonists, like M1) of the compounds described herein (e.g., Compound 1) is acidic. In some embodiments, when administered subcutaneously (e.g., by injection or infusion), the pH of the compositions provided herein sufficient to inhibit, reduce, or eliminate the formation of undesirable metabolites (such as full (V1a) agonists, like M1) of the compounds described herein (e.g., Compound 1) is about 3 or higher. In some embodiments, when administered subcutaneously (e.g., by injection or infusion), the pH of the compositions provided herein sufficient to inhibit, reduce, or eliminate the formation of undesirable metabolites (such as full (V1a) agonists, like M1) of the compounds described herein (e.g., Compound 1) is about 4 or 4.5.

[0403] In some embodiments, the compositions described herein (e.g., compositions suitable for intravenous or subcutaneous administration) comprise acetate buffer at a concentration of about 10 mM or higher. In some embodiments, the compositions described herein comprise acetate buffer at a concentration of about 50 mM or higher.

[0404] In some embodiments, the compositions described herein (e.g., compositions suitable for intravenous or subcutaneous administration) have a pH of about 3 or higher.

[0405] In some embodiments, the compositions described herein (e.g., compositions suitable for intravenous administration) comprise acetate buffer at a concentration of 10 mM and have a pH of 4.5. In some embodiments, the composition is suitable for intravenous administration. In some embodiments, the composition does not contain a preservative. In some embodiments, the composition is suitable for subcutaneous administration. In some embodiments, the composition is suitable for subcutaneous infusion.

[0406] In some embodiments, the compositions described herein (e.g., compositions suitable for subcutaneous administration) comprise acetate buffer at a concentration of 100 mM (or higher) and have a pH of about 4 or 4.5. In some embodiments, the composition is suitable for subcutaneous administration. In some embodiments, the composition is suitable for subcutaneous (bolus) injection. In some embodiments, the composition is suitable for subcutaneous infusion.

[0407] In some embodiments, the compositions described herein (e.g., compositions suitable for intravenous or subcutaneous administration) comprise acetate buffer at a concentration of about 10 mM or higher. In some embodiments, the compositions described herein comprise acetate buffer at a concentration of about 50 mM or higher.

[0408] In some embodiments, the compositions described herein comprise a compound at a concentration sufficient to inhibit, reduce, or eliminate the formation of an undesired metabolite (such as a full (V1a) agonist, like M1) of the compound (e.g., compound 1) described herein. In some instances, a composition comprising a relatively high drug concentration (e.g., 0.1 milligram per milliliter (mg / mL) or higher) saturates the local environment (e.g., at or near the injection site) with the drug such that more of the drug is absorbed before a large amount of the undesired metabolite of the drug (such as a full (V1a) agonist) is formed. In some embodiments, when administered subcutaneously (e.g., by injection or infusion), the compositions described herein having a relatively high concentration of the compounds provided herein are sufficient to inhibit, reduce, or eliminate the formation of an undesired metabolite (such as a full (V1a) agonist, like M1) of the compound (e.g., compound 1) described herein. In some embodiments, the drug concentration in the composition (e.g., the concentration of the compound described herein) is about 0.1 mg / mL or higher.

[0409] In some embodiments, the compositions provided herein have a concentration of the compounds described herein of about 0.1 mg / mL or higher. In some embodiments, the compositions provided herein have a concentration of the compounds described herein of about 1 mg / mL or higher. In some embodiments, the compositions provided herein have a concentration of the compounds described herein of about 100 mg / mL or lower. In some embodiments, the compositions provided herein have a concentration of the compounds described herein of from about 0.1 mg / mL to about 100 mg / mL. In some embodiments, the compositions provided herein have a concentration of the compounds described herein of from about 0.1 mg / mL to about 10 mg / mL. In some embodiments, the composition is suitable for subcutaneous administration. In some embodiments, the composition is suitable for subcutaneous (bolus) injection. In some embodiments, the composition is suitable for subcutaneous infusion. In some embodiments, the compositions provided herein have a concentration of the compounds described herein of about 0.1 mg / mL or lower. In some embodiments, the composition is suitable for intravenous administration.

[0410] In some embodiments, the compositions described herein are suitable for subcutaneous infusion. In some embodiments, the composition suitable for subcutaneous infusion is administered to an individual in a manner that reduces (injection site) injury or trauma. In some embodiments, the composition suitable for subcutaneous infusion is administered to an individual over a (prolonged) period of time. In some embodiments, the composition suitable for subcutaneous infusion is administered to an individual at a (relatively slow) rate such as by 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 of about 0.1 milliliter per hour (mL / h) or lower over a (prolonged) period of time (e.g., a period of about 24 hours or longer).

[0411] In some embodiments, there are provided pharmaceutical compositions that comprise 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.

[0412] In some embodiments, there are provided pharmaceutical compositions that comprise an amount of Compound 1 or a pharmaceutically acceptable salt thereof, and the composition is formulated for subcutaneous administration. In some embodiments, the amount of the compound is an effective amount of the compound.

[0413] In some embodiments, the compositions described herein are suitable for systemic delivery of the active agents described herein, such as compounds having a structure represented by Formula I. In some embodiments, the compositions described herein are suitable for administration of the active agents described herein in an outpatient setting (such as at home), such as compounds having a structure represented by Formula I. 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).

[0414] In some embodiments, the present disclosure provides 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 the device is positioned on the skin of the individual.

[0415] In some embodiments, the system comprises an adhesive body for fixing the (subcutaneous infusion) device to the skin surface of the individual. In some embodiments, the system comprises an adhesive body for reversibly fixing the (subcutaneous infusion) device to the skin surface of the individual.

[0416] In some embodiments, the system comprises a cavity and a hollow tube. In some embodiments, the composition is configured within the cavity. In some embodiments, the hollow tube comprises a first opening and a second opening. In some embodiments, the first opening is in fluid communication with the cavity. In some embodiments, after the subcutaneous infusion device is fixed to the skin of the individual, the second opening is subcutaneously disposed within the individual. In some embodiments, the hollow tube is a needle, such as any needle gauge suitable for subcutaneous administration (e.g., subcutaneous infusion).

[0417] In some embodiments, the system does not comprise an adhesive body. In some embodiments, the device is not attached to the skin surface of the individual. In some embodiments, the cavity is attached to an injection port. In some embodiments, the system does not comprise an adhesive body and the cavity is attached to an injection port.

[0418] In some embodiments, the (subcutaneous infusion) device further comprises a pump configured to subcutaneously infuse the composition (e.g., as described herein) to the individual at a constant or variable rate. In some embodiments, the system is configured to provide the composition to the individual over a period of about 24 hours or longer. In some embodiments, the system is configured to continuously provide the composition to the individual over a period of about 24 hours or longer.

[0419] In some embodiments, the device is configured to receive a vial and / or a cartridge of the composition.

[0420] In some embodiments, the device is a subcutaneous infusion device. In some embodiments, the device is a pump.

[0421] In some cases, the present disclosure provides a pharmaceutical composition 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 wherein the second compound sufficiently blocks the (e.g., local) vasoconstrictive effect of the first compound, such as providing sufficient uptake of the first compound to the circulatory system and / or internal organs (e.g., the kidney) of an individual (e.g., in need). In some embodiments, the pharmaceutical composition is injectable. In some cases, the pharmaceutical composition is suitable for intravitreal administration. In some cases, the pharmaceutical composition is suitable for subcutaneous administration. In some cases, the first compound is a vasopressin receptor 1A (V1AR) agonist. In some cases, the first compound is a selective V1AR agonist. In some cases, the second compound is a V1AR antagonist. In some cases, the second compound is a selective V1AR antagonist. In some cases, the second compound is a vasodilator.

[0422] In some cases, such as in the carbon tetrachloride model described in Example 6, administration (e.g., subcutaneously) of a compound described herein (e.g., Compound 1) to an individual (e.g., in need) improves renal perfusion, renal excretory function, and systemic hemodynamics of the individual (e.g., relative to vehicle-treated animals).

[0423] In some cases, a compound described herein (e.g., Compound 1) administered subcutaneously improves excretory renal function (see Example 6). In some cases, a compound described herein (e.g., Compound 1) administered twice daily by subcutaneous injection improves excretory renal function (see Example 6). In some cases, a compound described herein (e.g., Compound 1) administered twice daily by subcutaneous bolus injection improves excretory renal function (see Example 6). In some cases, a compound described herein (e.g., Compound 1) administered twice daily by subcutaneous injection over three days improves excretory renal function (see Example 6).

[0424] In some cases, such as in the bile duct ligation (BDL) and ascites model described in Example 6, administration (e.g., subcutaneously) of a compound described herein (e.g., Compound 1) to an individual (e.g., in need) reduces the amount of ascites, splenic vasodilation, fluid retention, body weight, and / or net fluid balance of the individual (e.g., relative to vehicle-treated animals). In some cases, such as in the bile duct ligation (BDL) and ascites model described in Example 6, administration (e.g., subcutaneously) of a compound described herein (e.g., Compound 1) to an individual (e.g., in need) provides improved urinary potassium and sodium excretion in the individual (e.g., relative to vehicle control).

[0425] In some cases, such as in the bile duct ligation (BDL) and ascites models described in Example 6, repeated subcutaneous administration of the compounds described herein (e.g., Compound 1) provides a reduction in ascites volume, a reduction in splanchnic vasodilation, a reduction in fluid retention, and / or significant urinary potassium and sodium excretion without immediate development of hyponatremia following administration of the compound. In some embodiments, repeated subcutaneous administration of the compounds described herein (e.g., Compound 1) provides a significant reduction in urinary potassium excretion (e.g., compared to a vehicle control), such as 5 - 24 hours after administration of the compound.

[0426] In some cases, the compounds described herein (e.g., Compound 1) administered subcutaneously reduce ascites volume, spleen weight, and body weight (e.g., relative to a vehicle control). In some cases, the compounds described herein (e.g., Compound 1) administered via subcutaneous bolus injection reduce ascites volume, spleen weight, and body weight (e.g., relative to a vehicle control). In some cases, the compounds described herein (e.g., Compound 1) administered daily via subcutaneous administration reduce ascites volume, spleen weight, and body weight (e.g., relative to a vehicle control). In some cases, the compounds described herein (e.g., Compound 1) administered twice daily via subcutaneous administration reduce ascites volume, spleen weight, and body weight (e.g., relative to a vehicle control). In some cases, the compounds described herein (e.g., Compound 1) administered twice daily via subcutaneous bolus injection reduce ascites volume, spleen weight, and body weight (e.g., relative to a vehicle control). In some cases, the compounds described herein (e.g., Compound 1) administered twice daily via subcutaneous administration for several consecutive days reduce ascites volume, spleen weight, and body weight (e.g., relative to a vehicle control). In some cases, the compounds described herein (e.g., Compound 1) administered twice daily via subcutaneous administration for two or more days reduce ascites volume, spleen weight, and body weight (e.g., relative to a vehicle control). In some cases, the compounds described herein (e.g., Compound 1) administered twice daily via subcutaneous administration for five or more days reduce ascites volume, spleen weight, and body weight (e.g., relative to a vehicle control).

[0427] In some cases, the compounds described herein (e.g., Compound 1) administered subcutaneously increase urine volume, urinary sodium excretion, and urinary potassium excretion (e.g., relative to a vehicle control). In some cases, the compounds described herein (e.g., Compound 1) administered via subcutaneous bolus injection increase urine volume, urinary sodium excretion, and urinary potassium excretion (e.g., relative to a vehicle control). In some cases, the compounds described herein (e.g., Compound 1) administered daily via subcutaneous administration increase urine volume, urinary sodium excretion, and urinary potassium excretion (e.g., relative to a vehicle control). In some cases, the compounds described herein (e.g., Compound 1) administered twice daily via subcutaneous administration increase urine volume, urinary sodium excretion, and urinary potassium excretion (e.g., relative to a vehicle control). In some cases, the compounds described herein (e.g., Compound 1) administered twice daily via subcutaneous bolus injection increase urine volume, urinary sodium excretion, and urinary potassium excretion (e.g., relative to a vehicle control). In some cases, the compounds described herein (e.g., Compound 1) administered twice daily via subcutaneous administration for several consecutive days increase urine volume, urinary sodium excretion, and urinary potassium excretion (e.g., relative to a vehicle control). In some cases, the compounds described herein (e.g., Compound 1) administered twice daily via subcutaneous administration for two or more days increase urine volume, urinary sodium excretion, and urinary potassium excretion (e.g., relative to a vehicle control). In some cases, the compounds described herein (e.g., Compound 1) administered twice daily via subcutaneous administration for five or more days increase urine volume, urinary sodium excretion, and urinary potassium excretion (e.g., relative to a vehicle control).

[0428] In some cases, the compounds described herein (e.g., Compound 1) administered subcutaneously reduce urinary potassium excretion (e.g., relative to a vehicle control). In some cases, the compounds described herein (e.g., Compound 1) administered via subcutaneous bolus injection reduce urinary potassium excretion (e.g., relative to a vehicle control). In some cases, the compounds described herein (e.g., Compound 1) administered daily via subcutaneous administration reduce urinary potassium excretion (e.g., relative to a vehicle control). In some cases, the compounds described herein (e.g., Compound 1) administered twice daily via subcutaneous administration reduce urinary potassium excretion (e.g., relative to a vehicle control). In some cases, the compounds described herein (e.g., Compound 1) administered twice daily via subcutaneous bolus injection reduce urinary potassium excretion (e.g., relative to a vehicle control). In some cases, the compounds described herein (e.g., Compound 1) administered twice daily via subcutaneous administration for several consecutive days reduce urinary potassium excretion (e.g., relative to a vehicle control). In some cases, the compounds described herein (e.g., Compound 1) administered twice daily via subcutaneous administration for two or more days reduce urinary potassium excretion (e.g., relative to a vehicle control). In some cases, the compounds described herein (e.g., Compound 1) administered twice daily via subcutaneous administration for five or more days reduce urinary potassium excretion (e.g., relative to a vehicle control).

[0429] In some embodiments, after subcutaneous administration of the compounds described herein or a pharmaceutically acceptable salt thereof to an individual, the urine volume of the individual increases (e.g., as compared to a vehicle control). In some embodiments, after subcutaneous administration of the compounds described herein or a pharmaceutically acceptable salt thereof to an individual, such as within the first 24 hours, the urine volume of the individual significantly increases (e.g., as compared to a vehicle control). In some embodiments, after subcutaneous administration of the compounds described herein or a pharmaceutically acceptable salt thereof to an individual, such as within the first 4 hours, the urine volume of the individual significantly increases (e.g., as compared to a vehicle control).

[0430] In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the urine output of the individual increases by about 25% or more (e.g., compared to a vehicle control). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the urine output of the individual increases by about 50% or more (e.g., compared to a vehicle control). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the urine output of the individual increases by about 100% or more (e.g., compared to a vehicle control). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the urine output of the individual increases by about 200% or more (e.g., compared to a vehicle control). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the urine output of the individual increases by about 300% or more (e.g., compared to a vehicle control). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the urine output of the individual increases by about 400% or more (e.g., compared to a vehicle control). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the urine output of the individual increases by about 500% or more (e.g., compared to a vehicle control).

[0431] In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the urine output of the individual increases by about 25% or less (e.g., compared to a vehicle control). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the urine output of the individual increases by about 50% or less (e.g., compared to a vehicle control). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the urine output of the individual increases by about 100% or less (e.g., compared to a vehicle control). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the urine output of the individual increases by about 200% or less (e.g., compared to a vehicle control). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the urine output of the individual increases by about 300% or less (e.g., compared to a vehicle control). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the urine output of the individual increases by about 400% or less (e.g., compared to a vehicle control). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the urine output of the individual increases by about 500% or less (e.g., compared to a vehicle control).

[0432] In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the urine volume of the individual increases by about 10% to about 1000% (e.g., compared to a vehicle control). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the urine volume of the individual increases by about 50% to about 500% (e.g., compared to a vehicle control). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the urine volume of the individual increases by about 100% to about 500% (e.g., compared to a vehicle control).

[0433] In some embodiments, at least one day after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the urine volume of the individual is about 10% or more higher. In some embodiments, at least one day after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the urine volume of the individual is about 50% or more. In some embodiments, at least one day after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the urine volume of the individual is about 100% or more higher. In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the urine volume of the individual is higher for two or more days. In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the urine volume of the individual is higher for three or more days.

[0434] In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the urinary sodium of the individual increases (e.g., compared to a vehicle control). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the urinary sodium of the individual significantly increases (e.g., compared to a vehicle control). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the urinary sodium excretion of the individual increases (e.g., compared to a vehicle control). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the urinary sodium excretion of the individual significantly increases (e.g., compared to a vehicle control).

[0435] In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the urinary potassium of the individual increases (e.g., as compared to a vehicle control). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the urinary potassium of the individual significantly increases (e.g., as compared to a vehicle control). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the urinary potassium excretion of the individual increases (e.g., as compared to a vehicle control). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the urinary potassium excretion of the individual significantly increases (e.g., as compared to a vehicle control).

[0436] In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the urinary potassium excretion of the individual decreases (e.g., as compared to a vehicle control). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the urinary potassium excretion of the individual significantly decreases (e.g., as compared to a vehicle control).

[0437] In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the individual's urinary sodium excretion increases by about 10% or more (e.g., compared to a vehicle control, such as within the first 4 hours of treatment). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the individual's urinary sodium excretion increases by about 100% or more (e.g., compared to a vehicle control, such as within the first 4 hours of treatment). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the individual's urinary sodium excretion increases by about 250% or more (e.g., compared to a vehicle control, such as within the first 4 hours of treatment). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the individual's urinary sodium excretion increases by about 500% or more (e.g., compared to a vehicle control, such as within the first 4 hours of treatment). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the individual's urinary sodium excretion increases by about 750% or more (e.g., compared to a vehicle control, such as within the first 4 hours of treatment). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the individual's urinary sodium excretion increases by about 1000% or more (e.g., compared to a vehicle control, such as within the first 4 hours of treatment). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the individual's urinary sodium excretion increases by about 1500% or more (e.g., compared to a vehicle control, such as within the first 4 hours of treatment). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the individual's urinary sodium excretion increases by about 2000% or more (e.g., compared to a vehicle control, such as within the first 4 hours of treatment).

[0438] In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the individual's urinary sodium excretion increases by about 10% to about 5000% (e.g., compared to a vehicle control, such as within the first 4 hours of treatment). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the individual's urinary sodium excretion increases by about 10% to about 2500% (e.g., compared to a vehicle control, such as within the first 4 hours of treatment). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the individual's urinary sodium excretion increases by about 10% to about 2000% (e.g., compared to a vehicle control, such as within the first 4 hours of treatment). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the individual's urinary sodium excretion increases by about 100% to about 2000% (e.g., compared to a vehicle control, such as within the first 4 hours of treatment). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the individual's urinary sodium excretion increases by about 100% to about 1000% (e.g., compared to a vehicle control, such as within the first 4 hours of treatment).

[0439] In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the individual's urinary sodium excretion increases by about 10% or more (e.g., compared to a vehicle control, such as within the first 4 hours of treatment). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the individual's urinary sodium excretion increases by about 100% or more (e.g., compared to a vehicle control, such as within the first 4 hours of treatment). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the individual's urinary sodium excretion increases by about 250% or more (e.g., compared to a vehicle control, such as within the first 4 hours of treatment). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the individual's urinary sodium excretion increases by about 500% or more (e.g., compared to a vehicle control, such as within the first 4 hours of treatment). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the individual's urinary sodium excretion increases by about 750% or more (e.g., compared to a vehicle control, such as within the first 4 hours of treatment). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the individual's urinary sodium excretion increases by about 1000% or more (e.g., compared to a vehicle control, such as within the first 4 hours of treatment). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the individual's urinary sodium excretion increases by about 1500% or more (e.g., compared to a vehicle control, such as within the first 4 hours of treatment). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the individual's urinary sodium excretion increases by about 2000% or more (e.g., compared to a vehicle control, such as within the first 4 hours of treatment).

[0440] In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the individual's urinary sodium excretion increases by about 10% to about 5000% (e.g., compared to a vehicle control, such as within the first 4 hours of treatment). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the individual's urinary sodium excretion increases by about 10% to about 2500% (e.g., compared to a vehicle control, such as within the first 4 hours of treatment). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the individual's urinary sodium excretion increases by about 10% to about 2000% (e.g., compared to a vehicle control, such as within the first 4 hours of treatment). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the individual's urinary sodium excretion increases by about 100% to about 2000% (e.g., compared to a vehicle control, such as within the first 4 hours of treatment). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the individual's urinary sodium excretion increases by about 100% to about 1000% (e.g., compared to a vehicle control, such as within the first 4 hours of treatment).

[0441] In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the urinary potassium excretion of the individual increases by about 10% or more (e.g., compared to a vehicle control, such as within the first 4 hours of treatment). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the urinary potassium excretion of the individual increases by about 100% or more (e.g., compared to a vehicle control, such as within the first 4 hours of treatment). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the urinary potassium excretion of the individual increases by about 250% or more (e.g., compared to a vehicle control, such as within the first 4 hours of treatment). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the urinary potassium excretion of the individual increases by about 500% or more (e.g., compared to a vehicle control, such as within the first 4 hours of treatment). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the urinary potassium excretion of the individual increases by about 750% or more (e.g., compared to a vehicle control, such as within the first 4 hours of treatment). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the urinary potassium excretion of the individual increases by about 1000% or more (e.g., compared to a vehicle control, such as within the first 4 hours of treatment). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the urinary potassium excretion of the individual increases by about 1500% or more (e.g., compared to a vehicle control, such as within the first 4 hours of treatment). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the urinary potassium excretion of the individual increases by about 2000% or more (e.g., compared to a vehicle control, such as within the first 4 hours of treatment).

[0442] In some embodiments, after subcutaneous administration of the compounds or pharmaceutically acceptable salts thereof described herein to an individual, the urinary potassium excretion of the individual increases by about 10% to about 5000% (e.g., compared to a vehicle control, such as within the first 4 hours of treatment). In some embodiments, after subcutaneous administration of the compounds or pharmaceutically acceptable salts thereof described herein to an individual, the urinary potassium excretion of the individual increases by about 10% to about 2500% (e.g., compared to a vehicle control, such as within the first 4 hours of treatment). In some embodiments, after subcutaneous administration of the compounds or pharmaceutically acceptable salts thereof described herein to an individual, the urinary potassium excretion of the individual increases by about 10% to about 2000% (e.g., compared to a vehicle control, such as within the first 4 hours of treatment). In some embodiments, after subcutaneous administration of the compounds or pharmaceutically acceptable salts thereof described herein to an individual, the urinary potassium excretion of the individual increases by about 100% to about 2000% (e.g., compared to a vehicle control, such as within the first 4 hours of treatment). In some embodiments, after subcutaneous administration of the compounds or pharmaceutically acceptable salts thereof described herein to an individual, the urinary potassium excretion of the individual increases by about 100% to about 1000% (e.g., compared to a vehicle control, such as within the first 4 hours of treatment).

[0443] In some embodiments, after subcutaneous administration of the compounds or pharmaceutically acceptable salts thereof described herein to an individual, the urinary potassium excretion of the individual decreases by about 10% or more (e.g., compared to a vehicle control, such as about 5 hours after treatment). In some embodiments, after subcutaneous administration of the compounds or pharmaceutically acceptable salts thereof described herein to an individual, the urinary potassium excretion of the individual decreases by about 100% or more (e.g., compared to a vehicle control, such as about 5 hours after treatment). In some embodiments, after subcutaneous administration of the compounds or pharmaceutically acceptable salts thereof described herein to an individual, the urinary potassium excretion of the individual decreases by about 250% or more (e.g., compared to a vehicle control, such as about 5 hours after treatment). In some embodiments, after subcutaneous administration of the compounds or pharmaceutically acceptable salts thereof described herein to an individual, the urinary potassium excretion of the individual decreases by about 500% or more (e.g., compared to a vehicle control, such as about 5 hours after treatment).

[0444] In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the urinary potassium excretion of the individual is reduced by about 10% to about 5000% (e.g., compared to a vehicle control, such as about 5 hours after treatment). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the urinary potassium excretion of the individual is reduced by about 10% to about 2500% (e.g., compared to a vehicle control, such as about 5 hours after treatment). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the urinary potassium excretion of the individual is reduced by about 10% to about 2000% (e.g., compared to a vehicle control, such as about 5 hours after treatment). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the urinary potassium excretion of the individual is reduced by about 10% to about 500% (e.g., compared to a vehicle control, such as about 5 hours after treatment). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the urinary potassium excretion of the individual is reduced by about 10% to about 100% (e.g., compared to a vehicle control, such as about 5 hours after treatment).

[0445] In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the amount of ascites fluid in the individual is reduced (e.g., compared to a vehicle control). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the amount of ascites fluid in the individual is significantly reduced (e.g., compared to a vehicle control).

[0446] In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the amount of ascites fluid in the individual is reduced by about 10% or more (e.g., compared to a vehicle control, such as when measured 3 days after treatment). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the amount of ascites fluid in the individual is reduced by about 50% or more (e.g., compared to a vehicle control, such as when measured 3 days after treatment). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the amount of ascites fluid in the individual is reduced by about 100% or more (e.g., compared to a vehicle control, such as when measured 3 days after treatment). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the amount of ascites fluid in the individual is reduced by about 200% or more (e.g., compared to a vehicle control, such as when measured 3 days after treatment). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the amount of ascites fluid in the individual is reduced by about 300% or more (e.g., compared to a vehicle control, such as when measured 3 days after treatment).

[0447] In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the amount of ascites fluid in the individual is reduced by about 10% to about 1000% (e.g., compared to a vehicle control, such as when measured 3 days after treatment). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the amount of ascites fluid in the individual is reduced by about 10% to about 500% (e.g., compared to a vehicle control, such as when measured 3 days after treatment). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the amount of ascites fluid in the individual is reduced by about 50% to about 300% (e.g., compared to a vehicle control, such as when measured 3 days after treatment).

[0448] In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the weight of the individual is reduced (e.g., compared to a vehicle control). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the weight of the individual is significantly reduced (e.g., compared to a vehicle control).

[0449] In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the weight of the individual is reduced by about 1% or more (e.g., compared to a vehicle control). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the weight of the individual is reduced by about 2.5% or more (e.g., compared to a vehicle control). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the weight of the individual is reduced by about 5% or more (e.g., compared to a vehicle control). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the weight of the individual is reduced by about 10% or more (e.g., compared to a vehicle control). In some embodiments, the change in weight is measured at least one day after administration of the compound. In some embodiments, the change in weight is measured two or more days after administration of the compound. In some embodiments, the change in weight is measured three or more days after administration of the compound. In some embodiments, the change in weight is measured four or more days after administration of the compound. In some embodiments, the change in weight is measured five or more days after administration of the compound.

[0450] In some embodiments, there are statistical differences in plasma chemical markers after subcutaneous administration of the compounds or their pharmaceutically acceptable salts described herein to an individual. In some embodiments, there are statistical differences in plasma chemical markers BUN, Cl, PHOS, Na, and / or the BUN / CREA ratio after subcutaneous administration of the compounds or their pharmaceutically acceptable salts described herein to an individual. In some embodiments, there are no statistical differences in plasma chemical markers ALB, ALP, ALT, AST, BCARB, Ca, CHOL, CPK, CREA, DBIL, GGT, GLOB, GLU, IBIL, K, LDH, TBIL, and TPRO after subcutaneous administration of the compounds or their pharmaceutically acceptable salts described herein to an individual.

[0451] In some embodiments, after subcutaneous administration of the compounds or their pharmaceutically acceptable salts described herein to an individual, the individual's body weight decreases by about 1% to about 10% (e.g., compared to a vehicle control). In some embodiments, after subcutaneous administration of the compounds or their pharmaceutically acceptable salts described herein to an individual, the individual's body weight decreases by about 1% to about 5% (e.g., compared to a vehicle control).

[0452] In some embodiments, the compounds described herein (e.g., compound 1) are safe (e.g., in humans) (e.g., see Example 1). In some embodiments, the compounds described herein (e.g., compound 1) are well-tolerated (e.g., in humans) (e.g., see Example 1). In some embodiments, the compounds described herein (e.g., compound 1) are safe and well-tolerated (e.g., in humans) (e.g., see Example 1). In some embodiments, the pharmacodynamic profile of the compounds described herein (e.g., compound 1) has a submaximal partial agonism consistent with a mixed agonist-antagonist of the V1a receptor.

[0453] In some cases, the compounds described herein (e.g., compound 1) are tested in a Phase 1, double-blind, placebo-controlled, dose-group randomized trial to study the safety, tolerability, and pharmacokinetic and pharmacodynamic (PD) profiles of the compounds administered to healthy adults aged 18 to 45 years (see Example 1). In some cases, the trial includes 2 treatment periods: Phase 1 (a 6-h intravenous [IV] infusion of the compound or placebo in the dose range of 0.1 to 0.9 mg) and Phase 2 (a once-daily subcutaneous [SC] injection of the compound 0.1, 0.3 mg, or placebo for 5 consecutive days). In some cases, Phase 1 includes 32 males and females. In some cases, 8 males and 5 females continue into Phase 2. In some cases, such as after intravenous administration, as determined by AUC and C maxThe measured exposures were approximately dose proportional over the dose range studied. In some cases, such as after subcutaneous administration, T max was 0.3 h, the exposure was supra-proportional, and the bioavailability was 18%, with no apparent accumulation after repeated dosing. In some cases, after intravenous and subcutaneous administration, the terminal half-lives (t 1 / 2 ) of the compounds described herein (e.g., Compound 1) were approximately 1.5 h and 1.0 h, respectively, such as indicating that absorption was not rate-limiting for elimination after subcutaneous administration. In some cases, in all dose groups, the diastolic blood pressure and (to a lesser extent) the systolic blood pressure (BP) increased, while the pulse rate decreased, in subjects treated with the compounds described herein (e.g., Compound 1). In some cases, the overall change in mean arterial pressure (MAP) after intravenous and subcutaneous administration was similar to the change in diastolic BP. In some cases, the absolute change in cardiac output measured by echocardiogram appeared to be dose-dependent, decreasing on average by 3% - 12% after a 0.9 mg intravenous dose, and ≤20% - 25% individually at any dose. In some cases, the adverse events (AEs) included abdominal pain and diarrhea, laboratory tests for mesenteric ischemia were negative, and no cases of mesenteric ischemia were reported. In some cases, the AEs were treatment-related, generally mild or moderate in severity, and attributable to the expected pharmacological effects.

[0454] In some embodiments, after administration of the compounds described herein or a pharmaceutically acceptable salt thereof (e.g., Compound 1), the diastolic blood pressure of an individual increases (e.g., compared to pre-treatment baseline measurements). In some embodiments, after subcutaneous administration of the compounds described herein or a pharmaceutically acceptable salt thereof (e.g., Compound 1), the diastolic blood pressure of an individual increases (e.g., compared to pre-treatment baseline measurements).

[0455] In some embodiments, after administration of the compounds described herein or a pharmaceutically acceptable salt thereof (e.g., Compound 1), the systolic blood pressure of an individual increases (e.g., compared to pre-treatment baseline measurements). In some embodiments, after subcutaneous administration of the compounds described herein or a pharmaceutically acceptable salt thereof (e.g., Compound 1), the systolic blood pressure of an individual increases (e.g., compared to pre-treatment baseline measurements).

[0456] In some embodiments, after administration of the compounds described herein or a pharmaceutically acceptable salt thereof (e.g., Compound 1), the diastolic and / or systolic blood pressure of an individual increases in a dose-dependent manner (e.g., compared to pre-treatment baseline measurements). In some embodiments, after subcutaneous administration of the compounds described herein or a pharmaceutically acceptable salt thereof (e.g., Compound 1), the diastolic and / or systolic blood pressure of an individual increases in a dose-dependent manner (e.g., compared to pre-treatment baseline measurements).

[0457] In some embodiments, the compounds provided herein have a maximum therapeutic concentration. In some embodiments, the maximum therapeutic concentration includes an increase in concentration that does not provide a dose-dependent increase in blood pressure, such as diastolic blood pressure, systolic blood pressure, and / or MAP. In some embodiments, the compounds provided herein have a non-linear dose-dependence, such as above the maximum therapeutic concentration. In some embodiments, the dose-dependent increase in blood pressure, such as diastolic blood pressure, systolic blood pressure, and / or MAP, includes the maximum therapeutic concentration. In some embodiments, dose-dependence includes a situation where the effect increases with the dose for at least a certain dose range. For example, a higher dose may not provide or may provide a lower dose-dependent increase.

[0458] In some embodiments, MAP is calculated from measurements of systolic and diastolic blood pressures. In some embodiments, MAP is calculated when considering the pressure during a single cardiac cycle. In some embodiments, MAP is 1 / 3 (systolic blood pressure - diastolic blood pressure) + diastolic blood pressure.

[0459] In some embodiments, after administration of the compounds provided herein or a pharmaceutically acceptable salt thereof (e.g., Compound 1), the pulse rate of an individual decreases (e.g., compared to a pre-treatment baseline measurement). In some embodiments, after administration of the compounds provided herein or a pharmaceutically acceptable salt thereof (e.g., Compound 1), the peripheral blood flow of an individual decreases (e.g., compared to a pre-treatment baseline measurement). In some embodiments, after administration of the compounds provided herein or a pharmaceutically acceptable salt thereof (e.g., Compound 1), the pulse rate and peripheral blood flow of an individual decrease (e.g., compared to a pre-treatment baseline measurement).

[0460] In some embodiments, administration of the compounds provided herein or a pharmaceutically acceptable salt thereof (e.g., Compound 1) to an individual (e.g., as described herein) improves the systemic hemodynamics of the individual. In some embodiments, subcutaneous administration of the compounds provided herein or a pharmaceutically acceptable salt thereof (e.g., Compound 1) to an individual (e.g., as described herein) improves the systemic hemodynamics of the individual.

[0461] In some embodiments, administering to an individual (e.g., as described herein) a compound or a pharmaceutically acceptable salt thereof (e.g., Compound 1) described herein reduces fluid retention in the individual. In some embodiments, administering to an individual (e.g., as described herein) a compound or a pharmaceutically acceptable salt thereof (e.g., Compound 1) described herein reduces fluid overload in the individual. In some embodiments, administering to an individual (e.g., as described herein) a compound or a pharmaceutically acceptable salt thereof (e.g., Compound 1) described herein reduces both fluid retention and overload in the individual. In some embodiments, administering subcutaneously to an individual (e.g., as described herein) a compound or a pharmaceutically acceptable salt thereof (e.g., Compound 1) described herein reduces fluid retention in the individual. In some embodiments, administering subcutaneously to an individual (e.g., as described herein) a compound or a pharmaceutically acceptable salt thereof (e.g., Compound 1) described herein reduces fluid overload in the individual. In some embodiments, administering subcutaneously to an individual (e.g., as described herein) a compound or a pharmaceutically acceptable salt thereof (e.g., Compound 1) described herein reduces both fluid retention and overload in the individual.

[0462] In some embodiments, administering to an individual (e.g., as described herein) (e.g., subcutaneously) a compound or a pharmaceutically acceptable salt thereof (e.g., Compound 1) described herein reduces the serum creatinine (sCr) (value) in the individual (e.g., compared to a pre-treatment baseline measurement). In some embodiments, administering to an individual (e.g., as described herein) (e.g., subcutaneously) a compound or a pharmaceutically acceptable salt thereof (e.g., Compound 1) described herein until at least the individual has an sCr value of 1.5 milligrams (mg) / deciliter (dL) or less. In some embodiments, administering to an individual (e.g., as described herein) (e.g., subcutaneously) a compound or a pharmaceutically acceptable salt thereof (e.g., Compound 1) described herein until at least the sCr value of the individual returns to normal (e.g., baseline).

[0463] In some cases, intravenous (i.v.) administration of a compound (e.g., Compound 1) described herein provides a terminal half-life of about 1.5 hours, with a clearance and volume of distribution of about 13 L / h and about 15 - 20 L, respectively. In some cases, after subcutaneous (s.c.) administration of a compound (e.g., Compound 1) described herein, the t max is about 0.3 hours and the terminal half-life is about 1 hour (e.g., without any accumulation upon repeated administration). In some cases, the bioavailability after subcutaneous (s.c.) administration of a compound (e.g., Compound 1) described herein is about 18%.

[0464] In some cases, a compound (e.g., Compound 1) described herein has an exposure (by AUC and C) after intravenous administration max) proportional increase. In some cases, the compounds described herein (e.g., Compound 1) exceed approximate proportionality after subcutaneous administration. In some cases, the compounds described herein (e.g., Compound 1) have higher exposure in females than in males, such as after intravenous infusion and subcutaneous injection.

[0465] In some cases, the compounds described herein (e.g., Compound 1) are metabolized to metabolite M1 (see Figure 14 ). M1 has a free-form structure as the structure circled 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 has the chemical formula C 60 H 98 N 19 O 16 S2 + . Compared to Compound 1, M1 has (significantly) lower activity (against V1a). Specifically, the activity of M1 against V1a is approximately one-tenth of that of Compound 1.

[0466] In some cases, such as in a single subject after intravenous administration, M1 is found in the plasma of individuals administered Compound 1. In some cases, such as in all studied subjects, M1 is found at comparable concentrations to Compound 1 after subcutaneous administration. In some cases, the compounds described herein (e.g., Compound 1) are metabolized (e.g., to M1) during transport to the circulation after subcutaneous injection. As discussed above, it is known that the full agonists described herein are toxic and cause (critical) adverse events when administered subcutaneously. Therefore, the formation of full agonists (e.g., M1), such as when the compounds described herein are administered by subcutaneous (bolus) injection, is undesirable, such as when used for the purposes described herein.

[0467] In some cases, compared to intravenous infusion of the compounds described herein (e.g., Compound 1), the non-dose-dependent increase in diastolic blood pressure and (to a lesser extent) systolic blood pressure is more significant (e.g., accompanied by a reflex decrease in pulse rate). In some cases, after intravenous and subcutaneous administration of the compounds described herein (e.g., Compound 1), peripheral blood flow decreases.

[0468] In some cases, individuals receiving a certain dose of the compounds described herein (e.g., Compound 1) have adverse events (AEs) (e.g., treatment-related). In some cases, the AE occurs at the start of the subcutaneous treatment period. In some cases, there are more AEs after subcutaneous administration compared to intravenous administration. In some cases, there are more AEs in females compared to males. In some cases, the AE has mild or moderate intensity. In some cases, the AE has severe intensity. In some cases, the AE of severe intensity is a mild elevation of troponin I.

[0469] In some cases, the compounds described herein (e.g., Compound 1) induce a reversible increase in diastolic blood pressure. In some cases, the compounds described herein (e.g., Compound 1) induce a reversible increase in systolic blood pressure. In some cases, the compounds described herein (e.g., Compound 1) induce a reversible increase in MAP. In some cases, the compounds described herein (e.g., Compound 1) induce a reversible increase in diastolic blood pressure and MAP. In some cases, the compounds described herein (e.g., Compound 1) induce a decrease in heart rate and cardiac output. In some cases, the evaluation of ECG, clinical chemistry, hematology, hemostasis, and urine analysis parameters does not provide any safety concerns for the compounds described herein (e.g., Compound 1).

[0470] In some cases, such as when administered as a single intravenous infusion, the compounds described herein (e.g., Compound 1) are safe and well-tolerated (e.g., in both males and females), such as at a dose of about 0.9 mg or less. In some cases, the maximum tolerated subcutaneous dose (MTD) of the compounds described herein (e.g., Compound 1) is about 0.1 mg.

[0471] In some cases, the pharmacokinetic parameters of the compounds described herein (e.g., in plasma for the 0.1 mg to 0.9 mg intravenous dose group) provide dose proportionality. In some cases, the pharmacokinetic parameters of the compounds described herein (e.g., in plasma for the 0.1 mg to 0.9 mg intravenous dose group) provide that non-dose-dependent PK parameters are comparable between dose groups (see Example 1). In some cases, males clear the compounds described herein (e.g., Compound 1) at a higher rate compared to females. In some cases, males administered the compounds described herein (e.g., Compound 1) have lower Compound C max In some cases, males administered the compounds described herein (e.g., Compound 1) have lower Compound AUC compared to females. In some cases, males administered the compounds described herein (e.g., Compound 1) have lower Compound Cmax and AUC.

[0472] In some cases, such as after subcutaneous administration of the compounds described herein (e.g., Compound 1), t max is consistent between the first and fifth doses. In some cases, such as after subcutaneous administration of the compounds described herein (e.g., Compound 1), t 1 / 2 is consistent between the first and fifth doses. In some cases, such as after subcutaneous administration of the compounds described herein (e.g., Compound 1), t max and t 1 / 2 is consistent between the first and fifth doses. In some cases, such as after subcutaneous administration of the compounds described herein (e.g., Compound 1), the AUC is variable between the first and fifth doses. In some cases, such as after subcutaneous administration of the compounds described herein (e.g., Compound 1), C max is variable between the first and fifth doses. In some cases, such as after subcutaneous administration of the compounds described herein (e.g., Compound 1), the AUC and C max are variable between the first and fifth doses. In some cases, the AUC and C max have dose proportionality that is proportional (e.g., only for C at the fifth administration max ).

[0473] In some cases, after intravenous administration, the terminal half-life of the compounds described herein (e.g., Compound 1) is about 1.5 hours. In some cases, after subcutaneous administration, the terminal half-life of the compounds described herein (e.g., Compound 1) is about 1 hour. In some cases, the terminal half-life of the compounds described herein (e.g., Compound 1) is comparable in males and females (e.g., indicating that absorption is not rate-limiting for elimination after subcutaneous administration, such as supported by a shorter time to C max (about 0.3 hours) and similar in both males and females). In some cases, the bioavailability of the compounds described herein (e.g., Compound 1) is about 18%. In some cases, the formation of metabolites after subcutaneous administration (such as producing metabolites and compounds with comparable concentrations) provides a bioavailability of about 18%. In some cases, after intravenous administration, the fraction of the unchanged excreted dose in urine is about <10%. In some cases, after subcutaneous administration, the fraction of the unchanged excreted dose of the compounds described herein (e.g., Compound 1) in urine is about <5%. In some cases, the fraction of the unchanged excreted dose of the compounds described herein (e.g., Compound 1) in urine is constant over the entire dose range (e.g., of the study provided in Example 1).

[0474] The presence of metabolite M1 (a full agonist) in plasma after subcutaneous administration (but present only at very low concentrations (<1% of compound 1) after intravenous administration) demonstrates that compound 1 is metabolized somewhere along the path between the subcutaneous tissue and the systemic circulation. In some cases, the half-life of M1 is longer than that of compound 1 after intravenous and subcutaneous administrations. In some cases, the half-life of compound 1 is shorter after subcutaneous administration compared to intravenous administration (e.g., approximately 2 hours and 4 hours, respectively). In some cases, the compounds described herein (e.g., compound 1) are metabolized in the kidney.

[0475] In some cases, the pharmacodynamic effects of the compounds described herein (e.g., compound 1) on blood pressure and heart rate are as expected for a vasopressin V1a specific agonist. In some cases, administration of the compounds described herein (e.g., compound 1) to an individual provides an increase in the diastolic blood pressure of the individual. In some cases, administration of the compounds described herein (e.g., compound 1) to an individual provides an increase in the systolic blood pressure of the individual. In some cases, administration of the compounds described herein (e.g., compound 1) to an individual provides an increase in the MAP of the individual. In some cases, administration of the compounds described herein (e.g., compound 1) to an individual provides a decrease in the pulse of the individual. In some cases, administration of the compounds described herein (e.g., compound 1) to an individual provides a decrease in the peripheral blood flow of the individual. In some cases, the effects on blood pressure and heart rate are non-dose-dependent (e.g., the changes observed in the lowest dose group are roughly the same as those observed in the higher dose groups). In some cases, subcutaneous injection provides a more significant PD effect compared to the same dose administered intravenously (e.g., although the C max is approximately 50% lower). In some cases, the active metabolite M1 (e.g., a full (V1a) agonist) in plasma after subcutaneous administration (significantly) contributes to the total (e.g., local and / or systemic) V1a vasopressor activity, such as in individuals who have (critical) adverse events after administration of the compounds described herein by subcutaneous (bolus) injection. In some cases, increased M1 formation (such as after subcutaneous (bolus) injection) provides a significant reduction in the (systemic) delivery of compound 1, such as resulting in undesired effects (e.g., due to less delivery of the active agent (e.g., M1 or a mixed V1a agonist-antagonist described herein) and / or increased vasoconstriction, which may increase the risk of ischemia, cyanosis, pain, inflammation, and / or necrosis).

[0476] In some cases, the safety evaluation of the compounds described herein (e.g., Compound 1) provides an improved profile compared to other (e.g., non-selective) vasopressin receptor agonists described herein. In some cases, the absolute change in mean cardiac output is dose-dependent. In some cases, the relative change in mean cardiac output is comparable between doses (e.g., and well separated from placebo). In some cases, the reduction in individual cardiac output is about 20%-25% (e.g., as observed in all active agent treatment groups (including the placebo group), after intravenous and subcutaneous administration). In some cases, the reduction in cardiac output is secondary to a reduced heart rate. In some cases, ECG evaluation does not indicate any effect of the compounds described herein (e.g., Compound 1). In some cases, clinical laboratory parameters do not show any signs of cardiac or mesenteric ischemia (e.g., or adverse effects on the liver or kidneys).

[0477] In some cases, the adverse events in individuals receiving a partial agonist described herein (e.g., Compound 1) (e.g., intravenously or subcutaneously) are comparable to the pharmacological vasopressor activity of the compounds described herein (e.g., Compound 1 or vasopressin). For example, subcutaneous administration of the compounds described herein (e.g., Compound 1) provides (significantly) more AEs compared to intravenous administration (see Example 1). In addition, the frequency of AEs after subcutaneous administration of the compounds described herein (e.g., Compound 1) decreases within 5 days of treatment. For example, in some cases, on Day 1, subcutaneous administration provides about 0.5-fold more AEs / administration compared to intravenous administration (e.g., although there were only 3 subjects receiving 0.3 mg subcutaneously compared to 35 subjects receiving 0.45 mg or higher doses intravenously). Additionally, subcutaneous administration of the partial agonist described herein (e.g., Compound 1) provides about 3-fold more AEs / administration compared to intravenous administration of the same compound (see Example 1). Given (1) the formation of M1 (a full (V1a) agonist) 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 at approximately equimolar concentrations after subcutaneous administration of M1, and (4) the exposure to Compound 1 after subcutaneous administration (by means of C max and AUC) is lower than after intravenous infusion, the presence of M1 (rather than Compound 1) in plasma after subcutaneous administration results in the total V1a vasopressor activity and (e.g., amplified) pharmacological effects and / or AE profile after subcutaneous administration of Compound 1.

[0478] In addition, in view of the fact that the presence of the vasopressin receptor full agonist M1 results in an increase in the number of vasoconstriction-related AEs compared to much higher concentrations of Compound 1, further demonstrating (a similar combination of pharmacodynamics and adverse effects to that of Compound 1 over a wide concentration range), Compound 1 is a partial agonist and / or mixed agonist-antagonist. In addition, the observations studied in Example 1 also demonstrate that the mechanism of action of the mixed agonist-antagonist caps one or more (local vasoconstriction) effects in an individual (and limits such effects to levels below the maximum possible level). As further support for this explanation, studies with terlipressin (a V1A receptor full agonist) have demonstrated that the increase in blood pressure is greater 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).

[0479] In some cases, the pharmacological effects of the compounds described herein (e.g., Compound 1) are attributed to vasopressin V1a receptor agonism. In some cases, having no effect on diuresis and hemostasis demonstrates a high degree of specificity for the V1a receptor (e.g., providing the desired pharmacological profile).

[0480] In some cases, the terminal half-life of the compounds described herein (e.g., Compound 1) is approximately 1.5 hours (after intravenous administration).

[0481] In some cases, the total clearance of the compounds described herein (e.g., Compound 1) is approximately 13 L / h (after intravenous administration).

[0482] In some cases, the terminal half-life of the compounds described herein (e.g., Compound 1) is approximately 1 hour (after subcutaneous administration). In some cases, the t max of the compounds described herein (e.g., Compound 1) is approximately 0.3 hour (after subcutaneous administration). In some cases, the bioavailability of the compounds described herein (e.g., Compound 1) is approximately 18% (without any apparent accumulation of the compounds described herein (e.g., Compound 1), such as after repeated subcutaneous administration).

[0483] In some cases, after intravenous administration of the compounds described herein (e.g., Compound 1), the increase in exposure of the compounds described herein (e.g., Compound 1) (e.g., by means of AUC and C max ) is approximately proportional for AUC and C max

[0484] In some cases, after intravenous infusion of the compounds described herein (e.g., Compound 1), the exposure of the compounds described herein (e.g., Compound 1) (by means of AUC and C max ​)Higher in females than in males.

[0485] In some cases, administration of a compound described herein (e.g., Compound 1) provides an increase in diastolic blood pressure in an individual receiving the compound. In some cases, administration of a compound described herein (e.g., Compound 1) provides an increase in systolic blood pressure in an individual receiving the compound. In some cases, administration of a compound described herein (e.g., Compound 1) provides an increase in MAP in an individual receiving the compound. In some cases, administration of a compound described herein (e.g., Compound 1) provides a reflex reduction in pulse rate in an individual receiving the compound (e.g., in an apparent non-dose-dependent manner).

[0486] In some cases, peripheral blood flow is reduced after intravenous and subcutaneous administration of a compound described herein (e.g., Compound 1).

[0487] In some cases, such as during subcutaneous administration of a compound described herein (e.g., Compound 1), an active metabolite M1 (a full (V1a) agonist) is produced, such as at concentrations comparable to those of Compound 1.

[0488] In some embodiments, such as those described in the study provided in Example 6, a compound described herein (e.g., a mixed V1AR agonist-antagonist, such as Compound 1) reduces portal pressure (PP) (after subcutaneous administration), and there is no excessive vasoconstriction within a wide dose range (e.g., 10 μg / kg to 500 μg / kg of Compound 1), see Figure 33 and Figure 35 . In some embodiments, such as those described in the study provided in Example 6, a compound described herein (e.g., a mixed V1AR agonist-antagonist, such as Compound 1) reduces PP (after subcutaneous administration), such as within a wide dose range (e.g., 10 μg / kg to 500 μg / kg of Compound 1), see Figure 33 and Figure 35 .

[0489] In some embodiments, the methods provided herein further comprise evaluating a biological sample (e.g., of an individual). In some embodiments, the method further comprises evaluating a biomarker of a biological sample of an individual, such as the biomarker 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).

[0490] In some embodiments, the biomarkers described herein, such as those described in Example 6, are evaluated at a first time point and a second time point. In some embodiments, the second time point is used to determine the reactivity or efficacy of a compound such as those 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 instances, the endpoint is used to determine the amount or level of a biomarker sufficient to achieve the desired reactivity or efficacy of a compound such as those described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1). In some embodiments, the methods provided herein further comprise administering to an individual a compound such as those described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1), at least until the level or amount of the (individual's) biomarker reaches the endpoint. In some embodiments, the method comprises continuing to administer the compound after the level or amount of the (individual's) biomarker reaches the endpoint.

[0491] In some embodiments, the level or amount of the biomarker described herein (such as those described in Example 6) is higher (e.g., at least 5%, at least 15%, at least 25%, at least 35%, at least 45%, at least 55%, at least 65%, at least 75%, at least 85%, at least 95% or higher) at the second time point compared to the first time point.

[0492] In some embodiments, the level or amount of the biomarker described herein (such as those described in Example 6) is lower (e.g., at most 95%, at most 85%, at most 75%, at most 65%, at most 55%, at most 45%, at most 35%, at most 25%, at most 15%, at most 5% or lower) at the second time point compared to the first time point.

[0493] In some cases, the compounds described herein (e.g., mixed V1AR agonists - antagonists such as Compound 1) have an effect (e.g., increase or decrease) on the levels of the biomarkers described herein (e.g., the biomarkers described in Example 5 or Example 6). In some embodiments, the biomarkers described herein are selected from the group consisting of: mean arterial pressure (MAP), (plasma) aldosterone, (plasma) renin, ascites volume, body weight, urine volume, (net) fluid balance, urinary sodium, urinary potassium, portal venous pressure, cardiac output, systemic vascular resistance, BUN, BUN / CREA, PHOS, spleen weight, skin blood flow (SBF), blood lactate concentration, heart rate, arterial systolic pressure, arterial diastolic 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 fluid 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 arterial systolic pressure. In some embodiments, the biomarker described herein is arterial diastolic pressure. In some embodiments, the biomarker described herein is heart rate. In some embodiments, the biomarker described herein is portal venous 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.

[0494] In some embodiments, such as those described in Example 6, the compounds described herein (e.g., mixed V1AR agonist - antagonists, such as Compound 1) reduce hyperaldosteronism in an individual (e.g., in need thereof). In some embodiments, the compounds provided herein (e.g., mixed V1AR agonist - antagonists, such as Compound 1) reduce aldosterone (e.g., in serum) in an individual (e.g., in need thereof). In some embodiments, the compounds provided herein reduce aldosterone (e.g., in serum) in an individual (e.g., in need thereof) by at least 20% (e.g., at least 30%, at least 40%, at least 50%, at least 60%). In some embodiments, the compounds provided herein reduce aldosterone (e.g., in serum) in an individual (e.g., in need thereof) by no more than 90% (e.g., no more than 80%, no more than 70%, no more than 60%). In some embodiments, the compounds provided herein reduce aldosterone in the serum of an individual (e.g., in need thereof) by more than 50% (e.g., compared to a control (e.g., vehicle) and / or a first time point).

[0495] In some instances, the reduction of portal hypertension and / or hyperaldosteronism provides diuretic and natriuretic effects (see Example 6). In some embodiments, the diuretic and natriuretic effects are associated with the (e.g., total) mobilization (e.g., improvement) of ascites, such as three days after subcutaneous treatment with the compounds described herein.

[0496] In some embodiments, the compounds provided herein (e.g., hybrid V1AR agonist - antagonists such as Compound 1) reduce the amount of ascites in an individual (e.g., in need thereof), such as after 5 days of treatment, as described in Example 6. In some embodiments, the compounds provided herein (e.g., hybrid V1AR agonist - antagonists such as Compound 1) reduce the amount of ascites 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, the compounds provided herein (e.g., hybrid V1AR agonist - antagonists such as Compound 1) reduce the amount of ascites in an individual (e.g., in need thereof) by no more than 95% (e.g., no more than 90%, no more than 85%, no more than 80%, no more than 75%). In some embodiments, the compounds provided herein (e.g., hybrid V1AR agonist - antagonists such as Compound 1) reduce the amount of ascites in an individual (e.g., in need thereof) by about 30% to about 95%. In some embodiments, the compounds provided herein (e.g., hybrid V1AR agonist - antagonists such as Compound 1) reduce the amount of ascites in an individual (e.g., in need thereof) by about 67%. In some embodiments, the compounds provided herein (e.g., hybrid V1AR agonist - antagonists such as Compound 1) reduce the amount of ascites in an individual (e.g., in need thereof) by about 80%. In some embodiments, the reduction in the amount of ascites is compared to a control (e.g., vehicle) and / or a first time point.

[0497] In some embodiments, the compounds described herein (e.g., hybrid V1AR agonist - antagonists such as Compound 1) increase the urine volume (excretion) in an individual (e.g., in need thereof) (see Example 6). In some embodiments, the compounds described herein (e.g., hybrid V1AR agonist - antagonists such as Compound 1) increase the urinary sodium (excretion) in an individual (e.g., in need thereof) (see Example 6). In some embodiments, the compounds described herein (e.g., hybrid V1AR agonist - antagonists such as Compound 1) increase the 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 cases, the increase in urine volume and urinary sodium excretion (fully) drains the ascites accumulated in the peritoneal cavity of an individual (e.g., in need thereof). In some embodiments, the increase in urine volume and urinary sodium excretion provides a reduction in the amount of ascites in an individual (e.g., in need thereof). In some embodiments, within 24 hours of treatment, the urine volume and / or urinary sodium excretion in an individual (e.g., in need thereof) increases.

[0498] In some embodiments, the compounds described herein (e.g., mixed V1AR agonist - antagonists such as Compound 1) increase urine volume as described in Example 6. In some embodiments, the urine volume is compared to a basal measurement (and is greater than the basal measurement) as described in Example 6. In some embodiments, the compounds described herein (e.g., mixed V1AR agonist - antagonists such as Compound 1) increase 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, the compounds described herein (e.g., mixed V1AR agonist - antagonists such as Compound 1) increase urine volume by about 75%. In some embodiments, the compounds described herein (e.g., mixed V1AR agonist - antagonists such as Compound 1) increase urine volume by at least 100% (at least 150%, at least 200%, at least 250%, at least 300%, at least 350%). In some embodiments, the compounds described herein (e.g., mixed V1AR agonist - antagonists such as Compound 1) increase urine volume by about 430%. In some embodiments, the compounds described herein (e.g., mixed V1AR agonist - antagonists such as Compound 1) increase urine volume by at most 750% (e.g., at most 500%, at most 400%, at most 300%). In some embodiments, within the first 4 hours of treatment, the urine volume of an individual (e.g., in need) increases. In some embodiments, after 1 day of treatment, the urine volume of an individual (e.g., in need) increases.

[0499] In some embodiments, the compounds described herein (e.g., mixed V1AR agonist - antagonists such as Compound 1) provide a positive net fluid balance for an individual (e.g., in need) as described in Example 6. In some embodiments, the urine volume of an individual (e.g., in need) is greater than the fluid intake.

[0500] In some embodiments, the compounds provided herein (e.g., mixed V1AR agonist-antagonists such as Compound 1) increase the urinary sodium excretion and / or urinary potassium excretion of an individual (e.g., in need thereof), such as described in Example 6. In some embodiments, the compounds provided herein (e.g., mixed V1AR agonist-antagonists such as Compound 1) increase the urinary sodium excretion by at least 20% (e.g., at least 100%, at least 250%, at least 500%, at least 750%). In some embodiments, the compounds provided herein (e.g., mixed V1AR agonist-antagonists such as Compound 1) increase the urinary sodium excretion by at most 1000% (e.g., at most 750%, at most 500%, at most 250%, at most 100%). In some embodiments, the compounds provided herein (e.g., mixed V1AR agonist-antagonists such as Compound 1) increase the urinary sodium excretion by about 600%. In some embodiments, the compounds provided herein (e.g., mixed V1AR agonist-antagonists such as Compound 1) increase the urinary potassium by at least 10% (e.g., at least 20%, at least 30%, at least 40%, at least 50%). In some embodiments, the compounds provided herein (e.g., mixed V1AR agonist-antagonists such as Compound 1) increase the urinary potassium by at most 100% (e.g., at most 75%, at most 50%, at most 40%, at most 30%). In some embodiments, the compounds provided herein (e.g., mixed V1AR agonist-antagonists such as Compound 1) increase the urinary potassium by about 20%. In some embodiments, the urinary sodium excretion and / or urinary potassium excretion is compared to a basal measurement (and is greater than the basal measurement). In some embodiments, within the first 4 hours of treatment, the urinary sodium excretion and / or urinary potassium excretion of an individual (e.g., in need thereof) increases. In some embodiments, 1 day after treatment, the urinary sodium excretion and / or urinary potassium excretion of an individual (e.g., in need thereof) increases.

[0501] In some embodiments, the compounds provided herein (e.g., mixed V1AR agonist-antagonists such as Compound 1) reduce urinary potassium excretion in an individual (e.g., in need thereof), such as described in Example 6. In some embodiments, the compounds provided herein (e.g., mixed V1AR agonist-antagonists such as Compound 1) reduce urinary potassium excretion by at least 10% (e.g., at least 20%, at least 30%, at least 40%, at least 50%). In some embodiments, the compounds provided herein (e.g., mixed V1AR agonist-antagonists such as Compound 1) reduce urinary potassium excretion by at most 100% (e.g., at most 75%, at most 50%, at most 40%, at most 30%). In some embodiments, the compounds provided herein (e.g., mixed V1AR agonist-antagonists such as Compound 1) reduce urinary potassium excretion by about 20%. In some embodiments, urinary potassium excretion is compared to a baseline measurement (and is greater than the baseline measurement).

[0502] In some embodiments, in an individual (e.g., in need thereof), urinary sodium excretion increases (such as within the first 4 hours of treatment), and urinary potassium excretion decreases (such as 5 hours or more after treatment).

[0503] In some embodiments, the compounds provided herein (e.g., mixed V1AR agonist-antagonists such as Compound 1) reduce the body weight of an individual (e.g., in need thereof), such as provided in Example 6. In some embodiments, the compounds provided herein (e.g., mixed V1AR agonist-antagonists such as Compound 1) reduce 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, the compounds provided herein (e.g., mixed V1AR agonist-antagonists such as Compound 1) reduce the body weight of an individual (e.g., in need thereof) by at most 15%, at most 13%, at most 11%, at most 9%). In some embodiments, the compounds provided herein (e.g., mixed V1AR agonist-antagonists such as Compound 1) reduce the body weight of an individual (e.g., in need thereof) by about 14%. In some embodiments, the body weight of the individual is compared to a baseline measurement (and is less than the baseline measurement). In some embodiments, the body weight of an individual (e.g., in need thereof) decreases after treatment for about 1 day or longer (such as 3 days).

[0504] In some embodiments, the compounds provided herein (e.g., hybrid V1AR agonist-antagonists such as Compound 1) reduce spleen weight as described in Example 6. In some embodiments, the compounds provided herein (e.g., hybrid V1AR agonist-antagonists such as Compound 1) reduce 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, the compounds provided herein (e.g., hybrid V1AR agonist-antagonists such as Compound 1) reduce the spleen weight of an individual (e.g., in need thereof) by at most 20% (e.g., at most 18%, at most 16%, at most 14%). In some embodiments, the compounds provided herein (e.g., hybrid V1AR agonist-antagonists such as Compound 1) reduce the spleen weight of an individual (e.g., in need thereof) by about 16%. In some embodiments, the spleen weight of an individual is compared to a baseline measurement (and is less than the baseline measurement). In some embodiments, after treatment for about 1 day or longer (such as 5 days later), the spleen weight of an individual (e.g., in need thereof) is reduced.

[0505] In some embodiments, the compounds provided herein (e.g., hybrid V1AR agonist-antagonists such as Compound 1) reduce the creatinine level of an individual (e.g., in need thereof) as described in Example 6. In some embodiments, the compounds provided herein (e.g., hybrid V1AR agonist-antagonists such as Compound 1) reduce the creatinine level of 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, the compounds provided herein (e.g., hybrid V1AR agonist-antagonists such as Compound 1) reduce the creatinine level of an individual (e.g., in need thereof) by at most 80% (e.g., at most 70%, at most 60%, at most 50%, at most 40%). In some embodiments, the compounds provided herein (e.g., hybrid V1AR agonist-antagonists such as Compound 1) reduce the creatinine level by about 50%. In some embodiments, the creatinine level of an individual (e.g., in need thereof) is reduced by about 80%. In some embodiments, the creatinine level of an individual is compared to a baseline measurement (and is less than the baseline measurement). In some embodiments, after treatment for about 1 day or hour (such as about 5 to 25 hours later), the creatinine level of an individual (e.g., in need thereof) is reduced.

[0506] In some embodiments, the compounds provided herein (e.g., hybrid V1AR agonist-antagonists such as Compound 1) increase the urinary creatinine level of an individual (e.g., in need thereof), as described in Example 6. In some embodiments, the compounds provided herein (e.g., hybrid V1AR agonist-antagonists such as Compound 1) increase the urinary creatinine level of 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, the compounds provided herein (e.g., hybrid V1AR agonist-antagonists such as Compound 1) increase the urinary creatinine level of an individual (e.g., in need thereof) by at most 80% (e.g., at most 70%, at most 60%, at most 50%, at most 40%). In some embodiments, the compounds provided herein (e.g., hybrid V1AR agonist-antagonists such as Compound 1) increase the urinary creatinine level by about 50%. In some embodiments, the urinary creatinine level of an individual (e.g., in need thereof) increases by about 80%. In some embodiments, the urinary creatinine level of the individual is compared to a baseline measurement (and is less than the baseline measurement). In some embodiments, the urinary creatinine level of an individual (e.g., in need thereof) increases about 1 day or hour after treatment (such as about 5 to 25 hours thereafter).

[0507] In some embodiments, the compounds provided herein (e.g., hybrid V1AR agonist-antagonists such as Compound 1) decrease the urinary creatinine level of an individual (e.g., in need thereof), as described in Example 6. In some embodiments, the compounds provided herein (e.g., hybrid V1AR agonist-antagonists such as Compound 1) decrease the urinary creatinine level of 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, the compounds provided herein (e.g., hybrid V1AR agonist-antagonists such as Compound 1) decrease the urinary creatinine level of an individual (e.g., in need thereof) by at most 80% (e.g., at most 70%, at most 60%, at most 50%, at most 40%). In some embodiments, the compounds provided herein (e.g., hybrid V1AR agonist-antagonists such as Compound 1) decrease the urinary creatinine level by about 50%. In some embodiments, the urinary creatinine level of an individual (e.g., in need thereof) decreases by about 80%. In some embodiments, the urinary creatinine level of the individual is compared to a baseline measurement (and is less than the baseline measurement). In some embodiments, the urinary creatinine level of an individual (e.g., in need thereof) decreases about 1 day or hour after treatment (such as about 5 to 25 hours thereafter).

[0508] In some cases, within the first 24 hours after treatment (such as after subcutaneous administration of a compound described herein (e.g., a mixed V1AR agonist - antagonist such as Compound 1)), one or more diuretic effects and / or natriuretic effects are identified in an individual, as described in the studies provided in Example 6. In some cases, after the first 24 hours after treatment (such as after subcutaneous administration of a compound described herein (e.g., a mixed V1AR agonist - antagonist such as Compound 1)), one or more diuretic effects and / or natriuretic effects are not identified in an individual, as described in the studies provided in Example 6. In some embodiments, after 24 hours of treatment with a compound described herein (e.g., a mixed V1AR agonist - antagonist such as Compound 1), urine volume and sodium excretion are observed to return to baseline levels. In some cases, the return of urine volume and sodium excretion to baseline levels is an indication that there is no longer excess fluid (available for removal) in the peritoneal cavity of the individual. In some cases, after administration of a compound described herein, there is minimal fluid overload or sodium or water retention, such as demonstrating a lack of V2 receptor activity for the compounds provided herein (such as mixed V1AR agonist antagonists (e.g., Compound 1)).

[0509] In some cases, hyponatremia is a potential risk observed during treatment with a vasopressin receptor agonist (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 result in hyponatremia, such as despite a significant increase in urinary sodium excretion after the first dose (e.g., relative to subjects treated with vehicle). In some embodiments, repeated administration of a compound described herein (e.g., a mixed V1AR agonist - antagonist such as Compound 1) within 5 days does not result in hyponatremia. In some cases, hyponatremia is defined as a blood sodium level of less than 120 mEq / L in rats.

[0510] In some embodiments, administration of a compound described herein (e.g., a mixed V1AR agonist - antagonist such as Compound 1) provides a beneficial effect on factors related to 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 a submaximal effect on vasoconstriction, such as demonstrating the dual benefits of improved therapeutic efficacy and safety, such as through a reduced risk of excessive vasoconstriction.

[0511] 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 the portal vein 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 the portal vein pressure in an individual (e.g., in need thereof) by at most 5 mmHg (e.g., at most 4 mmHg, at most 3 mmHg, at most 2 mmHg, at most 1 mmHg).

[0512] In some embodiments, such as those described in the studies provided in Example 6, the compounds described herein (e.g., mixed V1AR agonist-antagonists such as Compound 1) increase the mean arterial pressure (MAP) (after subcutaneous administration), such as within 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 studies provided in Example 6, the increase in MAP reaches a peak plateau or therapeutic ceiling (e.g., the MAP increases by about 10 to about 15 mmHg), see Figure 34 . In some embodiments, such as those described in the studies provided in Example 6, the increase in MAP reaches a peak plateau or therapeutic ceiling (e.g., the MAP increases by about 10 to about 15 mmHg), accompanied by a decrease in PP (about 2 to about 14 mmHg), see Figure 34 . In some cases, even after a 5-fold increase in dose (e.g., 100 μg / kg or 500 μg / kg of Compound 1), the compounds described herein do not produce a meaningful further change in effect, such as an increase in MAP, see Figure 34 .

[0513] In other cases, administration of a completely non-selective (V2, V1a) receptor agonist (such as terlipressin) provides a significantly higher increase in MAP (and beyond the 10 - 15 mmHg therapeutic window), such as although the decrease in PP is similar to those of the compounds described herein (e.g., mixed V1AR agonist-antagonists such as Compound 1), see Figure 34 .

[0514] In some embodiments, the compounds described herein (e.g., mixed V1AR agonist-antagonists such as Compound 1) increase the mean arterial pressure, arterial systolic pressure, and arterial diastolic pressure of an individual (e.g., a mammal), such as after subcutaneous administration (e.g., seeFigures 41A - 41C )。In some cases, the occurrence and magnitude of the maximum blood pressure increase are related to the dose of the compounds described herein (e.g., mixed V1AR agonist-antagonists, such as Compound 1) in an individual (e.g., a mammal), such as after subcutaneous administration. In some embodiments, the compounds described herein (e.g., mixed V1AR agonist-antagonists, such as Compound 1) increase the mean arterial pressure (MAP) of 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 (e.g., see Figure 43A )。In some embodiments, the compounds described herein (e.g., mixed V1AR agonist-antagonists, such as Compound 1) increase the mean arterial pressure (MAP) of an individual (e.g., a mammal) by at most about 50 mmHg (e.g., at most 40 mmHg, at most 30 mmHg, at most 20 mmHg, at most 10 mmHg), such as after subcutaneous administration. In some embodiments, the compounds described herein (e.g., mixed V1AR agonist-antagonists, such as Compound 1) increase the mean arterial pressure (MAP) of an individual (e.g., a mammal) by about 10 mmHg to about 50 mmHg, such as after subcutaneous administration. In some embodiments, the compounds described herein (e.g., mixed V1AR agonist-antagonists, such as Compound 1) increase the mean arterial pressure (MAP) of an individual (e.g., a mammal) by about 20 mmHg, such as after subcutaneous administration. In some embodiments, the compounds described herein (e.g., mixed V1AR agonist-antagonists, such as Compound 1) increase the mean arterial pressure (MAP) of an individual (e.g., a mammal) by about 40 mmHg, such as after subcutaneous administration. In some embodiments, the compounds described herein (e.g., mixed V1AR agonist-antagonists, such as Compound 1) increase the mean arterial pressure (MAP) of an individual (e.g., a mammal) by about 25 mmHg, such as after subcutaneous administration. In some embodiments, the compounds described herein (e.g., mixed V1AR agonist-antagonists, such as Compound 1) increase the mean arterial pressure (MAP) of an individual (e.g., a mammal) and maintain the increase for at least 75 minutes (e.g., at least 150 minutes, at least 300 minutes), such as after subcutaneous administration. In some cases, the compounds described herein (e.g., mixed V1AR agonist-antagonists, such as Compound 1) provide a change in the mean arterial pressure (MAP) of an individual (e.g., a mammal) that is statistically different from that of the vehicle, such as after subcutaneous administration. In some embodiments, the compounds described herein (e.g., mixed V1AR agonist-antagonists, such as Compound 1) increase the MAP of an individual (e.g., a mammal) and the MAP does not return to the baseline value, such as after subcutaneous administration.

[0515] In some embodiments, a full antagonist (such as terlipressin) increases the mean arterial pressure (MAP) of an individual (e.g., a mammal) (e.g., see Figure 43B ). In some embodiments, after intravenous administration, a full antagonist (such as terlipressin) increases the mean arterial pressure (MAP), and the effect lasts only for a short period of time, such as less than 90 minutes (e.g., not longer than 30, 75, or 90 minutes) (e.g., see Figure 43B ). In some embodiments, a full antagonist (such as terlipressin) provides an instantaneous effect on MAP (e.g., see Figure 43B ). In some embodiments, the compounds described herein (e.g., a mixed V1AR agonist - antagonist, such as Compound 1) provide an increase in MAP across a 50 - fold dose range in an individual (e.g., a mammal), which in some cases can represent the maximal effect on arterial pressure.

[0516] In some embodiments, the compounds described herein (e.g., a mixed V1AR agonist - antagonist, such as Compound 1) decrease the heart rate of an individual (e.g., a mammal), such as after subcutaneous administration, see Figure 41D . In some embodiments, the compounds described herein (e.g., a mixed V1AR agonist - antagonist, such as Compound 1) decrease the heart rate of an individual (e.g., a mammal) by at least 2% (e.g., at least 5%, at least 10%, at least 15%), such as after subcutaneous administration (e.g., see Figure 41D ). In some embodiments, the compounds described herein (e.g., a mixed V1AR agonist - antagonist, such as Compound 1) decrease the heart rate of an individual (e.g., a mammal) by at most 20% (e.g., at most 15%, at most 10%, at most 5%), such as after subcutaneous administration (e.g., see Figure 41D ). In some embodiments, the compounds described herein (e.g., a mixed V1AR agonist - antagonist, such as Compound 1) decrease the heart rate of an individual (e.g., a mammal) by about 5%, such as after subcutaneous administration (e.g., see Figure 41D ). In some cases, the compounds described herein (e.g., a mixed V1AR agonist - antagonist, such as Compound 1) provide a change in MAP associated with a measurable decrease in the heart rate of an individual (e.g., a mammal), such as after subcutaneous administration (e.g., see Figure 41D , Figure 43A ). In some cases, for the compounds described herein (e.g., a mixed V1AR agonist - antagonist, such as Compound 1), the changes in systolic and diastolic blood pressures are associated with the change in MAP of an individual (e.g., a mammal), such as after subcutaneous administration (e.g., see Figures 41A - 41C ).

[0517] In some embodiments, the compounds described herein (e.g., mixed V1AR agonist-antagonists such as Compound 1) have a terminal half-life (t 1 / 2term ) 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. In some embodiments, the compounds described herein (e.g., mixed V1AR agonist-antagonists such as Compound 1) have a terminal half-life (t 1 / 2term ) of at most 150 minutes (e.g., at most 130 minutes, at most 110 minutes, at most 90 minutes, at most 70 minutes) in an individual (e.g., a mammal), such as after subcutaneous injection. In some embodiments, the compounds described herein (e.g., mixed V1AR agonist-antagonists such as Compound 1) have a terminal half-life (t 1 / 2term ) of about 50 to about 150 minutes in an individual (e.g., a mammal), such as after subcutaneous injection. In some embodiments, the compounds described herein (e.g., mixed V1AR agonist-antagonists such as Compound 1) have a terminal half-life (t 1 / 2term ) of about 110 minutes in an individual (e.g., a mammal), such as after subcutaneous injection. In some embodiments, the compounds described herein (e.g., mixed V1AR agonist-antagonists such as Compound 1) have an elimination half-life (t 1 / 2elim ) 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. In some embodiments, the compounds described herein (e.g., mixed V1AR agonist-antagonists such as Compound 1) have an elimination half-life (t 1 / 2elim ) of at most 60 minutes (e.g., at most 40 minutes, at most 20 minutes, at most 10 minutes). In some embodiments, the compounds described herein (e.g., mixed V1AR agonist-antagonists such as Compound 1) have an elimination half-life (t 1 / 2elim ) of about 1 minute to about 40 minutes in an individual (e.g., a mammal). In some embodiments, the compounds described herein (e.g., mixed V1AR agonist-antagonists such as Compound 1) have an elimination half-life (t 1 / 2elim ) of about 20 minutes in an individual (e.g., a mammal). In some embodiments, after subcutaneous administration, the terminal half-life (t 1 / 2term ) of the compound is greater than the elimination half-life (t 1 / 2elim ).

[0518] In some embodiments, the compounds described herein (e.g., mixed V1AR agonist-antagonists such as compound 1) have a bioavailability of at least 40% (e.g., at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%) in an individual (e.g., a mammal), such as after subcutaneous administration. In some embodiments, the compounds described herein (e.g., mixed V1AR agonist-antagonists such as compound 1) have a bioavailability of at most 75% (e.g., at most 70%, at most 60%, at most 50%, at most 40%) in an individual (e.g., a mammal). In some embodiments, the compounds described herein (e.g., mixed V1AR agonist-antagonists such as compound 1) have a bioavailability of from about 40% to about 70% in an individual (e.g., a mammal). In some embodiments, the compounds described herein (e.g., mixed V1AR agonist-antagonists such as compound 1) have a bioavailability of about 60% in an individual (e.g., a mammal).

[0519] In some embodiments, the compounds described herein (e.g., mixed V1AR agonist-antagonists such as compound 1) have a clearance rate similar to the glomerular filtration rate (e.g., 5 - 15 mL / min / kg) in an individual (e.g., a mammal), such as after subcutaneous administration. In some embodiments, the compounds described herein (e.g., mixed V1AR agonist-antagonists such as compound 1) have 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, the compounds described herein (e.g., mixed V1AR agonist-antagonists such as compound 1) have a filtration rate of at most 25 mL / min / kg (e.g., at most 22 mL / min / kg, at most 18 mL / min / kg, at most 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.

[0520] In some embodiments, the compounds described herein (e.g., mixed V1AR agonist-antagonists such as compound 1) reduce the skin blood flow in an individual (e.g., a mammal), such as after intravenous administration (e.g., see Figure 40A)。In some embodiments, the compounds described herein (e.g., hybrid V1AR agonist-antagonists, such as Compound 1) reduce cutaneous 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, the compounds described herein (e.g., hybrid V1AR agonist-antagonists, such as Compound 1) reduce cutaneous 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, the compounds described herein (e.g., hybrid V1AR agonist-antagonists, such as Compound 1) reduce cutaneous blood flow in an individual (e.g., a mammal) by about 20% to about 60%. In some embodiments, the compounds described herein (e.g., hybrid V1AR agonist-antagonists, such as Compound 1) reduce cutaneous blood flow in an individual (e.g., a mammal) by about 40%. In some embodiments, the compounds described herein (e.g., hybrid V1AR agonist-antagonists, such as Compound 1) reduce 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, e.g., see Figure 40A . In some cases, the compounds described herein (e.g., hybrid V1AR agonist-antagonists, such as Compound 1) reduce cutaneous blood flow in an individual (e.g., a mammal) by about 40% after intravenous administration, and vasopressin reduces cutaneous blood flow in an individual (e.g., a mammal) by about 90% after intravenous administration, demonstrating that the hybrid V1AR agonist-antagonists described herein (such as Compound 1) are more suitable for intravenous administration compared to a fully non-selective (V2, V1a) agonist (e.g., vasopressin or terlipressin), such as by reducing (substantial) injection site reactions (e.g., local vasoconstriction) that prevent systemic delivery of the drug. In some cases, the lesser reduction in cutaneous blood flow of the compounds provided herein (e.g., hybrid V1AR agonist-antagonists, such as Compound 1) compared to vasopressin demonstrates less local vasoconstriction compared to vasopressin.

[0521] In some cases, increased serum lactate levels are a clinical marker of anaerobic metabolism and tissue hypoxia and are used as a surrogate marker for the development of vasoconstriction and tissue ischemia. In some embodiments, the compounds described herein (e.g., hybrid V1AR agonist-antagonists, such as Compound 1) do not (substantially) increase the blood lactate concentration in an individual, such as after intravenous administration (e.g., see Figure 40B)。In some embodiments, the compounds described herein (e.g., mixed V1AR agonist - antagonists such as Compound 1) do not (significantly) increase the blood lactate levels of an individual, while a similar dose of vasopressin significantly increases the blood lactate levels of an individual, such as after intravenous administration (e.g., see Figures 40B - 40C )。In some cases, vasopressin increases the blood lactate levels of an individual by at least 2 - fold (e.g., 3 - fold, 4 - fold), such as after intravenous administration (e.g., see Figure 40B )。

[0522] In some embodiments, the compounds described herein (e.g., mixed V1AR agonist - antagonists such as Compound 1) decrease plasma concentration (e.g., linearly) (see, for example, Figures 39A - 39B 、 Figures 42A - 42B )。

[0523] In some embodiments, the compounds described herein (e.g., mixed V1AR agonist - antagonists such as Compound 1) increase the blood pH of 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 the blood pH of an individual, such as after intravenous administration.

[0524] In some cases, the compounds described herein (e.g., mixed V1AR agonist - antagonists such as Compound 1) provide an initial apparent volume of the central compartment (V c ) 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) in an individual (e.g., a mammal), such as after intravenous administration. In some cases, the compounds described herein (e.g., mixed V1AR agonist - antagonists such as Compound 1) provide an initial apparent volume of the central compartment (V c ) of at most 150 mg / kg (e.g., at most 130 mg / kg, at most 110 mg / kg, at most 90 mg / kg) in an individual (e.g., a mammal), such as after intravenous administration.

[0525] In some cases, the compounds described herein (e.g., mixed V1AR agonist - antagonists such as Compound 1) provide a steady - state volume of distribution (V ss), such as after intravenous administration. In some cases, the compounds described herein (e.g., mixed V1AR agonist-antagonists such as Compound 1) provide a steady-state volume of distribution (V of up to 200 mL / kg (e.g., up to 180 mL / kg, up to 160 mL / kg, up to 140 mL / kg) in an individual (e.g., a mammal). ss ), such as after intravenous administration.

[0526] In some cases, the compounds described herein (e.g., mixed V1AR agonist-antagonists such as Compound 1) provide a maximum plasma concentration (C of at least 200 ng / mL / mg / kg (e.g., at least 300 ng / mL / mg / kg, at least 500 ng / mL / mg / kg, at least 600 ng / mL / mg / kg, at least 700 ng / mL / mg / kg) / unit dose, such as after subcutaneous administration. In some cases, the compounds described herein (e.g., mixed V1AR agonist-antagonists such as Compound 1) provide a maximum plasma concentration (C max ) / unit dose of up to 1000 ng / mL / mg / kg (e.g., up to 900 ng / mL / mg / kg, up to 700 ng / mL / mg / kg, up to 500 ng / mL / mg / kg, up to 400 ng / mL / mg / kg), such as after subcutaneous administration. In some cases, the compounds described herein (e.g., mixed V1AR agonist-antagonists such as Compound 1) provide a time (T to maximum plasma concentration of at least 5 minutes (e.g., at least 10 minutes, at least 20 minutes, at least 30 minutes), such as after subcutaneous administration. In some cases, the compounds described herein (e.g., mixed V1AR agonist-antagonists such as Compound 1) provide a time (T max ) to maximum plasma concentration 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 )), such as after subcutaneous administration. max ), such as after subcutaneous administration.

[0527] In some cases, the compounds described herein (e.g., mixed V1AR agonist - antagonists such as Compound 1) provide an area under the curve (AUC) / unit dose of at least 40,000 min·ng / mL / mg / kg (e.g., at least 45,000 min·ng / mL / mg / kg, at least 50,000 min·ng / mL / mg / kg, at least 55,000 min·ng / mL / mg / kg, at least 60,000 min·ng / mL / mg / kg) in an individual (e.g., a mammal), such as after subcutaneous administration. In some cases, the compounds described herein (e.g., mixed V1AR agonist - antagonists such as Compound 1) provide an area under the curve (AUC) / unit dose of at most 70,000 min·ng / mL / mg / kg (e.g., 65,000 min·ng / mL / mg / kg, 60,000 min·ng / mL / mg / kg, 55,000 min·ng / mL / mg / kg, 50,000 min·ng / mL / mg / kg) in an individual (e.g., a mammal), such as after subcutaneous administration.

[0528] In some cases, the compounds described herein (e.g., mixed V1AR agonist - antagonists such as Compound 1) provide an apparent total clearance (CL / F) 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) in an individual (e.g., a mammal), such as after subcutaneous administration. In some cases, the compounds described herein (e.g., mixed V1AR agonist - antagonists such as Compound 1) provide an apparent total clearance (CL / F) 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) in an individual (e.g., a mammal), such as after subcutaneous administration.

[0529] In some embodiments, provided herein is a method of treating a complication (such as ascites (e.g., refractory ascites)) of end - stage liver disease in an individual (e.g., in need thereof), the method 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).

[0530] In some embodiments, the individual described herein has cirrhotic 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.

[0531] In some embodiments, the compounds described herein (e.g., compound 1) provide a significantly improved therapeutic index (e.g., caused by lower maximal vasoconstrictor effects and lower risk of tissue hypoxia), such as when compared to a full (V1A) receptor agonist. In some embodiments, the compounds described herein (e.g., compound 1) provide approximately half of the maximal vasoconstriction produced by a full agonist, such as without any accompanying signs of ischemia. In some embodiments, the compounds described herein (e.g., compound 1) are (clinically) effective vasoconstrictors (e.g., having a favorable benefit / risk profile, such as having low to no organ toxicity).

[0532] In some embodiments, provided herein is a method of treating end-stage liver disease (ESLD) in an individual (e.g., in need thereof), the method comprising administering to the individual a therapeutically effective amount of a compound described herein (e.g., compound 1) or a pharmaceutically acceptable salt thereof (e.g., acetate).

[0533] In some embodiments, provided herein is a method of treating a complication of ESLD in an individual (e.g., in need thereof), the method comprising administering to the individual a therapeutically effective amount of a compound described herein (e.g., compound 1) or a pharmaceutically acceptable salt thereof (e.g., acetate).

[0534] In some embodiments, provided herein is a method of treating ascites in an individual (e.g., in need thereof), the method comprising administering to the individual a therapeutically effective amount of a compound described herein (e.g., compound 1) or a pharmaceutically acceptable salt thereof (e.g., acetate).

[0535] 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 non-responsive 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-non-responsive ascites. In some embodiments, the individual has diuretic-resistant ascites. In some embodiments, the individual has diuretic-refractory ascites.

[0536] In some embodiments, provided herein are methods of treating refractory ascites in an individual (e.g., in need thereof), the methods 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).

[0537] In some embodiments, provided herein are methods of treating ascites in an individual (such as an individual who has developed ascites as a complication of cirrhosis), the methods 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).

[0538] In some embodiments, provided herein are methods of 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), the methods 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).

[0539] 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).

[0540] 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.

[0541] In some embodiments, the therapeutically effective amount of the compound described herein (e.g., Compound 1) or a pharmaceutically acceptable salt (e.g., acetate) is from about 5 μg to about 55 μg. In some embodiments, the therapeutically effective amount of the compound described herein (e.g., Compound 1) or a pharmaceutically acceptable salt (e.g., acetate) is from about 8 μg to about 50 μg. In some embodiments, the therapeutically effective amount of the compound described herein (e.g., Compound 1) or a pharmaceutically acceptable salt (e.g., acetate) is from about 20 μg to about 35 μg. In some embodiments, the therapeutically effective amount of the compound described herein (e.g., Compound 1) or a pharmaceutically acceptable salt (e.g., acetate) is from about 25 μg to about 35 μg. In some embodiments, the therapeutically effective amount of the compound described herein (e.g., Compound 1) or a pharmaceutically acceptable salt (e.g., acetate) is about 30 μg. In some embodiments, the therapeutically effective amount of the compound described herein (e.g., Compound 1) or a pharmaceutically acceptable salt (e.g., acetate) is administered over a period of time (such as over a number of hours (e.g., continuously for up to 24 h)) for several days (e.g., up to 10 days).

[0542] In some embodiments, a compound described herein (e.g., Compound 1) or a pharmaceutically acceptable salt (e.g., acetate) is administered intravenously to an individual. In some embodiments, Compound 1 or a pharmaceutically acceptable salt (e.g., acetate) is administered to an individual by intravenous infusion.

[0543] In some embodiments, a compound described herein (e.g., Compound 1) or a pharmaceutically acceptable salt (e.g., acetate) is administered subcutaneousl...

Claims

1. A method of treating end-stage liver disease (ESLD) or its symptoms (e.g., complications) in an individual (e.g., in need), the method comprising subcutaneous infusion into the individual (e.g., in need) of a composition comprising a certain (effective) amount of a compound that is a mixed vasopressin receptor 1A (V1AR) agonist-antagonist.

2. The method according to claim 1, wherein the mixed vasopressin receptor 1A (V1AR) agonist-antagonist has a higher selectivity for V1AR than for V2R.

3. The method according to 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 according to any one of the preceding claims, wherein the compound comprises a first moiety having agonist activity and a second moiety having antagonist activity.

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

6. A method of treating end-stage liver disease (ESLD) or its symptoms (e.g., complications) in an individual (e.g., in need), the method comprising subcutaneous infusion into the individual (e.g., in need) of a composition comprising a certain (effective) amount of a compound having a structure represented by Formula I: D1-L-D2 Formula I or a pharmaceutically acceptable salt thereof, wherein: D1 is a vasopressin receptor 1A (V1AR) agonist; D2 is a V1AR antagonist; and L is a linker.

7. The method according to claim 6, wherein D1 has a higher selectivity for V1AR than for V2R.

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

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

10. The method according to any one of claims 6-9, wherein D1 has or comprises the following structure:

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

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

13. The method according to any one of claims 6-12, wherein D2 has or comprises the following structure:

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

15. The method according to any one of claims 6-13, 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 according to any one of claims 6-15, wherein L is a bond, a substituted or unsubstituted alkyl, or a substituted or unsubstituted heteroalkyl.

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

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

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

20. The method according to any one of claims 6 - 19, wherein L has or comprises the following structure:

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

22. A method of treating end - stage liver disease (ESLD) or its symptoms (e.g., complications) in an individual (e.g., in need thereof), the method comprising subcutaneously infusing into the individual (e.g., in need thereof) a composition comprising a certain (effective) amount of Compound 1 or a pharmaceutically acceptable salt thereof.

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

24. The method according to any one of the preceding claims, wherein the method further comprises attaching a subcutaneous infusion device to the skin of the individual, the subcutaneous infusion device comprising a cavity and a hollow tube, the composition being configured within the cavity, the hollow tube comprising a first opening and a second opening, the first opening being in fluid communication with the cavity, and after attaching the subcutaneous infusion device to the skin, the second opening is subcutaneously disposed within the individual.

25. The method according to 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 its symptoms (e.g., complications) in an individual (e.g., in need thereof), the method comprising subcutaneously administering to the individual (e.g., in need thereof) a composition comprising a certain (effective) amount of a compound that is a mixed vasopressin receptor 1A (V1AR) agonist - antagonist.

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

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

29. The method according to any one of the preceding claims, wherein when the composition is subcutaneously administered 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).

30. The method according to any one of the preceding claims, wherein when the composition is subcutaneously administered 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).

31. The method according to any one of the preceding claims, wherein when the composition is subcutaneously administered 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. The method according to any one of the preceding claims, wherein when the composition is subcutaneously administered 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. The method according to any one of the preceding claims, wherein when the composition is subcutaneously infused to the individual, less M1 is formed relative to the administration of an otherwise identical composition administered by subcutaneous (bolus) injection.

34. The method according to any one of the preceding claims, wherein when the composition is subcutaneously infused to the individual, less M1 is formed systemically relative to the administration of an otherwise identical composition administered by subcutaneous (bolus) injection.

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

36. The method according to any one of the preceding claims, wherein subcutaneous infusion of the composition to the individual improves tolerance (e.g., based on reduced M1 formation) relative to subcutaneous (bolus) injection.

37. The method according to any one of the preceding claims, wherein subcutaneous infusion of the composition to the individual reduces unwanted systemic events (e.g., unwanted vasoconstriction, such as leading to ischemia), reduces unwanted site-of-administration events (e.g., local site vasoconstriction, such as leading to site-of-administration ischemia), or both.

38. The method according to any one of the preceding claims, wherein the composition is continuously subcutaneously infused to the individual for at least one hour.

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

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

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

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

43. The method according to any one of the preceding claims, wherein the composition comprises a buffer at a concentration of from about 5 mM to about 250 mM.

44. The method according to any one of the preceding claims, wherein the composition comprises a buffer at a concentration of from about 5 mM to about 25 mM.

45. The method according to any one of claims 1-43, wherein the composition comprises a buffer at a concentration of from about 50 mM to about 250 mM.

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

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

48. The method according to any one of the preceding claims, wherein the composition has a pH of from about 4.5 to about 5.

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

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

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

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

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

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

55. The method according to any one of the preceding claims, wherein the composition further comprises a solubilizer.

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

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

58. A method of reducing local vasoconstriction such as (incidence of) ischemia (at the injection site) in an individual in need thereof, the method comprising subcutaneous infusion of a composition to the individual in need thereof, the composition comprising 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, wherein: D1 is a vasopressin receptor 1A (V1AR) agonist; D2 is a V1AR antagonist; and L is a linker.

59. A method of treating end-stage liver disease (ESLD) in an individual in need thereof, the method comprising subcutaneous infusion of a composition into the individual in need thereof, the composition comprising 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, wherein: D1 is a vasopressin receptor 1A (V1AR) agonist; D2 is a V1AR antagonist; and L is a linker, wherein less than 50% of the compound of Formula I degrades (e.g., subcutaneously).

60. The method according to any one of the preceding claims, wherein after subcutaneous administration of the compound or a pharmaceutically acceptable salt thereof according to any one of the preceding claims to the individual, (e.g., within the first 24 hours, such as within the first 4 hours), the urine volume of the individual (significantly) increases (e.g., as compared to a vehicle control).

61. The method according to any one of the preceding claims, wherein after subcutaneous administration of the compound or a pharmaceutically acceptable salt thereof according to any one of the preceding claims to the individual, the urine volume of the individual increases 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., as compared to a vehicle control).

62. The method according to any one of the preceding claims, wherein at least one day (e.g., 3 days or longer) after subcutaneous administration of the compound or a pharmaceutically acceptable salt thereof according to any one of the preceding claims to the individual, the urine volume of the individual is about 50% or more or 100% or more higher.

63. The method according to any one of the preceding claims, wherein after subcutaneous administration of the compound or a pharmaceutically acceptable salt thereof according to any one of the preceding claims to the individual, the urinary sodium (excretion) of the individual (significantly) increases (e.g., as compared to a vehicle control).

64. The method according to any one of the preceding claims, wherein after subcutaneous administration of the compound or a pharmaceutically acceptable salt thereof according to any one of the preceding claims to the individual, the urinary sodium and / or urinary potassium (excretion) of the individual increases 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., as compared to a vehicle control, such as within the first 4 hours of treatment).

65. The method according to any one of the preceding claims, wherein after subcutaneous administration of the compound or a pharmaceutically acceptable salt thereof according to any one of the preceding claims to the individual, the ascites volume of the individual (significantly) decreases (e.g., as compared to a vehicle control).

66. The method according to any one of the preceding claims, wherein after subcutaneous administration of the compound or a pharmaceutically acceptable salt thereof according to any one of the preceding claims to the individual, the ascites volume of the individual decreases by about 25% or more, 50% or more, 100% or more, about 200% or more, or about 300% or more (e.g., as compared to a vehicle control, such as when measured 3 days after treatment).

67. The method according to any one of the preceding claims, wherein after subcutaneous administration of the compound or a pharmaceutically acceptable salt thereof according to any one of the preceding claims to the individual, the body weight of the individual (significantly) decreases (e.g., as compared to a vehicle control).

68. The method according to any one of the preceding claims, wherein after subcutaneous administration of the compound or a pharmaceutically acceptable salt thereof according to any one of the preceding claims to the individual, the body weight of the individual decreases by about 1% or more, 2.5% or more, 5% or more, or about 10% or more (e.g., as compared to a vehicle control).

69. The method according to any one of the preceding claims, wherein at least one day (e.g., 3 days or longer (e.g., 5 days)) after subcutaneous administration of the compound or a pharmaceutically acceptable salt thereof according to any one of the preceding claims to the individual, the body weight of the individual decreases by at least about 1%, at least about 2.5%, at least about 5%, or at least about 10%.

70. The method according to any one of the preceding claims, wherein after subcutaneous administration of the compound or a pharmaceutically acceptable salt thereof according to any one of the preceding claims to the individual, the mean arterial pressure (MAP) of the individual increases (e.g., as compared to the baseline measurement before treatment).

71. The method according to any one of the preceding claims, wherein after administration of the compound or a pharmaceutically acceptable salt thereof according to any one of the preceding claims to the individual, the MAP of the individual increases by about 1% to about 10% (e.g., as compared to the baseline measurement before treatment).

72. The method according to any one of the preceding claims, wherein after administration of the compound or a pharmaceutically acceptable salt thereof according to any one of the preceding claims to the individual, the MAP of the individual increases in a dose-dependent manner.

73. The method according to any one of the preceding claims, wherein subcutaneous administration of the compound or a pharmaceutically acceptable salt thereof according to any one of the preceding claims to the individual improves the systemic hemodynamics of the individual.

74. The method according to any one of the preceding claims, wherein subcutaneous administration of the compound or a pharmaceutically acceptable salt thereof according to any one of the preceding claims to the individual reduces the fluid retention and / or overload of the individual.

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

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

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

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

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

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

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

82. The method according to any one of the preceding claims, wherein the method comprises administering (subcutaneously) to the individual a compound or a pharmaceutically acceptable salt thereof according to any one of the preceding claims by subcutaneous bolus injection.

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

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

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

86. The method according to any one of the preceding claims, wherein the individual has ascites.

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

88. The method according to any one of the preceding claims, wherein the individual has developed (refractory) ascites as a complication of ESLD.

89. The method according to any one of the preceding claims, wherein the method further comprises reducing the serum creatinine (sCr) (value) of the individual (e.g., as compared to a pre-treatment baseline measurement).

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

91. The method according to any one of the preceding claims, wherein, after administering a compound or a pharmaceutically acceptable salt thereof according to any one of the preceding claims, the individual has an improvement in renal function.

92. The method according to 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 composition according to claim 55, wherein the compound has a structure represented by Formula I: D1 - L - D2 Formula I or a pharmaceutically acceptable salt thereof, wherein: D1 is a vasopressin receptor 1A (V1AR) agonist; D2 is a V1AR antagonist; and L is a linker.

95. The composition according to claim 55 or 56, wherein the compound is Compound 1.

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

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

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

99. A subcutaneous formulation comprising 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, wherein: D1 is a vasopressin receptor 1A (V1AR) agonist; D2 is a V1AR antagonist; and L is a linker, wherein less than 50% of the compound of Formula I degrades (e.g., subcutaneously).

100. A subcutaneous formulation comprising 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, wherein: D1 is a vasopressin receptor 1A (V1AR) agonist; D2 is a V1AR antagonist; and L is a linker, and the formulation has a concentration of the compound of Formula I of about 0.1 mg / mL to about 100 mg / mL.

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

102. The subcutaneous formulation according to claims 99 - 101, further comprising: a preservative.

103. A subcutaneous formulation comprising: a. A compound having a structure represented by Formula I or a pharmaceutically acceptable salt thereof: D1-L-D2 Formula I Wherein: D1 is a vasopressin receptor 1A (V1AR) agonist; D2 is a V1AR antagonist; and L is a linker, and b. A preservative.

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

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

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

107. The subcutaneous formulation according to any one of claims 99-106, wherein the compound of Formula I is less prone to degradation, such as in the subcutaneous layer of an individual to whom the formulation is subcutaneously administered.

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

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

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

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

112. The subcutaneous formulation according to any one of claims 99-111, further comprising: a buffer having a pKa of about 3.0 to about 6.0 at 25°C.

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

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

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

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

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

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

119. The system according to claim 118, wherein the system comprises an adhesive body for (e.g., reversibly) fixing the (subcutaneous infusion) device to the skin surface of the individual.

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

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

122. The system according to any one of claims 118-121, wherein the first opening is in fluid communication with the cavity.

123. The system according to any one of claims 118-122, wherein after the subcutaneous infusion device is fixed to the skin of the individual, the second opening is subcutaneously disposed within the individual.

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

125. The system according to any one of claims 118-124, wherein the system is configured to continuously provide the composition to the individual over a period of about 24 hours or longer.

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

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

128. The system according to any one of claims 118-127, wherein the composition is the composition or formulation according to any one of the preceding claims.

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