Mixed vasopressin receptor agonist-antagonists for regulating mean arterial pressure

Abstract

Provided herein are compositions suitable for, eg, subcutaneous administration, and methods for regulating mean arterial pressure (MAP) in an individual using mixed V1A receptor agonist-antagonists.

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 63 / 378,010, filed September 30, 2022, U.S. Provisional Patent Application No. 63 / 432,974, filed December 15, 2022, and U.S. Provisional Patent Application No. 63 / 471,712, filed June 7, 2023, each of which is incorporated by reference in its entirety. [Background technology]

[0002] End-stage liver disease (ESLD) complications are responsible for approximately one million deaths annually. Patients with end-stage liver disease often develop portal hypertension. ESLD patients are prone to a variety of decompensatory events that can impair renal perfusion pressure and lead to progressive functional kidney injury. Hepatorenal syndrome with acute kidney injury (HRS-AKI) is a life-threatening complication and decompensatory event that occurs in patients with ESLD, with an untreated mortality rate approaching 90% (e.g., within 90 days) and a median survival time of less than four weeks. However, if treated promptly, HRS-AKI is potentially reversible.

[0003] Hepatorenal syndrome with acute kidney injury (HRS-AKI) is a severe and rapidly progressive consequence of end-stage liver disease (ESLD), leading to acute renal failure and, in many cases, death. HRS-AKI affects an estimated 75,000 individuals annually (e.g., worldwide) and is associated with a mortality rate of over 50 percent 90 days after diagnosis. As the incidence of (chronic) liver disease increases, the prevalence of HRS-AKI is expected to increase as well. Therapeutic interventions often produce only modest benefits and / or are insufficient to achieve the goals of reversing renal failure and extending survival in critically ill patients.

[0004] The management of decompensated cirrhosis often involves the use of vasoconstrictors that are full vasopressin 1a receptor (V1AR) agonists. Full (vasopressin V2 receptor (V2R) and V1AR) agonists reduce portal vein pressure by increasing splanchnic arteriolar vasoconstriction, thereby redistributing blood volume to the systemic circulation, thereby increasing glomerular filtration rate and improving renal perfusion. However, (non-selective) full (V1AR, V2R) agonists (e.g., having only an agonist portion and no antagonist portion) may cause undesirable events, such as undesirable systemic events such as vasoconstriction resulting in ischemia (e.g., organ ischemia and / or local (injection) site ischemia), administration (e.g., injection) site events (e.g., reactions) such as local (site) vasoconstriction resulting in administration site ischemia, or both (e.g., when administered subcutaneously). Such events can preclude the use of such compounds in outpatient settings (e.g., home use), for example, limiting their use to intravenous administration and short-term application in inpatient settings under close specialist supervision (e.g., making them unsuitable for chronic and outpatient settings). Furthermore, given the risk profile of full (V2R, V1AR) agonists, careful dose titration and monitoring are often required to prevent the development of serious adverse events (AEs) related to, for example, tissue hypoxia and ischemia due to excessive vasoconstriction.

[0005] Furthermore, it is difficult to use nonselective full (V1AR, V2R) agonists such as vasopressin to increase mean arterial pressure (MAP) by 10–15 mmHg, which strongly correlates with recovery from HRS-AKI. In some cases, achieving and / or maintaining a 10–15 mmHg increase in MAP is the therapeutic goal of current therapies. Due to the pharmacokinetics and very steep concentration-response curve of the vasopressin system, it may be easier to underdose (losing clinical efficacy) or cause excessive vasoconstriction, which can lead to severe, potentially life-threatening adverse events (AEs). Second, individuals with decompensated cirrhosis may already have high endogenous vasopressin levels, which promote water retention through a V2-mediated antidiuretic effect. Clinical vasopressin agonists are primarily V2 agonists and, at pharmacological concentrations, act secondarily as V1a agonists. Intrinsic V2 activity may contribute to the adverse event profile associated with fluid overload and respiratory complications associated with clinical vasopressin agonists. Summary of the Invention [Means for solving the problem]

[0006] Some embodiments herein provide compounds (e.g., mixed agonist-antagonists) that are selective for the V1a receptor. In some embodiments, the compounds reach and maintain a (target) level of vasoconstriction, avoiding fluid retention, e.g., via a uniform administration profile. In some cases, the compounds have a reduced incidence of (serious) adverse events and improved clinical efficacy (e.g., compared to clinical vasopressin agonists). In some cases, it is not necessary to titrate the compounds to achieve, e.g., a reduced incidence of (serious) adverse events and improved clinical efficacy (e.g., compared to clinical vasopressin agonists). In some cases, the compounds described herein (e.g., mixed V1a agonist-antagonists) can be administered at higher doses (than necessary) to effectively reach maximum efficacy. Conversely, administration of relatively high doses of non-selective full (V1a, V2) agonists, such as terlipressin, can be toxic and result in (serious) adverse events.

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

[0008] In some cases, a compound described herein (e.g., a mixed V1a agonist-antagonist, e.g., Compound 1) is metabolized to a full vasopressin agonist, for example, when administered subcutaneously. In some cases, the formation of a full vasopressin agonist is associated with a higher risk of an individual experiencing an adverse event, for example, after subcutaneous (bolus) injection of the mixed V1a agonist-antagonist. In some cases, the adverse event is a systemic event, a local administration site event, or both. In some embodiments, the adverse event is associated with excessive vasopressin constriction. In some cases, the full vasopressin agonist is partially active (compared to a mixed V1a agonist-antagonist). In some cases, subcutaneous administration of a mixed V1a agonist-antagonist described herein (e.g., by subcutaneous (bolus) injection) provides an overproduction of the full vasopressin agonist (e.g., within the subcutaneous space of an individual). For example, overproduction of a full vasopressin agonist (e.g., within an individual's subcutaneous space) is undesirable because the parent compound (e.g., a mixed V1a agonist-antagonist described herein, e.g., Compound 1) is delivered systemically, thereby increasing the risk of undesirable (systemic) events (e.g., toxicity associated with excessive (local and / or systemic) vasoconstriction), e.g., via full agonism of the V1a receptor by a full vasopressin agonist. Additional problems arising from overproduction of a full vasopressin agonist (e.g., within an individual's subcutaneous space) after administration of a composition described herein include reduced efficacy, increased side effects, and / or difficulty controlling potency (e.g., dose titration). As shown in FIG. 15, full agonism of the vasopressin receptor can induce severe side effects and / or be fatal.

[0009] Some embodiments described herein include methods and formulations that reduce the formation of full vasopressin agonists (e.g., Ml) after subcutaneous (bolus) injection of, for example, a mixed Vla agonist-antagonist described herein (e.g., Compound 1). In some embodiments, reducing the formation of full vasopressin agonists (e.g., Ml) after, for example, subcutaneous administration of a mixed Vla agonist-antagonist described herein reduces the risk of an individual experiencing undesirable (systemic) events (e.g., toxicity associated with excessive (local and / or systemic) vasoconstriction), e.g., via full agonism of the Vla receptor by the full vasopressin agonist. In some embodiments, reducing the formation of a full vasopressin agonist (e.g., Ml), e.g., after subcutaneous administration of a mixed V1a agonist-antagonist described herein, increases the efficacy of a (e.g., mixed V1a agonist-antagonist) treatment described herein, reduces side effects (e.g., associated with overproduction of the full agonist), and / or improves control of the efficacy (e.g., titration) of a (e.g., mixed V1a agonist-antagonist) treatment described herein. In some embodiments, subcutaneous infusion of a mixed V1a agonist-antagonist reduces metabolite (Ml) formation (e.g., as measured systemically, e.g., by serum / plasma concentrations). In some embodiments, increasing the buffer concentration of a composition comprising a mixed V1a agonist-antagonist reduces metabolite (Ml) formation (e.g., as measured systemically, e.g., by serum / plasma concentrations), e.g., in vitro and in vivo (e.g., after 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, e.g., by serum / plasma concentrations), e.g., in vitro and in vivo (e.g., after subcutaneous administration).In some embodiments, subcutaneous injection and increasing the concentration of the mixed V1a agonist-antagonist in the composition reduces metabolite (M1) formation (e.g., as measured systemically, e.g., by serum / plasma concentrations), e.g., in vitro and in vivo (e.g., after subcutaneous administration), e.g., when the compositions described herein are administered at a relatively slow administration rate. In some embodiments, any combination of subcutaneous injection, increased buffer concentration in the composition, and increased drug concentration in the composition reduces metabolite (M1) formation (e.g., as measured systemically, e.g., by serum / plasma concentrations) after subcutaneous administration. In some embodiments, subcutaneous injection of a compound described herein, increased buffer concentration in the composition described herein, and / or increased drug concentration in the composition described herein improves systemic delivery of the mixed agonist-antagonist described herein.

[0010] Some embodiments herein provide a compound (e.g., a mixed V1AR receptor agonist-antagonist, e.g., Compound 1) that reduces portal pressure (PP) in an individual (e.g., in need thereof) without excessive vasoconstriction over a wide dose range, e.g., 10 μg / kg to 500 μg / kg, after subcutaneous administration.

[0011] Some embodiments herein provide compounds (e.g., mixed V1a receptor agonist-antagonists, e.g., Compound 1) that increase mean arterial pressure (MAP) in an individual (e.g., in need thereof) after, e.g., subcutaneous administration. In some embodiments, the increase in MAP reaches a peak plateau of, e.g., about +10 to +15 mmHg (even at doses as high as 100 to 500 μg / kg). In contrast, administration of a fully non-selective (V2, V1a) receptor agonist described herein, e.g., terlipressin, at similarly high doses provides significantly higher increases in MAP, e.g., well beyond the therapeutic window of +10 to +15 mmHg. Such large increases in MAP can significantly increase the likelihood of (serious) side effects (in the individual receiving treatment).

[0012] In some embodiments, a compound described herein (e.g., a mixed V1AR receptor agonist-antagonist, e.g., Compound 1) achieves an upper therapeutic limit (e.g., when administered subcutaneously) such that the effect (e.g., increasing MAP) does not change (significantly) (e.g., increase or decrease) even after increasing the dose of the compound (e.g., to doses as high as 100-500 μg / kg).

[0013] In some cases, increasing the dose of a compound described herein (e.g., a fully non-selective (V2R, V1AR) agonist, such as terlipressin) does not provide a (significant) change (e.g., an increase) in the effect (e.g., MAP). In some cases, increasing the dose of a compound described herein (e.g., a fully non-selective (V2R, V1AR) agonist, such as terlipressin) may continue to increase the effect (e.g., MAP) to levels that may be harmful to the individual receiving the compound and / or may result in (severe) side effects.

[0014] In some cases, increasing the dose of a mixed V1a agonist-antagonist described herein, e.g., Compound 1, does not result in a sustained increase in MAP in an individual (e.g., even at doses as high as 100-500 μg / kg), whereas increasing the dose of a fully non-selective (V2, V1a) agonist, e.g., terlipressin, does result in a sustained increase in MAP in an individual. In some cases, a mixed agonist-antagonist described herein, e.g., Compound 1, can be safely used subcutaneously to treat ESLD or its symptoms and / or complications, e.g., without the risk of the individual developing (serious) side effects and / or without the effect of MAP developing to dangerous or harmful levels. In some cases, the therapeutic window (and safety profile) of a mixed V1AR agonist-antagonist described herein, e.g., Compound 1, is significantly improved compared to a V1AR agonist (e.g., not including a separate V1AR antagonist moiety), e.g., terlipressin.

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

[0016] In some embodiments, a compound described herein (e.g., a mixed V1a agonist-antagonist, e.g., Compound 1) is not a full or non-selective (V2, V1a) receptor agonist. In some embodiments, subcutaneous administration of a compound described herein (e.g., a mixed V1a agonist-antagonist, e.g., Compound 1) is not toxic (at therapeutic levels), even at doses as high as 100-500 μg / kg, for example. In some embodiments, a compound described herein (e.g., a mixed V1a agonist-antagonist, e.g., Compound 1) has a wide therapeutic index and is selective for the V1a receptor, e.g., at therapeutic doses. In some embodiments, a compound described herein (e.g., a mixed V1a agonist-antagonist, e.g., Compound 1) is useful for subcutaneous administration. In some embodiments, a compound described herein (e.g., a mixed V1a agonist-antagonist, e.g., Compound 1) increases mean arterial pressure (MAP) in individuals receiving one or more subcutaneously administered doses of the compound. In some embodiments, a compound described herein (e.g., a mixed V1a agonist-antagonist, e.g., Compound 1) reduces portal venous pressure (PP) in individuals receiving one or more (subcutaneously administered) doses of the compound. In some embodiments, a compound described herein (e.g., a mixed V1a agonist-antagonist, e.g., Compound 1) increases MAP and reduces PP in individuals receiving one or more (subcutaneously administered) doses of the compound. In some embodiments, after a period of time (e.g., about 10 minutes) following subcutaneous administration of, for example, a compound described herein (e.g., a mixed V1a agonist-antagonist, e.g., Compound 1), MAP plateaus or reaches a therapeutic maximum. In some cases, after a period of time (e.g., about 20 minutes) following subcutaneous administration of, for example, a compound described herein (e.g., a fully non-selective (V2, V1a) agonist, e.g., terlipressin), MAP rapidly increases and peaks. In some embodiments, the PP plateau is altered, eg, after subcutaneous administration of a compound described herein (eg, a mixed V1a agonist-antagonist, eg, Compound 1).In some embodiments, for example, after subcutaneous administration of a compound described herein (e.g., a mixed V1a agonist-antagonist, e.g., Compound 1), the MAP and PP plateaus change or reach a therapeutic maximum after a period of time (e.g., about 10 minutes).

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

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

[0019] 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 desired vasoconstriction of splanchnic blood vessels (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 effect, which raises safety concerns with other drugs. In some cases, for example, at therapeutic concentrations, the compounds described herein (e.g., Compound 1) do not activate the vasopressin V2 receptor (e.g., causing undesirable water retention).

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

[0021] In some cases, the mixed V1A agonist-antagonist is suitable for systemic delivery, provided that the mixed agonist-antagonist properties of the mixed V1A agonist-antagonist prevent (significant) injection site reactions (e.g., local vasoconstriction), for example, at the subcutaneous injection site. In some cases, the mixed V1A agonist-antagonist provided herein does not have (functional) vasopressin 2 (V2) receptor activity, for example, at therapeutic concentrations. In some embodiments, the mixed V1A receptor agonist-antagonist is Compound 1.

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

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

[0024] In some cases, the mixed V1A agonist-antagonists provided herein reduce portal pressure, for example, by increasing splanchnic arteriolar vasoconstriction.

[0025] In some embodiments, the mixed V1A agonist-antagonists provided herein are used to treat complications of ESLD (e.g., cirrhosis portal hypertension), such as HRS-AKI.

[0026] In some embodiments, the mixed V1A agonist-antagonists provided herein are used to treat ESLD (eg, cirrhotic portal hypertension) or its complications, such as HRS-AKI.

[0027] In some embodiments, Compound 1 is used to treat complications of ESLD (e.g., cirrhosis portal hypertension), such as HRS-AKI.

[0028] In some cases, the mixed V1A agonist-antagonists provided herein (e.g., Compound 1) provide a substantially improved therapeutic index (e.g., resulting from a lower maximum vasoconstriction effect and a lower risk of tissue hypoxia), e.g., when compared to a full, non-selective (V2, V1A) receptor agonist. In some cases, the mixed V1A agonist-antagonists provided herein (e.g., Compound 1) provide approximately half the maximum vasoconstriction produced by a full agonist, e.g., without concomitant signs of ischemia. In some cases, the mixed V1A agonist-antagonists provided herein (e.g., Compound 1) are (clinically) effective vasoconstrictors, e.g., with little local toxicity, e.g., when administered subcutaneously. In some cases, the mixed V1A agonist-antagonists provided herein (e.g., Compound 1) are (clinically) effective vasoconstrictors (e.g., with a favorable benefit / risk profile (e.g., when administered subcutaneously), e.g., with little local toxicity). In some cases, the mixed V1A agonist-antagonists provided herein (e.g., Compound 1) provide sufficient splanchnic vasoconstriction to reduce elevated portal vein pressure while minimizing the risk of excessive vasoconstriction in other vascular beds with associated adverse events, such as mesenteric ischemia.

[0029] In some embodiments herein, there is provided a method of regulating mean arterial pressure (MAP) in an individual (e.g., in need thereof), the method comprising subcutaneously administering to the individual (e.g., in need thereof) an effective amount of a compound, wherein the compound is a mixed vasopressin receptor 1A (V1AR) agonist-antagonist.

[0030] In some embodiments herein, there is provided a method of regulating mean arterial pressure (MAP) in an individual (e.g., in need thereof), the method comprising subcutaneously injecting into the individual (e.g., in need thereof) a composition comprising an (effective) amount of a compound, wherein the compound is a mixed vasopressin receptor 1A (V1AR) agonist-antagonist.

[0031] In some embodiments herein, there is provided a method of regulating mean arterial pressure (MAP) in an individual (e.g., in need thereof), the method comprising subcutaneously injecting the individual (e.g., in need thereof) with a composition comprising an (effective) amount of a compound, wherein the compound is a mixed vasopressin receptor 1A (V1AR) agonist-antagonist.

[0032] In some embodiments, the mixed vasopressin receptor 1A (V1AR) agonist-antagonist is selective for V1AR over V2R, hi some embodiments, the mixed vasopressin receptor 1A (V1AR) agonist-antagonist has no V2R activity, e.g., 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, modulating mean arterial pressure (MAP) in an individual comprises increasing MAP by at least 5% above baseline, hi some embodiments, modulating mean arterial pressure (MAP) in an individual comprises increasing MAP by at least 5 mmHg above baseline (e.g., by 5 mmHg or more, or by 10 mmHg or more).

[0035] In some embodiments, the compound has the structure represented by Formula I: D1-L-D2 Formula I or a pharmaceutically acceptable salt thereof, (In the formula: D1 is a vasopressin receptor 1A (V1AR) agonist; D2 is a V1AR antagonist; L is a linker It has.

[0036] In some embodiments herein, there is provided a method of regulating mean arterial pressure (MAP) in an individual (e.g., in need thereof), the method comprising administering an effective amount of a compound having a structure represented by Formula I: D1-L-D2 Formula I a compound having or a pharmaceutically acceptable salt thereof, to an individual (e.g., in need thereof) (In the formula: D1 is a vasopressin receptor 1A (V1AR) agonist; D2 is a V1AR antagonist; L is a linker).

[0037] In some embodiments herein, there is provided a method of regulating mean arterial pressure (MAP) in an individual (e.g., in need thereof), the method comprising administering an (effective) amount of a compound having a structure represented by Formula I: D1-L-D2 Formula I or a pharmaceutically acceptable salt thereof and subcutaneously injecting into an individual (e.g., in need thereof) a composition comprising (In the formula: D1 is a vasopressin receptor 1A (V1AR) agonist; D2 is a V1AR antagonist; L is a linker).

[0038] In some embodiments, D1 is selective for V1AR over V2R.

[0039] In some embodiments, D1 is or comprises a (e.g., cyclic) peptide. In some embodiments, D1 is or comprises a cyclic nonapeptide. In some embodiments, D1 has the following structure: [ka] having or including

[0040] In some embodiments, D1 has the following structure: [ka] having or including

[0041] In some embodiments, D2 is or comprises a (e.g., linear) peptide. In some embodiments, D2 is a linear peptide comprising about 7 or more amino acid residues. In some embodiments, D2 has the following structure: [ka] having or including

[0042] In some embodiments, D2 has the following structure: [ka] having or including

[0043] In some embodiments, L is a non-hydrolyzable linker. In some embodiments, L comprises one or more linker groups, each linker group independently selected from the group consisting of substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl. In some embodiments, L is a bond, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. In some embodiments, L is substituted or unsubstituted heteroalkyl or comprises substituted or unsubstituted heteroalkyl. In some embodiments, L is 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 the following structure: [ka] having or including

[0044] In some embodiments, L has the following structure: [ka] having or including

[0045] In some embodiments, the compound is Compound 1, or a pharmaceutically acceptable salt thereof.

[0046] In some embodiments herein, there is provided a method for regulating mean arterial pressure (MAP) in an individual (e.g., in need thereof), the method comprising subcutaneously administering to the individual (e.g., in need thereof) an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof.

[0047] In some embodiments herein, there is provided a method for regulating mean arterial pressure (MAP) in an individual (e.g., in need thereof), the method comprising subcutaneously injecting into the individual (e.g., in need thereof) a composition comprising an (effective) amount of Compound 1, or a pharmaceutically acceptable salt thereof.

[0048] 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 injecting a composition comprising a compound having a structure represented by Formula I, or a pharmaceutically acceptable salt thereof, into the individual in need thereof.

[0049] In some embodiments, the composition further comprises a liquid vehicle or solvent (eg, water or an aqueous vehicle).

[0050] In some embodiments, the method further includes securing a subcutaneous infusion device to the skin of the individual, the subcutaneous infusion device comprising a chamber body and a hollow tube body, the composition configured to be within the chamber body, the hollow tube body comprising a first opening and a second opening, the first opening in fluid communication with the chamber body and the second opening configured to be subcutaneous in the individual after securing the subcutaneous infusion device to the skin.

[0051] In some embodiments, the subcutaneous infusion device further comprises a pump configured to subcutaneously infuse the composition into the individual at a constant or variable rate.

[0052] In some embodiments, subcutaneous injection of the composition into an individual improves tolerability compared to subcutaneous (bolus) injection (e.g., based on reduced Ml overproduction subcutaneously). In some embodiments, subcutaneous injection of the composition into an individual reduces undesirable systemic events (e.g., undesirable vasoconstriction, e.g., leading to ischemia), reduces undesirable administration site events (e.g., local site vasoconstriction, e.g., leading to administration site ischemia), or both.

[0053] In some embodiments herein, there is provided a method of regulating mean arterial pressure (MAP) in an individual in need thereof, the method comprising subcutaneously injecting a composition comprising a compound having a structure represented by Formula I, or a pharmaceutically acceptable salt thereof, to the individual in need thereof, wherein less than 50% of the compound of Formula I is degraded (e.g., subcutaneously).

[0054] In some embodiments herein, there is provided a method of regulating mean arterial pressure (MAP) in an individual in need thereof, the method comprising subcutaneously injecting a composition comprising a compound having a structure represented by Formula I, or a pharmaceutically acceptable salt thereof, to the individual in need thereof, wherein less than 50% of the compound of Formula I is degraded (e.g., subcutaneously).

[0055] In some embodiments, for example, when the composition is administered subcutaneously to an individual (e.g., by subcutaneous (bolus) injection or subcutaneous infusion), less than 50% of the compound of Formula I degrades (e.g., subcutaneously). In some embodiments, for example, when the composition is administered subcutaneously to an individual (e.g., by subcutaneous (bolus) injection or subcutaneous infusion), less than 30% of the compound of Formula I degrades (e.g., subcutaneously). In some embodiments, for example, when the composition is administered subcutaneously to an individual (e.g., by subcutaneous (bolus) injection or subcutaneous infusion), less than 50% of the compound of Formula I degrades (e.g., subcutaneously) to form Ml. In some embodiments, for example, when the composition is administered subcutaneously to an individual (e.g., by subcutaneous (bolus) injection or subcutaneous infusion), less than 30% of the compound of Formula I degrades (e.g., subcutaneously) to form Ml. In some embodiments, for example, when the composition is injected subcutaneously to an individual (e.g., by subcutaneous (bolus) injection or subcutaneous infusion), less Ml is formed compared to administration of an otherwise identical composition administered by subcutaneous (bolus) injection. In some embodiments, for example, when the composition is injected subcutaneously into an individual, less Ml is formed systemically compared to administration of an otherwise identical composition administered by subcutaneous (bolus) injection. In some embodiments, for example, when the composition is injected subcutaneously into an individual, less Ml is formed locally (at the injection / infusion site) compared to administration of an otherwise identical composition administered by subcutaneous (bolus) injection.

[0056] In some embodiments, the composition is continuously infused subcutaneously into the individual for at least 1 hour, hi some embodiments, the composition is infused subcutaneously into the individual at a rate of about 0.005 milliliters per hour (mL / hr) to about 1 mL / hr during the administration period.

[0057] In some embodiments, the compound is administered to an individual (eg, continuously) in an amount of from about 0.001 milligrams (mg) to about 100 mg for a period of one or more days.

[0058] In some embodiments, the composition comprises a compound at a concentration of about 0.001 milligrams per milliliter (mg / mL) to about 100 mg / mL. In some embodiments, the composition comprises a compound at a concentration of about 0.1 mg / mL to about 100 mg / mL. In some embodiments, the composition comprises a compound at a concentration of about 1 mg / mL to about 10 mg / mL.

[0059] 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.

[0060] In some embodiments, the composition further comprises a preservative, hi some embodiments, the preservative is present in an amount of about 1 mg / mL to about 20 mg / mL.

[0061] In some embodiments, the composition further comprises a solubilizing agent, in some embodiments, the solubilizing agent is present in an amount of about 1 mg / mL to about 100 mg / mL (e.g., about 60-80 mg / mL).

[0062] In some embodiments, the composition comprises a buffering agent. In some embodiments, the buffering agent is selected from the group consisting of acetate buffer, succinate buffer, and citrate buffer. In some embodiments, the composition comprises a buffering agent at a concentration of about 1 millimolar (mM) to about 1 molar (M). In some embodiments, the composition comprises a buffering agent at a concentration of about 5 mM to about 250 mM. In some embodiments, the composition comprises a buffering agent at a concentration of about 5 mM to about 25 mM. In some embodiments, the composition comprises a buffering agent at a concentration of about 50 mM to about 250 mM.

[0063] 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.

[0064] In some embodiments, the individual's mean arterial pressure (MAP) increases (e.g., compared to a baseline measurement before treatment) after subcutaneous administration of Compound 1. In some embodiments, the individual's MAP increases by about 1% to about 10% (e.g., compared to a baseline measurement before treatment) after administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the individual's MAP increases in a dose-dependent manner after administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual.

[0065] In some embodiments, the diastolic blood pressure of the individual is increased (e.g., compared to a baseline measurement before treatment) following administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual.

[0066] In some embodiments, the systolic blood pressure of the individual is increased (e.g., compared to a baseline measurement before treatment) following administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual.

[0067] In some embodiments, the diastolic and / or systolic blood pressure of the individual is increased in a dose-dependent manner following administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual.

[0068] In some embodiments, the pulse rate and / or peripheral blood flow of an individual is decreased following administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual.

[0069] In some embodiments, (subcutaneous) administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to an individual improves the individual's systemic hemodynamics.

[0070] In some embodiments, (subcutaneous) administration of a compound described herein, or a pharmaceutically acceptable salt thereof, to an individual reduces fluid retention and / or overload in the individual.

[0071] In some embodiments, the method includes administering a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual on day 1 and day 2 (e.g., day 2 is one or more days after day 1).

[0072] In some embodiments, the individual receives an initial (e.g., intravenous infusion) dose of a compound described herein, or a pharmaceutically acceptable salt thereof, on day 1 (e.g., to acclimate the individual to vasoconstriction before receiving the first subcutaneous therapeutic dose). In some embodiments, the initial (e.g., intravenous infusion) dose is from about 0.01 milligrams (mg) to about 100 mg. In some embodiments, the initial (e.g., intravenous infusion) dose is from about 0.01 milligrams (mg) to about 10 mg. In some embodiments, the compound described herein, or a pharmaceutically acceptable salt thereof, is administered to the individual (e.g., by intravenous infusion) for about 4 hours to about 8 hours (e.g., about 6 hours) on day 1. In some embodiments, the initial (e.g., intravenous infusion) dose of a compound described herein, or a pharmaceutically acceptable salt thereof, is a low dose, for example, from about 5 μg / hour to about 15 μg / hour (e.g., about 8 μg / hour). In some embodiments, the method further comprises administering (subcutaneously) a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual one or more days after day 1. In some embodiments, the method comprises administering (subcutaneously) a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual daily for two or more days (e.g., 4-10 days) (e.g., after day 1). In some embodiments, the method further comprises administering (subcutaneously) a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual on consecutive days after day 1. In some embodiments, the method comprises administering (subcutaneously) a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual on multiple days. In some embodiments, the individual receives repeated subcutaneous injections of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0073] In some embodiments, the individual is administered a compound described herein, or a pharmaceutically acceptable salt thereof, subcutaneously multiple times, e.g., over several days. In some embodiments, the compound is administered to the individual continuously, e.g., over several days.

[0074] In some embodiments, the method comprises subcutaneously administering a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual once daily (e.g., on two or more (e.g., five or more) consecutive days).

[0075] In some embodiments, the method includes administering a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual by subcutaneous (bolus) injection, e.g., when the compound is administered to the individual as a single dose (e.g., all at once).

[0076] In some embodiments, the method comprises administering a compound described herein, or a pharmaceutically acceptable salt thereof, to an individual by subcutaneous infusion. In some embodiments, the method comprises administering a compound described herein, or a pharmaceutically acceptable salt thereof, to an individual by continuous subcutaneous infusion.

[0077] In some embodiments, the method includes administering (e.g., subcutaneously) to the individual a compound described herein, or a pharmaceutically acceptable salt thereof, in an amount of about 0.01 milligrams (mg) per day to about 100 mg per day (e.g., about 0.01 milligrams (mg) per day to about 10 mg per day (e.g., about 0.01 mg per day to about 1 mg per day)).

[0078] In some embodiments, the individual has hepatorenal syndrome associated with HRS-AKI.

[0079] In some embodiments, the individual has end-stage liver disease (ESLD).

[0080] In some embodiments, the individual develops HRS-AKI as a complication of ESLD.

[0081] In some embodiments, the method further comprises lowering serum creatinine (sCr) in the individual (e.g., compared to a baseline measurement before treatment). In some embodiments, the method comprises administering a compound described herein, or a pharmaceutically acceptable salt thereof, to the individual at least until the individual has an sCr of 1.5 milligrams (mg) per deciliter (dL) or less. In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1), is administered (e.g., subcutaneously) to an individual (e.g., as described herein) at least until the individual's sCr returns to normal (e.g., baseline).

[0082] In some embodiments herein, a pharmaceutical composition is provided 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.

[0083] In some embodiments, the compound has the structure represented by Formula I: D1-L-D2 Formula I or a pharmaceutically acceptable salt thereof (In the formula: D1 is a vasopressin receptor 1A (V1AR) agonist; D2 is a V1AR antagonist; L is a linker It has.

[0084] In some embodiments herein, an effective amount of a compound having a structure according to Formula I: D1-L-D2 Formula I or a pharmaceutically acceptable salt thereof a pharmaceutical composition comprising (In the formula: D1 is a vasopressin receptor 1A (V1AR) agonist; D2 is a V1AR antagonist; L is a linker The composition is formulated for subcutaneous administration.

[0085] 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.

[0086] In some embodiments, the compositions are suitable for a route of administration other than intravenous administration, for example subcutaneous administration.

[0087] In some cases, the mixed V1A agonist-antagonist provided herein (eg, Compound 1) is administered in the form described in Example 1.

[0088] In some embodiments, a pharmaceutical composition is provided comprising an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, wherein the composition is formulated for subcutaneous administration.

[0089] In some embodiments herein, a subcutaneous formulation is provided 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).

[0090] In some embodiments herein, there is provided a subcutaneous formulation comprising a compound having a structure represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein the formulation has a concentration of the compound of Formula I from about 0.1 mg / mL to about 100 mg / mL.

[0091] In some embodiments herein, there is provided a subcutaneous formulation comprising a compound having a structure represented by Formula I, or a pharmaceutically acceptable salt thereof, and a buffering agent at a concentration of about 1 millimolar (mM) to about 1 M.

[0092] In some embodiments, the formulation comprises a buffering agent at a concentration of about 1 millimolar (mM) to about 1 M. In some embodiments, the buffering agent has a pKa of about 3.0 to about 6.0, e.g., at 25° C. In some embodiments, the buffering agent is selected from the group consisting of acetate, citrate, succinate, and phosphate.

[0093] In some embodiments, the formulation comprises a pH sufficient to inhibit (e.g., deactivate or inactivate) proteases (e.g., trypsin), e.g., in the subcutaneous layer of an individual to whom the formulation is administered subcutaneously. In some embodiments, the pH of the formulation is about 4 to about 5 (e.g., about 4.5).

[0094] In some embodiments, the pH of the subcutaneous formulation does not (substantially) change when administered subcutaneously to an individual (eg, by subcutaneous (bolus) injection or subcutaneous infusion).

[0095] In some embodiments, the formulation has an ionic strength of about 5 mM to about 200 mM (eg, about 10 mM to about 100 mM).

[0096] In some embodiments, the subcutaneous formulation further comprises a preservative.

[0097] In some embodiments, provided herein are subcutaneous formulations comprising a compound having a structure according to Formula I, or a pharmaceutically acceptable salt thereof, and a preservative.

[0098] In some embodiments, the preservative is any suitable preservative, such as meta-(m)-cresol. In some embodiments, the formulation comprises a preservative (e.g., m-cresol) at a concentration of about 1 mg / mL to about 100 mg / mL.

[0099] In some embodiments, provided herein are subcutaneous formulations comprising a compound having a structure according to Formula I, or a pharmaceutically acceptable salt thereof, and a solubilizing agent.

[0100] In some embodiments, the preservative is any suitable solubilizing agent, such as cyclodextrin. In some embodiments, the formulation comprises a solubilizing agent (e.g., cyclodextrin) at a concentration of about 1 mg / mL to about 100 mg / mL (e.g., about 60-80 mg / mL).

[0101] In some embodiments, the compound of formula I is relatively resistant to degradation, for example, in the subcutaneous layer of an individual to which the formulation is administered subcutaneously.

[0102] In some embodiments, for example, over a period of about one day or more (e.g., about one day, about two days, or more), less than 50% of the compound of Formula I degrades (e.g., in the vial and / or subcutaneously).

[0103] 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.

[0104] In some embodiments, the compound is Compound 1.

[0105] In some embodiments, the compositions are suitable for systemic delivery of an active agent, eg, Compound 1.

[0106] In some cases, the mixed V1A agonist-antagonist provided herein (eg, Compound 1) is administered in the form of an acetate salt.

[0107] In some cases, the mixed V1A agonist-antagonist provided herein (e.g., Compound 1) is administered in the form described in any of the examples described herein, such as any one of Examples 1-6.

[0108] In some embodiments, provided herein is a system for regulating mean arterial pressure (MAP), the system comprising: a composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof; and a device configured to provide subcutaneous infusion of the composition to an individual when placed on the skin of the individual.

[0109] In some embodiments, the system includes an adhesive for (e.g., reversibly) securing the (subcutaneous infusion) device to the surface of the individual's skin. In some embodiments, the system includes a chamber body and a hollow tube body, and the composition is configured to be within the chamber body. In some embodiments, the hollow tube body includes a first opening and a second opening. In some embodiments, the first opening is fluidly connected to the chamber body. In some embodiments, the second opening is configured to be subcutaneous in the individual after securing the subcutaneous infusion device to the skin.

[0110] In some embodiments, the (subcutaneous infusion) device further comprises a pump configured to subcutaneously infuse the composition into the individual at a constant or variable rate.

[0111] In some embodiments, the system is configured to provide the composition to the individual (continuously) for a period of about 24 hours or more.

[0112] In some embodiments, the device is configured to receive a vial and / or cartridge of the composition.

[0113] In some embodiments, the device is a subcutaneous infusion device (eg, a pump).

[0114] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description and accompanying drawings (also referred to herein as "Figure" and "FIG") that set forth illustrative embodiments, in which the principles of the invention are utilized: [Brief explanation of the drawings]

[0115] [Figure 1] The study design described in Example 1 is shown for each subject in Period 1 (intravenous infusion) and Period 2 (subcutaneous injection). [Figure 2] 1 shows the time course of Compound 1 concentration after intravenous administration during Period 1. [Figure 3A] 1 shows the time course of Compound 1 concentration after the first subcutaneous dose of Period 2. [Figure 3B] 1 shows the time course of Compound 1 concentration after the fifth subcutaneous dose of Period 2. [Figure 4A] Diastolic blood pressure and intravenous infusion (mean values) are shown. [Figure 4B] Diastolic blood pressure, intravenous infusion (mean percent change) is shown. [Figure 5A] Diastolic blood pressure, repeated subcutaneous injections (mean values) are shown. [Figure 5B] Diastolic blood pressure, repeated subcutaneous injections (mean percent change) are shown. [Figure 6A] Systolic blood pressure and intravenous infusion (mean values) are shown. [Figure 6B] Systolic blood pressure, intravenous infusion (mean percent change) is shown. [Figure 7A] Systolic blood pressure and subcutaneous injection (mean values) are shown. [Figure 7B] Systolic blood pressure, subcutaneous injection (mean percent change) is shown. [Figure 8A] Changes in mean arterial pressure over time are shown (mean percentage change from baseline in mean arterial pressure after intravenous infusion). [Figure 8B] Changes in mean arterial pressure over time are shown (mean percentage change from baseline in mean arterial pressure after repeated subcutaneous injections). [Figure 9A] Pulse rates (mean values) after intravenous injection are shown. [Figure 9B] Pulse rate (mean percent change) after intravenous infusion is shown. [Figure 10A] The pulse rate (mean value) after subcutaneous injection is shown. [Figure 10B] Pulse rate (mean percent change) after subcutaneous injection is shown. [Figure 11] The amount of Compound 1 excreted unchanged in urine after intravenous infusion is shown. [Figure 12A] The amount of Compound 1 excreted after the first subcutaneous injection is shown. [Figure 12B] The amount of Compound 1 excreted after the fifth subcutaneous injection is shown. [Figure 13A] 1 shows the mean plasma concentrations of metabolite M1 after the first sc injection of Compound 1. [Figure 13B] 1 shows the mean plasma concentrations of metabolite M1 after the fifth sc injection of Compound 1. [Figure 14] The structure of M1 (circled) related to compound 1 is shown. [Figure 15] Exemplary dose-response curves for a full agonist, a partial agonist, and a weak agonist are shown. Figure 15 shows that, in general, a wider therapeutic window of vasoconstriction can be achieved with curve 2 than with curves 1 or 3. Part A indicates the level of full agonist where vasoconstriction may be fatal. Part B indicates the level of full agonist where vasoconstriction may induce severe side effects. [Figure 16] 1 shows the time course of portal pressure (ΔPP) in rats with bile duct ligation (BDL) after subcutaneous administration of various doses of mixed V1a agonist-antagonist. [Figure 17] Figure 1 shows the time course of portal mean arterial pressure (ΔMAP) in methionine / choline deficient (MCD) diet-fed rats after subcutaneous administration of a full non-selective (V2, V1a) agonist and various doses of a mixed V1a agonist-antagonist. [Figure 18] 1 shows the time course of portal pressure (ΔPP) in methionine / choline deficient (MCD) diet-fed rats after subcutaneous administration of a full non-selective (V2, V1a) agonist and various doses of a mixed V1a agonist-antagonist. [Figure 19] 1 shows exemplary dose-response curves of the maximum possible effects of a full non-selective (V2, V1a) agonist and a mixed V1a agonist-antagonist at the human V1a (hV1a) receptor. [Figure 20] 1 shows exemplary dose-response curves of the maximum possible effect of a mixed V1a agonist-antagonist at human V1a (hV1a) and human V2 (hV2) receptors. [Figure 21] 1 shows exemplary dose-response curves of contractility of human mesenteric resistance arteries in response to mixed V1a agonist-antagonists. [Figure 22A]1 shows the normalized plasma concentration time profile of Compound 1 following IV administration (10 mg / kg) in an individual (eg, a mammal). [Figure 22B] 1 shows the normalized plasma concentration time profile of Compound 1 following subcutaneous administration (1.0 mg / kg) in an individual (eg, a mammal). [Figure 23A] 1 shows the dose response of Compound 1, vasopressin, and vehicle on skin blood flow (SBF) (% baseline) in an individual (eg, a mammal) after IV administration. [Figure 23B] 1 shows the dose response of Compound 1, vasopressin, and vehicle on blood lactate concentration (mM) in individuals (eg, mammals) after IV administration. [Figure 23C] 1 shows a comparison of blood lactate concentrations in individuals (eg, mammals) following administration of vehicle, Compound 1, or vasopressin (AVP). [Figure 24A] 1 shows mean arterial pressure (MAP) following subcutaneous administration of Compound 1 in an individual (eg, a mammal). [Figure 24B] 1 shows systolic arterial blood pressure following subcutaneous administration of Compound 1 in an individual (eg, a mammal). [Figure 24C] 1 shows diastolic arterial blood pressure following subcutaneous administration of Compound 1 in an individual (eg, a mammal). [Figure 24D] 1 shows heart rate following subcutaneous administration of Compound 1 in an individual (eg, a mammal). [Figure 25A] 1 shows the normalized plasma concentration (ng / mL) time profile of Compound 1 following IV bolus (0.05 mg / kg) administration in an individual (e.g., a mammal). [Figure 25B] 1 shows the normalized plasma concentration time profile of Compound 1 following subcutaneous bolus (0.5 mg / kg) administration in an individual (eg, a mammal). [Figure 26A] 1 shows the change from baseline in mean arterial pressure (ΔMAP) following administration of Compound 1 over 480 minutes in an individual (eg, a mammal). [Figure 26B]1 shows the change from baseline in mean arterial pressure (ΔMAP) following administration of terlipressin over 480 minutes in an individual (eg, a mammal). [Figure 27] Following intravenous (IV) infusion (Panel A), little metabolism of Compound 1 occurs in healthy humans, and following subcutaneous (bolus) injection (Panel B), concentrations of Compound 1 and M1 are nearly equimolar in healthy humans. [Figure 28] 1 shows that little metabolism of Compound 1 occurs in minipigs after subcutaneous (SC) injection of relatively low (Panels A and B) and high (Panels C and D) doses of Compound 1. [Figure 29] Figure 28, panels A and B show the compound 1 / Ml ratios. [Figure 30] 1 shows that little metabolism of Compound 1 occurs in minipigs after relatively slow subcutaneous (SC) injection of relatively low (Panels A and B) and high (Panels C and D) doses of Compound 1. [Figure 31] Figure 30, panels A-D show the compound 1 / Ml ratios. DETAILED DESCRIPTION OF THE INVENTION

[0116] Specific Definitions As used herein and in the appended claims, the singular forms "a," "and," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, a reference to an "agent" includes a plurality of such agents; a reference to a "cell" includes a reference to one or more cells (or cells) and equivalents thereof known to those of skill in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulas, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term "about," when referring to a number or numerical range, means that the referenced number or numerical range is approximate within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary by 1% to 15% of the stated number or numerical range. Any description of "about" provided herein also includes a disclosure of the number itself. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude it from other specific embodiments; for example, any composition of matter, composition of matter, method, or process, etc., described herein can "consist" or "consist essentially of" the recited features.

[0117] As used herein, the terms "treat," "treating," or "treatment" include reducing, alleviating, relieving, ameliorating, managing, alleviating, or diminishing the symptoms associated with a disease, disease state, condition, or indication (e.g., as provided herein) in either a chronic or acute treatment scenario. Treatment of a disease or disease state described herein also includes disclosure of the use of such compounds or compositions for the treatment of such disease, disease state, disorder, or indication.

[0118] As used herein, the term "modulate" or "modulating" refers to a change in a biological, chemical, and / or biochemical response, e.g., a physiological response, in an individual. In some cases, the change is an increase in the individual's biological, chemical, and / or biochemical response. In some cases, the change is a decrease in the individual's biological, chemical, and / or biochemical response. In some cases, the change is observed (e.g., immediately, 30 minutes or more, 1 hour or more, 6 hours or more, 12 hours or more, 24 hours or more, or 1 week or more after a compound described herein is administered to the individual).

[0119] The term "adverse event" or "AE" as used herein refers to an untoward medical occurrence in an individual, such as an individual participating in a clinical trial. In some cases, an AE is, for example, an untoward and / or unintended sign, symptom, or illness temporarily associated with the use of an investigational medicinal product (IMP), regardless of whether it is considered to be caused by the IMP. For example, an AE can include accidental injury, any reason for a change in medication (drug and / or dose), any reason for a medical, nursing, or pharmacy consultation, or reason for hospitalization or surgical procedure, as well as overdose and medication errors, with or without clinical consequences. In some cases, an AE is expected based on the pharmacological effect of the IMP. In some cases, an AE is a laboratory abnormality, vital sign, or finding from a physical or gynecological examination that is assessed by the investigator as clinically significant. In some cases, a pretreatment adverse event is any untoward medical occurrence that occurs or is observed between the signing of informed consent and the first administration of the IMP. In some cases, a treatment-emergent adverse event is an AE that occurs after administration of IMP and within the time of residual drug effect, or a pre-treatment adverse event or pre-existing medical condition that worsens in intensity after administration of IMP and within the time of residual drug effect. In some cases, the time of residual drug effect is the estimated period after administration of IMP during which the product's effect is still considered to be present based on PK, PD, or other material properties. In some cases, the residual drug effect is five times the elimination half-life. In some cases, the elimination half-life of Compound 1 is approximately 1.5 to 2 hours. In some cases, the residual drug effect is within the time until the final assessment of Period 1 and the follow-up visit for Period 2 (as described in the Examples herein below). In some cases, a treatment-emergent adverse event is an AE that occurs after the time of IMP residual drug effect (e.g., before the first dose of Period 2 after the final assessment of Period 1 and after the follow-up visit for Period 2).

[0120] "Amino" refers to the -NH2 radical.

[0121] "Cyano" refers to the -CN radical.

[0122] "Nitro" refers to the -NO2 radical.

[0123] "Oxo" refers to the =O radical.

[0124] "Hydroxyl" refers to the -OH radical.

[0125] "Alkyl" generally refers to an alkyl group consisting solely of carbon and hydrogen atoms, e.g., of 1 to 15 carbon atoms (e.g., C1-C 15 "Alkyl" refers to an acyclic (e.g., straight or branched chain) or cyclic hydrocarbon (e.g., chain) radical having 1 to 13 carbon atoms (e.g., C1 to C6). Unless otherwise specified, alkyl is saturated or unsaturated (e.g., alkenyl containing at least one carbon-carbon double bond). The disclosure provided herein of "alkyl" is intended to include independent mention of saturated "alkyl" unless otherwise specified. Alkyl groups described herein are generally monovalent, but can also be divalent (which may also be described herein as "alkylene" or "alkylenyl" groups). In certain embodiments, alkyl is an alkyl group having 1 to 13 carbon atoms (e.g., C1 to C6). 13 In certain embodiments, alkyl contains 1 to 8 carbon atoms (e.g., C1-C8 alkyl). In other embodiments, alkyl contains 1 to 5 carbon atoms (e.g., C1-C5 alkyl). In other embodiments, alkyl contains 1 to 4 carbon atoms (e.g., C1-C4 alkyl). In other embodiments, alkyl contains 1 to 3 carbon atoms (e.g., C1-C3 alkyl). In other embodiments, alkyl contains 1 to 2 carbon atoms (e.g., C1-C2 alkyl). In other embodiments, alkyl contains 1 carbon atom (e.g., C1 alkyl). In other embodiments, alkyl contains 5 to 15 carbon atoms (e.g., C5-C6 alkyl). 15In other embodiments, alkyl includes 5 to 8 carbon atoms (e.g., C5-C8 alkyl). In other embodiments, alkyl includes 2 to 5 carbon atoms (e.g., C2-C5 alkyl). In other embodiments, alkyl includes 3 to 5 carbon atoms (e.g., C3-C5 alkyl). In other embodiments, alkyl groups are selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tent-butyl), and 1-pentyl (n-pentyl). The alkyl is attached to the remainder of the molecule by a single bond. In general, each alkyl group is independently substituted or unsubstituted. Each reference to "alkyl" provided herein includes specific and explicit recitation of unsaturated "alkyl" groups unless otherwise specified. Similarly, unless stated otherwise in detail herein, alkyl groups are optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -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 -O) t N(R a )2 (where t is 1 or 2), where each R aare independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0126] "Alkoxy" refers to a radical attached through an oxygen atom of the formula --O-alkyl, where alkyl is an alkyl chain as defined above.

[0127] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group, consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond and having from 2 to 12 carbon atoms. In certain embodiments, an alkenyl contains from 2 to 8 carbon atoms. In other embodiments, an alkenyl contains from 2 to 4 carbon atoms. An alkenyl is optionally substituted as described above for the "alkyl" group.

[0128] "Alkylene" or "alkylene chain" generally refers to a straight or branched chain divalent alkyl group, e.g., having 1 to 12 carbon atoms, that attaches the remainder of the molecule to a radical group, e.g., methylene, ethylene, propylene, i-propylene, n-butylene, etc. Unless stated otherwise in detail herein, the alkylene chain is optionally substituted as described herein for alkyl groups.

[0129] "Aryl" refers to a radical derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and carbon atoms from 5 to 18 carbon atoms, where at least one ring within the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) π-electron system according to the Hueckel theory. Ring systems from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin, and naphthalene. Unless stated otherwise in detail herein, the term "aryl" or the prefix "ar-" (e.g., in "aralkyl") means any of alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2-R b -N(R a )C(O)OR a , -R b -N(R a )C(O)Ra , -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), wherein each R a are independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl); and each R b is independently a direct bond or a straight or branched chain alkylene or alkenylene chain, and W is a straight or branched chain alkylene or alkenylene chain, wherein each of the above substituents is unsubstituted unless otherwise indicated.

[0130] An "aralkyl" or "aryl-alkyl" is an alkyl group of the formula -R c-aryl radical, where R c is an alkylene chain as defined above, e.g., methylene, ethylene, etc. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0131] "Carbocyclyl" or "cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical, consisting solely of carbon and hydrogen atoms, including fused or bridged ring systems having 3 to 15 carbon atoms. In certain embodiments, a carbocyclyl contains 3 to 10 carbon atoms. In other embodiments, a carbocyclyl contains 5 to 7 carbon atoms. A carbocyclyl is attached to the rest of the molecule by a single bond. A carbocyclyl or cycloalkyl can be saturated (i.e., contain only single C-C bonds) or unsaturated (i.e., contain one or more double or triple bonds). Examples of saturated cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Unsaturated carbocyclyls are also referred to as "cycloalkenyls." Examples of monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless specifically stated otherwise in this specification, the term "carbocyclyl" includes alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Rb -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)0R 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), wherein each R aare independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl); and each R b are independently a direct bond or a straight or branched alkylene or alkenylene chain; R c is a straight or branched alkylene or alkenylene chain, wherein each of the above substituents is unsubstituted unless otherwise indicated.

[0132] A "carbocyclylalkyl" is a group of the formula -R c - refers to a carbocyclyl radical, where R c is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical are optionally substituted as defined above.

[0133] "Carbocyclylalkenyl" refers to a group of the formula -R c - refers to a carbocyclyl radical, where R c is an alkenylene chain as defined above. The alkenylene chain and the carbocyclyl radical are optionally substituted as defined above.

[0134] "Carbocyclylalkoxy" refers to a group of the formula -OR c-refers to a radical attached through the oxygen atom of a carbocyclyl, where R c is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical are optionally substituted as defined above.

[0135] "Halo" or "halogen" refers to a fluoro, bromo, chloro, or iodo substituent.

[0136] "Haloalkyl" refers to an alkyl radical, as defined above, substituted with one or more halogen radicals, as defined above, e.g., trihalomethyl, dihalomethyl, halomethyl, etc. In some embodiments, the haloalkyl is a fluoroalkyl, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.

[0137] The term "heteroalkyl" refers to an alkyl group, as defined above, in which one or more skeletal carbon atoms of the alkyl have been replaced with a heteroatom (e.g., -CH- can be replaced with -NH- or O-, with the appropriate number of substituents or valences). For example, each substituted carbon atom is independently replaced with a heteroatom, e.g., carbon is replaced with nitrogen, oxygen, sulfur, or other suitable heteroatom. In some cases, each substituted carbon atom is independently replaced with oxygen, nitrogen (e.g., -NH-, -N(alkyl)-, or N(aryl), or bearing another substituent contemplated herein), or sulfur (e.g., -, -S(=O)-, or S(=O)-). In some embodiments, a heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In some embodiments, a heteroalkyl is attached to the remainder of the molecule at a heteroatom of the heteroalkyl. In some embodiments, a heteroalkyl is a C1-C6 18 In some embodiments, heteroalkyl is C1-C 12Heteroalkyl. In some embodiments, heteroalkyl is C1-C6 heteroalkyl. In some embodiments, heteroalkyl is C1-C4 heteroalkyl. In some embodiments, heteroalkyl includes alkylamino, alkylaminoalkyl, aminoalkyl, heterocycloalkyl, heterocycloalkyl, heterocyclyl, and heterocycloalkylalkyl, as defined herein. Unless stated otherwise in detail herein, heteroalkyl does not include alkoxy, as defined herein. Unless stated otherwise in detail herein, heteroalkyl groups are optionally substituted as defined above for alkyl groups.

[0138] "Heteroalkylene" refers to a divalent heteroalkyl group, as defined above, that links one moiety of a molecule to another moiety of a molecule. Unless specifically stated otherwise, the heteroalkylene is optionally substituted as defined above for an alkyl group.

[0139] "Heterocyclyl" refers to a stable 3- to 18-membered non-aromatic ring radical containing 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. Unless specifically stated otherwise in this specification, a heterocyclyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which optionally includes fused or bridged ring systems. The heteroatoms of the heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. A heterocyclyl radical is partially or fully saturated. A heterocyclyl radical is saturated (i.e., contains only single C-C bonds) or unsaturated (e.g., contains one or more double or triple bonds in the ring system). In some cases, a heterocyclyl radical is saturated. In some cases, a heterocyclyl radical is both saturated and substituted. In some cases, a heterocyclyl radical is unsaturated. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless specifically stated otherwise in this specification, the term "heterocyclyl" includes any of the following: alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -ORa , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, R b -C(O)R a , R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (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), wherein each R aare independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl); and each R b are independently a direct bond or a straight or branched alkylene or alkenylene chain; R c is a straight or branched alkylene or alkenylene chain, wherein each of the above substituents is unsubstituted unless otherwise indicated.

[0140] "N-heterocyclyl" or "N-linked heterocyclyl" refers to a heterocyclyl radical as defined above containing at least one nitrogen and wherein the point of attachment of the heterocyclyl radical to the rest of the molecule is through the nitrogen atom of the heterocyclyl radical. The N-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such N-heterocyclyl radicals include, but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

[0141] "C-heterocyclyl" or "C-linked heterocyclyl" refers to a heterocyclyl radical as defined above containing at least one heteroatom and wherein the point of attachment of the heterocyclyl radical to the rest of the molecule is through a carbon atom of the heterocyclyl radical. The C-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such C-heterocyclyl radicals include, but are not limited to, 2-morpholinyl, 2-, 3-, or 4-piperidinyl, 2-piperazinyl, 2-, or 3-pyrrolidinyl, and the like.

[0142] "Heterocyclylalkyl" refers to a group of the formula -R c - refers to a heterocyclyl radical, where R c is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl portion of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group.

[0143] "Heterocyclylalkoxy" refers to -OR c -refers to a radical attached through an oxygen atom of a heterocyclyl, where R c is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl portion of the heterocyclylalkoxy radical is optionally substituted as defined above for a heterocyclyl group.

[0144] "Heteroaryl" refers to a radical derived from a 3- to 18-membered aromatic ring radical containing 2 to 17 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, a heteroaryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system in which at least one ring within the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) π-electron system according to Hueckel theory. Heteroaryl includes fused or bridged ring systems. Heteroatoms in a heteroaryl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. A heteroaryl is attached to the rest of the molecule through any atom of the ring. Examples of heteroaryl include azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[d]pyrimidinyl, ... Chloropenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexaphenyl 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, isoquinolyl, indolizinyl, isoxazolyl, 5,8-Methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pterinidinyl, 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 These include, but are not limited to, thiazolyl, 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]pridinyl, and thiophenyl (i.e., thienyl). Unless specifically stated otherwise in this specification, the term "heteroaryl" includes alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R, b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(Ra )2, -R b -N(R a )2, -R b -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -OR c -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )S(O) t R a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), wherein each R a are independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl); and each Rb are independently a direct bond or a straight or branched alkylene or alkenylene chain; R c is a straight or branched alkylene or alkenylene chain, wherein each of the above substituents is unsubstituted unless otherwise indicated.

[0145] "N-heteroaryl" refers to a heteroaryl radical, as defined above, containing at least one nitrogen and wherein the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom of the heteroaryl radical. The N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0146] "C-heteroaryl" refers to a heteroaryl radical as defined above, where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom of the heteroaryl radical. The C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0147] "Heteroarylalkyl" refers to a group of the formula -R c - refers to a heteroaryl radical, where R c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heteroaryl portion of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.

[0148] "Heteroarylalkoxy" refers to a group of the formula -OR c - refers to a radical attached through an oxygen atom of a heteroaryl, where R cis an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heteroaryl portion of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.

[0149] The compounds disclosed herein, in some embodiments, contain one or more asymmetric centers, thereby giving rise to enantiomers, diastereomers, and other stereoisomeric forms defined in terms of absolute stereochemistry as (R)- or (S)-. Unless otherwise specified, all stereoisomeric forms of the compounds disclosed herein are intended to be contemplated by the present disclosure. When a compound described herein contains an alkene double bond, unless otherwise specified, the present disclosure is intended to include both E and Z geometric isomers (e.g., cis or trans). Similarly, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms, are intended to be included. The term "geometric isomer" refers to the E or Z geometric isomers (e.g., cis or trans) of the alkene double bond. The term "positional isomer" refers to structural isomers around a central ring, e.g., ortho, meta, and para isomers around a benzene ring.

[0150] In general, each optionally substituted group is independently substituted or unsubstituted. Each description of an optionally substituted group provided herein includes, unless otherwise specified, an independent and explicit description of both the unsubstituted group and the substituted group (e.g., substituted in certain embodiments and unsubstituted in certain other embodiments). Unless otherwise specified, substituted groups (e.g., substituted alkyl) provided herein are substituted with one or more substituents, each of which may be halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR, or the like. a , -SR a , -OC(O)-R a , -N(R a)2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t R a (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; and each R a are independently hydrogen, alkyl (e.g., optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (e.g., optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (e.g., optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (e.g., optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (e.g., optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (e.g., optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (e.g., optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (e.g., optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (e.g., optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0151] "Pharmaceutically acceptable salts" includes both acid addition salts and base addition salts. A pharmaceutically acceptable salt of any one of the pharmacological agents described herein is intended to encompass any 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.

[0152] "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like, which retain the biological effectiveness and properties of the free base and which are not biologically or otherwise undesirable. Also included are salts formed with organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, 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, and the like. Thus, exemplary salts include sulfate, pyrosulfite, bisulfite, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, malate, tartrate, methanesulfonate, and the like. Salts of amino acids, such as arginate, gluconate, and galacturonate, are also contemplated (see, e.g., Berge SM et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt, according to methods and techniques familiar to those skilled in the art.

[0153] "Pharmaceutically acceptable base addition salts" refer to salts that retain the biological effectiveness and properties of the free acids and are not biologically or otherwise undesirable. These salts are prepared from the addition of inorganic or organic bases to the free acids. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. See Berge et al., supra.

[0154] The compounds disclosed herein, in some embodiments, contain one or more asymmetric centers, thereby giving rise to enantiomers, diastereomers, and other stereoisomeric forms defined in terms of absolute stereochemistry as (R)- or (S)-. Unless otherwise specified, all stereoisomeric forms of the compounds disclosed herein are intended to be contemplated by the present disclosure. When a compound described herein contains an alkene double bond, unless otherwise specified, the present disclosure is intended to include both E and Z geometric isomers (e.g., cis or trans). Similarly, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms, are intended to be included. The term "geometric isomer" refers to the E or Z geometric isomers (e.g., cis or trans) of the alkene double bond. The term "positional isomer" refers to structural isomers around a central ring, e.g., ortho, meta, and para isomers around a benzene ring.

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

[0156] Systemic hemodynamic complications may manifest as cirrhosis and portal hypertension (PHT). Individuals often develop elevated portal vein pressure (PP) due to increased intrahepatic resistance. The combination of increased blood flow and elevated intrahepatic resistance can lead to the development of PHT and the common symptoms of decompensated cirrhosis. Clinical PHT can occur when the hepatic venous pressure gradient (HVPG) is >5 mmHg. PHT can then lead to a hyperkinetic state characterized by decreased splanchnic and systemic vascular resistance, which can further increase portal vein blood flow. As advanced cirrhosis progresses, vasodilation of splanchnic arterioles can worsen PHT, which in turn can lead to a further increase in HVPG, resulting in renal hypoperfusion of 10 mmHg or more. The kidneys can sense low perfusion pressure and a decrease in glomerular filtration rate as hypovolemia, which can then activate the renin-angiotensin-aldosterone (RAAS) and vasopressin systems, resulting in severe vasoconstriction within the kidney and sodium and water retention. If renal hypoperfusion is severe, this can lead to the development of ascites and kidney injury in the form of hepatorenal syndrome-acute kidney injury (HRS-AKI).

[0157] Management of HRS-AKI often focuses on targeting the vasopressin system to restore systemic arterial blood pressure and reduce PHT through splanchnic vasoconstriction, with the long-term goal being liver transplantation. Although monitoring and titration are challenging, increased vasoconstriction (i.e., mean arterial pressure (MAP)) correlates with improved hemodynamic parameters. Vasoconstrictors, including terlipressin, norepinephrine, and midodrine / octreotide, have been used as treatments for patients with HRS-AKI in an attempt to restore renal perfusion and function. Terlipressin (a vasopressin analog) plus albumin has been used as first-line therapy for HRS-AKI because it reduces short-term mortality compared with placebo. Albumin is added to increase circulating volume. Terlipressin is approved by the US Food and Drug Administration for the treatment of adults with HRS accompanied by a rapid decline in renal function.

[0158] There are three vasopressin receptors: V1a, V1b, and V2. V1a receptors are found throughout the circulatory system and regulate vasoconstriction. V2 receptors regulate aquaresis through their antidiuretic effect at the kidney level by mediating water reabsorption in the collecting duct. V1b receptors are found in the anterior pituitary gland and peripheral tissues, and one potential role is to mediate the release of adrenocorticotropic hormone, which can stimulate water retention. Vasopressin, also known as arginine vasopressin (AVP) or antidiuretic hormone, is a peptide involved in water balance and vascular tone. At normal physiological concentrations, there is little activity on the V1a system; only at supraphysiological concentrations is there significant vasoconstriction. By pharmacological application, potent vasoconstriction can be achieved in a concentration-dependent manner.

[0159] Arginine vasopressin (AVP) is the endogenous ligand for vasopressin V1A, V1B, and V2 G-protein-coupled receptors (V1AR, V1BR, V2R). Homeostatic mechanisms of the vasopressin system, such as regulation of blood osmolality and pressor effect, are mediated by the V2 and V1A receptor subtypes. Activation of V2 receptors, located in the renal collecting duct, plays a role in regulating fluid balance through antidiuretic effects. Activation of V1A receptors, located on vascular smooth muscle cells, results in vasoconstriction and an increase in arterial pressure.

[0160] Lysine vasopressin (LVP), the active metabolite of terlipressin, is active at V1a, V1b, and V2 receptors and is a full agonist. Despite significantly improving renal function, the use of terlipressin has been associated with serious adverse events, including gastrointestinal disorders, sepsis, and respiratory failure. These adverse effects, which may be due to the strength of LVP binding to V1a and off-target effects of V2, can lead to further water retention. As a result of the potential for serious side effects, terlipressin has a black box warning from the US FDA regarding serious or fatal respiratory failure.

[0161] 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 their potential to induce severe vasoconstriction and tissue hypoperfusion when used at therapeutic doses. The pharmacological activity of V1AR partial agonists (e.g., compounds with reduced maximal potency at the V1A receptor) can be used in a variety of conditions where a moderate increase in blood flow and / or blood pressure without hypoperfusion is desirable. For example, such indications include hepatorenal syndrome, refractory ascites, hemorrhagic esophageal varices, anesthesia-induced hypotension, vasodilatory shock, paracentesis-induced circulatory dysfunction, and spontaneous bacterial peritonitis.

[0162] Individuals with cirrhosis often develop a number of clinical complications, among which ascites accumulation is the most serious and indicates a poor prognosis.In some cases, ascites formation is caused by the constant activation of the endogenous sodium and water retention system to counteract circulatory dysfunction, for example, 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.

[0163] In some embodiments, a compound described herein (e.g., a mixed V1a agonist / antagonist, e.g., Compound 1) is delivered systemically to an individual after intravenous (IV) and / or subcutaneous (SC) administration of a composition comprising the compound (see Example 1). In some embodiments, an individual experiences a systemic effect, such as a change in MAP, after the compound is administered intravenously and / or subcutaneously. In some embodiments, the compound is administered by intravenous infusion. In some embodiments, the compound is administered by subcutaneous (bolus) injection. While the systemic effects observed after IV infusion and SC (bolus) injection are comparable, more adverse events were measured in individuals receiving SC (bolus) injections of the composition (see Example 1). In general, the compound was well tolerated by individuals receiving the composition by IV infusion.

[0164] In some cases, metabolites (e.g., substantial amounts of metabolite M1 (e.g., overproduction of M1)) are formed after SC (bolus) injection of a composition comprising a compound described herein (e.g., a mixed V1a agonist / antagonist, e.g., Compound 1) (see Figure 27, panel B). In some cases, minimal amounts of metabolites (e.g., less than 15% of metabolite M1) are formed after IV infusion of a composition comprising a compound described herein (e.g., a mixed V1a agonist / antagonist, e.g., Compound 1) (see Figure 27, panel A). As discussed herein, full vasopressin receptor agonists described herein (e.g., terlipressin) are known to cause (serious) adverse events when administered subcutaneously. Thus, overproduction of the full agonist (M1) after SC (bolus) injection provides an explanation for the difference between the tolerability profiles of the compositions in healthy individuals after IV infusion and (SC) bolus injection.

[0165] As described herein, in some cases, metabolite (Ml) formation is reduced by subcutaneously injecting a composition comprising a compound described herein into an individual (see Example 3). Additionally, in some cases, metabolite (Ml) formation is reduced by increasing the buffer concentration of a composition comprising a compound described herein (see Example 4). Furthermore, in some cases, metabolite (Ml) 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 (Ml) formation is reduced via any one or more combinations of subcutaneous injection, increasing buffer concentration, and increasing drug concentration.

[0166] In some embodiments, provided herein are methods for regulating mean arterial pressure (MAP) in an individual in need thereof, the methods comprising subcutaneously injecting a composition comprising a compound described herein, e.g., a compound having a structure represented by Formula I, or a pharmaceutically acceptable salt thereof, to the individual in need thereof. In some embodiments, less than 50% of the compound, e.g., a compound of Formula I, is degraded. In some embodiments, less than 50% of the compound, e.g., a compound of Formula I, is degraded subcutaneously.

[0167] In some embodiments, a composition described herein is administered subcutaneously to an individual and less than 50% of the compound of Formula I degrades (e.g., subcutaneously). In some embodiments, a composition described herein is administered subcutaneously to an individual by subcutaneous (bolus) injection and less than 50% of the compound of Formula I degrades (e.g., subcutaneously). In some embodiments, a composition described herein is administered subcutaneously to an individual by subcutaneous infusion and less than 50% of the compound of Formula I degrades (e.g., subcutaneously). In some embodiments, the compound of Formula I degrades subcutaneously to form Ml.

[0168] In some embodiments, after, e.g., subcutaneous (bolus) injection, greater than 50% of the parent compound (e.g., Compound 1) degrades (e.g., forming M1). In some embodiments, after, e.g., subcutaneous (bolus) injection, greater than 60% of the parent compound (e.g., Compound 1) degrades (e.g., forming M1). In some embodiments, after, e.g., subcutaneous (bolus) injection, greater than 70% of the parent compound (e.g., Compound 1) degrades (e.g., forming M1). In some embodiments, after, e.g., subcutaneous (bolus) injection, greater than 80% of the parent compound (e.g., Compound 1) degrades (e.g., forming M1).

[0169] In some embodiments, a composition described herein is administered subcutaneously to an individual and less than 30% of the compound of Formula I degrades (e.g., subcutaneously). In some embodiments, a composition described herein is administered subcutaneously to an individual by subcutaneous (bolus) injection and less than 30% of the compound of Formula I degrades (e.g., subcutaneously). In some embodiments, a composition described herein is administered subcutaneously to an individual by subcutaneous infusion and less than 30% of the compound of Formula I degrades (e.g., subcutaneously). In some embodiments, the compound of Formula I degrades subcutaneously to form Ml.

[0170] In some embodiments, the composition is injected subcutaneously into an individual and results in less Ml formation compared to administration of an otherwise identical composition administered by subcutaneous (bolus) injection.

[0171] In some embodiments, the composition is injected subcutaneously into an individual, resulting in less Ml being formed systemically compared to administration of an otherwise identical composition administered by subcutaneous (bolus) injection.

[0172] In some embodiments, the composition is injected subcutaneously into an individual, resulting in the formation of less M1 locally (at the injection / infusion site) compared to administration of an otherwise identical composition administered by subcutaneous (bolus) injection.

[0173] In some embodiments, subcutaneous injection of the composition into an individual improves tolerability, hi some embodiments, subcutaneous injection of the composition into an individual improves tolerability compared to subcutaneous (bolus) injection, e.g., based on reduced subcutaneous Ml overproduction.

[0174] In some embodiments, subcutaneous injection of the composition into an individual reduces undesired systemic events, such as undesired vasoconstriction leading to ischemia. In some embodiments, subcutaneous injection of the composition into an individual reduces undesired administration site events, such as local site vasoconstriction leading to administration site ischemia. In some embodiments, subcutaneous injection of the composition into an individual reduces undesired systemic events and undesired administration site events.

[0175] 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 for reducing (the incidence of) local vasoconstriction in an individual in need thereof. In some embodiments, the method is for reducing (the incidence of) ischemia in an individual in need thereof. In some embodiments, the method is for reducing (the incidence of) injection site ischemia in an individual in need thereof. In some embodiments, the method comprises subcutaneously injecting a composition comprising a compound described herein, e.g., a compound having a structure represented by Formula I, or a pharmaceutically acceptable salt thereof, into an individual in need thereof.

[0176] In some cases, the compounds described herein (eg, Compound 1) are used to treat complications of ESLD.

[0177] In some embodiments, provided herein are methods of regulating mean arterial pressure (MAP) in an individual (e.g., in need thereof), the methods comprising subcutaneously injecting into the individual (e.g., in need thereof) a composition comprising an (effective) amount of a compound described herein, e.g., a mixed vasopressin receptor 1A (V1AR) agonist-antagonist described herein. In some embodiments, the compound has a structure represented by Formula I. In some embodiments, the compound is Compound 1.

[0178] In some embodiments, the method further includes securing a subcutaneous infusion device to the skin (e.g., skin surface) of the individual. In some embodiments, the subcutaneous infusion device includes a chamber body and a hollow tube body. In some embodiments, the composition is configured to be within the chamber body. In some embodiments, the hollow tube body includes a first opening and a second opening. In some embodiments, the first opening is fluidly connected to the chamber body. In some embodiments, the second opening is configured to be subcutaneously within the individual after securing the subcutaneous infusion device to the skin. In some embodiments, the hollow tube is a needle, e.g., having any gauge suitable for subcutaneous administration (e.g., subcutaneous injection).

[0179] In some embodiments, the subcutaneous infusion device further comprises a pump configured to subcutaneously infuse the composition into the individual at a constant rate. In some embodiments, the subcutaneous infusion device further comprises a pump configured to subcutaneously infuse the composition into the individual at a variable rate. In some embodiments, the rate is a flow rate. In some embodiments, the continuous infusion is at a rate insufficient to provide a stream of the composition. In some embodiments, the continuous infusion is at a flow rate that provides a continuous drip into the individual. In some embodiments, the composition is subcutaneously infused into the individual at a rate of about 0.001 milliliters per hour (mL / hr) or greater. In some embodiments, the composition is subcutaneously infused into the individual at a rate of about 1 mL / hr or less. In some embodiments, the composition is subcutaneously infused into the individual at a rate of about 0.005 mL / hr to about 1 mL / hr for the administration period. In some embodiments, the composition is subcutaneously infused into the individual at a rate of about 0.01 mL / hr to about 1 mL / hr for the administration period. In some embodiments, the composition is subcutaneously infused into the individual at a rate of about 0.04 mL / hr to about 1 mL / hr for the administration period. In some embodiments, the administration period is at least about 1 hour. In some embodiments, the administration period is at least about 1 day. In some embodiments, the administration period is at least about 1 week. In some embodiments, the administration period is at least about 1 month. In some embodiments, the administration period is about 1 month or longer. In some embodiments, the administration period is about 2 months or longer. In some embodiments, the administration period is about 3 months or longer. In some embodiments, the administration period is about 4 months or longer. In some embodiments, the administration period is about 5 months or longer. In some embodiments, the administration period is about 6 months or longer. In some embodiments, the administration period is about 9 months or longer. In some embodiments, the administration period is about 12 months or longer.

[0180] In some embodiments, the compositions described herein are subcutaneously infused into an individual for at least 1 hour. In some embodiments, the compositions are subcutaneously infused into an individual for at least 1 day. In some embodiments, the compositions are subcutaneously infused into an individual for at least 1 week. In some embodiments, the compositions are subcutaneously infused into an individual for at least 1 month.

[0181] In some embodiments, the compositions described herein are continuously subcutaneously infused into an individual for at least 1 hour. In some embodiments, the compositions are continuously subcutaneously infused into an individual for at least 1 day. In some embodiments, the compositions are continuously subcutaneously infused into an individual for at least 1 week. In some embodiments, the compositions are continuously subcutaneously infused into an individual for at least 1 month.

[0182] In some embodiments, a compound described herein is administered to an individual (e.g., continuously) in an amount of about 0.001 milligrams (mg) to about 100 mg. In some embodiments, a compound is administered to an individual (e.g., continuously) in an amount of about 0.01 mg to about 50 mg. In some embodiments, a compound is administered to an individual (e.g., continuously) in an amount of about 0.01 mg to about 20 mg. In some embodiments, a compound is administered to an individual (e.g., continuously) in an amount of about 0.01 mg to about 10 mg. In some embodiments, a compound is administered to an individual (e.g., continuously) in an amount of about 0.1 mg to about 1 mg. In some embodiments, a compound is administered to an individual (e.g., continuously) in an amount of about 0.2 mg. In some embodiments, a composition is administered to an individual for one or more days.

[0183] In some embodiments, the compositions described herein comprise a compound at a concentration of about 0.001 milligrams per milliliter (mg / mL) or greater. In some embodiments, the compositions comprise a compound at a concentration of about 100 mg / mL or less. In some embodiments, the compositions comprise a compound at a concentration of about 0.001 mg / mL to about 100 mg / mL. In some embodiments, the compositions comprise a compound at a concentration of about 0.01 mg / mL to about 100 mg / mL. In some embodiments, the compositions comprise a compound at a concentration of about 0.1 mg / mL to about 100 mg / mL. In some embodiments, the compositions comprise a compound at a concentration of about 1 mg / mL to about 100 mg / mL. In some embodiments, the compositions comprise a compound at a concentration of about 0.1 mg / mL to about 50 mg / mL. In some embodiments, the compositions comprise a compound at a concentration of about 1 mg / mL to about 50 mg / mL. In some embodiments, the compositions comprise a compound at a concentration of about 0.1 mg / mL to about 10 mg / mL. In some embodiments, the composition comprises a concentration of the compound from about 1 mg / mL to about 10 mg / mL.

[0184] 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 described herein are administered to the described individual in need thereof continuously.

[0185] In some embodiments, provided herein are methods for regulating mean arterial pressure (MAP) in an individual, the methods comprising subcutaneously administering to the individual an effective amount of a compound, wherein the compound is a mixed vasopressin receptor 1A (V1AR) agonist-antagonist. In some embodiments, the individual is in need of an increase in MAP. In some embodiments, the individual has end-stage liver disease (ESLD) or complications thereof.

[0186] In some embodiments, the individual's MAP increases (e.g., compared to a pre-treatment baseline measurement) after subcutaneous administration of a compound described herein (e.g., Compound 1). In some embodiments, the individual's MAP increases (e.g., compared to a pre-treatment baseline measurement) after subcutaneous administration of Compound 1.

[0187] In some embodiments, an individual's MAP increases by about 1% or more (e.g., compared to a baseline measurement before treatment) after administration of a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1). In some embodiments, an individual's MAP increases by about 5% or more (e.g., compared to a baseline measurement before treatment) after administration of a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1). In some embodiments, an individual's MAP increases by about 10% or more (e.g., compared to a baseline measurement before treatment) after administration of a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1). In some embodiments, an individual's MAP increases by about 15% or more (e.g., compared to a baseline measurement before treatment) after administration of a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1). In some embodiments, an individual's MAP increases by about 20% or more (e.g., compared to a baseline measurement before treatment) after administration of a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1). In some embodiments, an individual's MAP increases by about 1% to about 20% (e.g., compared to a baseline measurement before treatment) after administration of a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1). In some embodiments, an individual's MAP increases by about 5% to about 20% (e.g., compared to a baseline measurement before treatment) after administration of a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1). In some embodiments, an individual's MAP increases by about 10% to about 20% (e.g., compared to a baseline measurement before treatment) after administration of a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1). In some embodiments, an individual's MAP increases by about 1% to about 10% (e.g., compared to a baseline measurement before treatment) after administration of a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1). In some embodiments, the increase in MAP occurs about 1 hour or more after the compound, or a pharmaceutically acceptable salt thereof, is administered to the individual. In some embodiments, the increase in MAP occurs about 2 hours or more after the compound, or a pharmaceutically acceptable salt thereof, is administered to the individual.In some embodiments, the increase in MAP occurs about 3 hours or more after the compound, or a pharmaceutically acceptable salt thereof, is administered to the individual. In some embodiments, the increase in MAP occurs about 4 hours or more after the compound, or a pharmaceutically acceptable salt thereof, is administered to the individual. In some embodiments, the increase in MAP occurs about 5 hours or more after the compound, or a pharmaceutically acceptable salt thereof, is administered to the individual. In some embodiments, the increase in MAP occurs about 6 hours or more after the compound, or a pharmaceutically acceptable salt thereof, is administered to the individual. In some embodiments, the increase in MAP occurs about 12 hours or more after the compound, or a pharmaceutically acceptable salt thereof, is administered to the individual. In some embodiments, the increase in MAP occurs about 1-12 hours after the compound, or a pharmaceutically acceptable salt thereof, is administered to the individual. In some embodiments, the increase in MAP occurs about 1-6 hours after the compound, or a pharmaceutically acceptable salt thereof, is administered to the individual. In some embodiments, the increase in MAP occurs about 4-6 hours after the compound, or a pharmaceutically acceptable salt thereof, is administered to the individual.

[0188] In some embodiments, the individual's MAP increases in a dose-dependent manner after administration of the compound, or a pharmaceutically acceptable salt thereof.

[0189] 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 MAP. In some embodiments, the compounds provided herein have a non-linear dose-dependence, e.g., beyond the maximum therapeutic concentration. In some embodiments, the dose-dependent increase in MAP includes the maximum therapeutic concentration. In some embodiments, dose-dependence includes a situation where the effect increases with dose, at least in a certain dose range. For example, a higher dose may not provide a dose-dependent increase or may provide a lower dose-dependent increase.

[0190] In some embodiments, a compound described herein (e.g., Compound 1) is a selective vasopressin V1a receptor partial agonist. In some embodiments, a compound described herein (e.g., Compound 1) is a mixed agonist-antagonist. In some embodiments, a compound described herein (e.g., Compound 1) is selective for the V1AR. In some embodiments, a compound described herein (e.g., Compound 1) is selective for the V1AR over the vasopressin 2 (V2) receptor (V2R). In some cases, a compound described herein (e.g., Compound 1) does not have functional V2R activity. In some cases, a compound described herein (e.g., Compound 1) does not have functional V2R activity at therapeutic concentrations. In some embodiments, a therapeutic concentration is a concentration sufficient to modulate the V1AR.

[0191] In some cases, the activity and selectivity of the compounds described herein (e.g., mixed agonist-antagonists, e.g., Compound 1) are illustrated by Tables 14 and 15. In some cases, the activity and selectivity of the compounds described herein (e.g., mixed agonist-antagonists, e.g., Compound 1) are illustrated by Figures 19-21.

[0192] In some embodiments, a compound described herein (e.g., Compound 1) is more than 10-fold selective for the V1AR over the V2R. In some embodiments, a compound described herein (e.g., Compound 1) is more than 100-fold selective for the V1AR over the V2R. In some embodiments, a compound described herein (e.g., Compound 1) is more than 1,000-fold selective for the V1AR over the V2R. In some embodiments, a compound described herein (e.g., Compound 1) is more than 10,000-fold selective for the V1AR over the V2R. In some embodiments, a compound described herein (e.g., Compound 1) is inactive at the V2R.

[0193] In some embodiments, a compound described herein (e.g., Compound 1) comprises a first moiety having agonist activity. In some embodiments, a compound described herein (e.g., Compound 1) comprises a second moiety having antagonist activity. In some embodiments, a compound described herein (e.g., Compound 1) comprises a first moiety having agonist activity and a second moiety having antagonist activity.

[0194] In some embodiments, the compounds provided herein have a ratio of agonist to antagonist activity of about 90:10 to about 10:90, hi some embodiments, the compounds provided herein have a ratio of agonist to antagonist activity of about 50:50.

[0195] In some embodiments, agonist-antagonist refers to a compound having an agonist portion and an antagonist portion. In certain embodiments, the agonist portion and the antagonist portion are different.

[0196] In some embodiments, V1AR agonist-antagonists have a broader therapeutic window than V1AR agonists. In some embodiments, the V1AR agonist-antagonists described herein have a selective V1a agonist portion and a selective V1a antagonist portion. In some cases, either the selective V1a agonist portion or the selective V1a antagonist portion binds to V1AR such that both the selective V1a agonist portion and the selective V1a antagonist portion do not bind to V1AR simultaneously. In some cases, the V1a antagonist portion competes with the selective V1a agonist portion for binding to V1AR. In some cases, V1AR agonism provides a (desired) vasoconstrictor effect. In some cases, V1AR antagonism prevents maximum activation of the V1a pathway.

[0197] In some cases, Figure 15, curve 1 shows a concentration-response curve for a compound (e.g., a fully non-selective (V2, V1a) agonist, e.g., terlipressin) that provides lethal levels of vasoconstriction (e.g., at relatively high doses, as shown in part A of Figure 15) and / or serious adverse events (e.g., at supratherapeutic doses and at sublethal levels of vasoconstriction, as shown in part B of Figure 15). In some embodiments, a compound described herein (e.g., a fully non-selective (V2, V1a) agonist, e.g., terlipressin) has a concentration-response curve as shown in Figure 15, line 1. In some cases, Figure 15, line 1 shows a compound described herein (e.g., a fully non-selective (V2, V1a) agonist, e.g., terlipressin) that has a relatively narrow therapeutic window. In some cases, Figure 15, line 1 shows that at relatively high doses, compounds described herein (e.g., full non-selective (V2, V1a) agonists, such as terlipressin) provide levels of vasoconstriction that are fatal (shown as part A in Figure 15) and / or associated with serious adverse events, such as elevated lactate and / or vasoconstriction with ischemia (shown as part B in Figure 15).

[0198] In some embodiments, Figure 15, curve 2 shows the concentration-response curve of a compound (e.g., a mixed V1a agonist-antagonist, e.g., Compound 1) that has a safety and efficacy profile. In some embodiments, a compound described herein (e.g., a mixed V1a agonist-antagonist, e.g., Compound 1) has the concentration-response curve shown in Figure 15, line 2. In some cases, Figure 15, line 2 shows that even at high doses, a compound described herein (e.g., a mixed V1a agonist-antagonist, e.g., Compound 1) has a relatively large therapeutic window. In some cases, Figure 15, line 2 shows that even at high doses, a compound described herein (e.g., a mixed V1a agonist-antagonist, e.g., Compound 1) is safe and effective.

[0199] In some cases, Figure 15, curve 3 shows the concentration-response curve for a subtherapeutic compound. In some cases, Figure 15, curve 3 shows the concentration-response curve for a full non-selective (V2, V1a) agonist or a partial V1a agonist, e.g., a compound with relatively low activity at the V1AR.

[0200] In some cases, Figures 15-21 show that a compound described herein (e.g., a mixed V1a agonist-antagonist, e.g., Compound 1) can be safely used (over a large dose range) to treat ESLD or its symptoms and / or complications. In some cases, Figure 15 shows that even at excessively high concentrations, a compound described herein (e.g., a mixed V1a agonist-antagonist, e.g., Compound 1) provides a maximal effect (e.g., a change (increase) in MAP) in an individual (e.g., after subcutaneous administration). In some cases, Figures 15-21 show that a compound described herein (e.g., a mixed V1a agonist-antagonist, e.g., Compound 1) provides a robust effect (e.g., a change (increase) in MAP) in an individual (e.g., after subcutaneous administration). In some cases, Figures 15-21 show that a compound described herein (e.g., a mixed V1a agonist-antagonist, e.g., Compound 1) reaches, maintains, and does not exceed a safe and effective therapeutic effect (e.g., a change (increase) in MAP), e.g., after subcutaneous administration. In some cases, Figures 15-21 show that a compound described herein (e.g., a mixed V1a agonist-antagonist, e.g., Compound 1) maintains (safe levels of) therapeutic efficacy (e.g., after subcutaneous administration) for an extended period of time, e.g., for at least 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 minutes or more. In some cases, Figures 15-21 show that a compound described herein (e.g., a fully non-selective (V2, V1a) agonist, e.g., terlipressin) rapidly reaches toxic and potentially harmful concentrations, e.g., at relatively high doses. In some cases, Figures 15-21 show that the effects of compounds described herein (e.g., fully non-selective (V2, V1a) agonists, such as terlipressin), fully non-selective (V2, V1a) agonists decrease rapidly, quickly falling below therapeutic levels, e.g., after a relatively short period of time (e.g., after about 80 minutes or more).

[0201] In some embodiments, a compound described herein (e.g., Compound 1) modulates (e.g., increases) mean arterial pressure (MAP). In some embodiments, a compound described herein (e.g., Compound 1) is administered subcutaneously and modulates (e.g., increases) MAP. In some embodiments, a compound described herein (e.g., Compound 1) is administered subcutaneously and modulates (e.g., increases) MAP without (significant) injection site reactions (e.g., local vasoconstriction), e.g., at the subcutaneous injection site. In some embodiments, a compound described herein (e.g., Compound 1) is suitable for subcutaneous administration for the treatment of one or more complications of ESLD, e.g., HRS-AKI.

[0202] In some embodiments, modulating mean arterial pressure (MAP) in an individual comprises increasing MAP by at least 5% above baseline (e.g., levels before administration of, e.g., a compound described herein (e.g., Compound 1)). In some embodiments, modulating MAP in an individual comprises increasing MAP by at least 10% above baseline (e.g., levels before administration of, e.g., a compound described herein (e.g., Compound 1)). In some embodiments, modulating MAP in an individual comprises increasing MAP by at least 15% above baseline (e.g., levels before administration of, e.g., a compound described herein (e.g., Compound 1)). In some embodiments, the baseline is a level before administration of a compound described herein (e.g., Compound 1). In some cases, the baseline is a level compared to a control, such as a placebo.

[0203] In some embodiments, modulating mean arterial pressure (MAP) in an individual comprises increasing MAP by up to 5% above baseline (e.g., levels before administration of, e.g., a compound described herein (e.g., Compound 1)). In some embodiments, modulating MAP in an individual comprises increasing MAP by up to 10% above baseline (e.g., levels before administration of, e.g., a compound described herein (e.g., Compound 1)). In some embodiments, modulating MAP in an individual comprises increasing MAP by up to 15% above baseline (e.g., levels before administration of, e.g., a compound described herein (e.g., Compound 1)). In some embodiments, the baseline is a level before administration of a compound described herein (e.g., Compound 1). In some cases, the baseline is a level compared to a control, such as a placebo.

[0204] In some embodiments, modulating MAP in an individual comprises increasing MAP by at least 5 mmHg above baseline (e.g., levels before administration of, e.g., a compound described herein (e.g., Compound 1)). In some embodiments, modulating MAP in an individual comprises increasing MAP by 1 mmHg or more above baseline (e.g., levels before administration of, e.g., a compound described herein (e.g., Compound 1)). In some embodiments, modulating MAP in an individual comprises increasing MAP by 5 mmHg or more above baseline (e.g., levels before administration of, e.g., a compound described herein (e.g., Compound 1)). In some embodiments, modulating MAP in an individual comprises increasing MAP by 10 mmHg or more above baseline (e.g., levels before administration of, e.g., a compound described herein (e.g., Compound 1)). In some embodiments, modulating MAP in an individual comprises increasing MAP by about 20 mmHg or more above baseline (e.g., levels before administration of, e.g., a compound described herein (e.g., Compound 1)). In some embodiments, the baseline is the level before administration of a compound described herein (e.g., Compound 1).

[0205] In some embodiments herein, a method for regulating mean arterial pressure (MAP) in an individual is provided (e.g., as described herein above), the method 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.

[0206] In some embodiments, a compound described herein (e.g., Compound 1) has a structure represented by Formula I: D1-L-D2. In some embodiments, D1 is a vasopressin receptor 1A (V1AR) agonist. In some embodiments, D2 is a V1AR antagonist. In some embodiments, L is a linker. In some embodiments, the compound is administered to an individual as a pharmaceutically acceptable salt.

[0207] In some embodiments, D1 is selective for V1AR. In some embodiments, D1 is selective for V1AR over V2R. In some embodiments, D1 is more than 10-fold selective for V1AR over V2R. In some embodiments, D1 is more than 100-fold selective for V1AR over V2R. In some embodiments, D1 is more than 1,000-fold selective for V1AR over V2R. In some embodiments, D1 is more than 10,000-fold selective for V1AR over V2R. In some embodiments, D1 is inactive at V2R.

[0208] In some embodiments, D1 comprises a peptide. In some embodiments, D1 is a peptide. In some embodiments, D1 comprises a cyclic peptide. In some embodiments, D1 is a cyclic peptide. In some embodiments, D1 comprises a cyclic nonapeptide. In some embodiments, D1 is a cyclic nonapeptide.

[0209] In some embodiments, D1 has the following structure: [ka] having or including

[0210] In some embodiments, D1 has the following structure: [ka] having or including

[0211] In some cases, D2 is selective for V1AR. In some embodiments, D2 is selective for V1AR over V2R. In some cases, D2 is more than 10-fold selective for V1AR over V2R. In some cases, D2 is more than 100-fold selective for V1AR over V2R. In some cases, D2 is more than 1,000-fold selective for V1AR over V2R. In some cases, D2 is more than 10,000-fold selective for V1AR over V2R. In some cases, D2 is inactive at V2R.

[0212] In some embodiments, at least one of D1 and D2 is selective for the V1AR. In some embodiments, at least one of D1 and D2 is selective for the V1AR over the V2R.

[0213] In some embodiments, D2 comprises a peptide. In some embodiments, D2 is a peptide. In some embodiments, D2 comprises a linear peptide. In some embodiments, D2 is a linear peptide. In some embodiments, D2 is a linear polypeptide comprising about 7 or more amino acid residues. In some embodiments, D2 comprises 7-12 amino acid residues.

[0214] In some embodiments, D2 has the following structure: [ka] having or including

[0215] In some embodiments, D2 has the following structure: [ka] having or including

[0216] In some embodiments, L is a non-hydrolyzable linker.

[0217] 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.

[0218] In some embodiments, L comprises one or more linker groups, each linker independently selected from the group consisting of substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl. In some embodiments, L is a bond, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. In some embodiments, L is substituted or unsubstituted heteroalkyl or comprises substituted or unsubstituted heteroalkyl. In some embodiments, L is heteroalkyl substituted with one or more substituents, each substituent independently selected from the group consisting of oxo, amino, and substituted heteroalkyl. In some embodiments, L is an alkylamine substituted with one or more substituents, each substituent independently selected from the group consisting of oxo, amino, and substituted heteroalkyl. In some embodiments, L is an alkylamine substituted with oxo.

[0219] In some embodiments, L has the following structure: [ka] having or including

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

[0221] In some embodiments, the compound described herein is Compound 1, or a pharmaceutically acceptable salt thereof.

[0222] In some cases, compound 1 is glycinamide, L-cysteinyl-L-phenylalanyl-L-isoleucyl-L-glutaminyl-L-asparaginyl-L-cysteinyl-L-prolyl-N4-(phenylacetyl-O-methyl-D-tyrosyl-L-phenylalanyl-L-glutaminyl-L-asparaginyl-L-alanyl-L-prolyl-L-arginyl-L-isoglutamyl-N5-acetyl-L-lysyl-L-ε-lysyl)-L-2,4-diaminobutyryl-, cyclic (1→6)-disulfide.

[0223] In some cases, compound 1 is C 110 H 161 N 31 O 27 It has the empirical molecular formula of S2.

[0224] In some cases, compound 1 has an average molecular mass of 2413.78 u.

[0225] In some cases, the mixed V1A agonist-antagonist provided herein (eg, Compound 1) is a white to off-white powder.

[0226] In some cases, the mixed V1A agonist-antagonists provided herein (eg, Compound 1) have a water solubility of at least 10 mg / mL.

[0227] In some embodiments, Compound 1 has Formula (IA): [ka] or a pharmaceutically acceptable salt thereof.

[0228] In some cases, the mixed V1A agonist-antagonists provided herein (e.g., Compound 1) are 20-mer monocyclic branched peptides that include, for example, natural and non-natural amino acids, for example, of non-animal origin. In some cases, the mixed V1A agonist-antagonists provided herein (e.g., Compound 1) include, for example, a Cys 1 residues and Cys 6 There is an S—S bridge between the residues. In some cases, the branch is attached via the side chain amino function at position 8.

[0229] In some cases, formula (IB): [ka] or a pharmaceutically acceptable salt thereof. (In the formula: Dab is 2,4-diaminobutyric acid, D-Tyr(Me) is O-methyl-D-tyrosine, PhAc is phenylacetic acid (e.g., where L-2,4-diaminobutyric acid, Nc-acetyl-L-lysine, L-isoglutamine, and O-methyl-D-tyrosine are unnatural and the N-terminal moiety is substituted with phenylacetic acid).

[0230] In some cases, the mixed V1A agonist-antagonist provided herein (e.g., Compound 1) is provided as a pharmaceutically acceptable salt. In some cases, the mixed V1A agonist-antagonist provided herein (e.g., Compound 1) is provided as an acetate salt. In some cases, the mixed V1A agonist-antagonist provided herein (e.g., Compound 1) is administered in the form described in Example 1.

[0231] In some embodiments, the compounds described herein are any compounds described in either U.S. Pat. No. 9,644,000 or U.S. Pat. No. 9,388,214 (each of which is incorporated by reference herein in its entirety, particularly with respect to the compounds provided herein).

[0232] In some cases, compound 1 has the empirical molecular formula C 110 H 161 N 31 O 27 S2(AcOH) z where z is any integer (eg, 1 to 100).

[0233] In some embodiments herein, there is provided a method of regulating 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.

[0234] In some embodiments herein, provided are pharmaceutical compositions comprising an amount of a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1). In some embodiments, the amount of the compound is an effective amount of the compound. In some embodiments, the compound is a mixed vasopressin receptor 1A (V1AR) agonist-antagonist. In some embodiments, the composition is formulated for subcutaneous administration. In some embodiments, the compound has a structure represented by Formula I. In some embodiments, the compound is Compound 1.

[0235] In some embodiments herein, there is provided a subcutaneous formulation comprising a compound described herein, for example, a compound having a structure represented by Formula I, or a pharmaceutically acceptable salt thereof.

[0236] In some embodiments, less than 50% of the compound, e.g., a compound of Formula I, degrades. In some embodiments, less than 50% of the compound, e.g., a compound of Formula I, degrades to form Ml. In some embodiments, less than 50% of the compound, e.g., a compound of Formula I, degrades subcutaneously. In some embodiments, less than 50% of the compound, e.g., a compound of Formula I, degrades subcutaneously to form Ml.

[0237] In some embodiments, less than 30% of the compound, e.g., a compound of Formula I, degrades. In some embodiments, less than 30% of the compound, e.g., a compound of Formula I, degrades to form Ml. In some embodiments, less than 30% of the compound, e.g., a compound of Formula I, degrades subcutaneously. In some embodiments, less than 30% of the compound, e.g., a compound of Formula I, degrades subcutaneously to form Ml.

[0238] In some embodiments, the compositions described herein further comprise a liquid vehicle or solvent (eg, water or an aqueous vehicle).

[0239] In some embodiments herein, subcutaneous formulations are provided having a concentration of a compound described herein, e.g., a compound having a structure represented by Formula I, of about 0.001 milligram (mg) / milliliter (mL) or more. In some embodiments, the subcutaneous formulation has a concentration of a compound described herein, e.g., a compound having a structure represented by Formula I, of about 100 mg / mL or less. In some embodiments, the subcutaneous formulation has a concentration of a compound described herein, e.g., a compound having a structure represented by Formula I, of about 0.001 mg / mL to 100 mg / mL. In some embodiments, the subcutaneous formulation comprises 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.

[0240] In some embodiments, the compound is formulated as described in the Examples herein. In some embodiments, the compound is formulated as an aqueous solution. In some embodiments, the compound is formulated as an aqueous solution having a compound concentration of at least about 0.01 mg / mL. In some embodiments, the compound is formulated as an aqueous solution having a compound concentration of at least about 0.1 mg / mL. In some embodiments, the compound is formulated as an aqueous solution having a compound concentration of at least about 1 mg / mL. In some embodiments, the compound is formulated as an aqueous solution having a compound concentration of at least about 10 mg / mL. In some embodiments, the compound is formulated as an aqueous solution having a compound concentration of up to about 50 mg / mL. In some embodiments, the compound is formulated as an aqueous solution having a compound concentration of up to about 10 mg / mL. In some embodiments, the compound is formulated as an aqueous solution having a compound concentration of up to about 1 mg / mL. In some embodiments, the compound is formulated as an aqueous solution having a compound concentration of up to about 0.1 mg / mL. In some embodiments, the compound is formulated as an aqueous solution having a compound concentration of up to about 0.01 mg / mL. In some embodiments, the compound is formulated as an aqueous solution having a compound concentration of about 0.01 mg / mL to about 50 mg / mL. In some embodiments, the compound is formulated as an aqueous solution having a compound concentration of about 0.01 mg / mL to about 10 mg / mL. In some embodiments, the compound is formulated as an aqueous solution having a compound concentration of about 1 mg / mL to about 10 mg / mL. In some embodiments, the composition is formulated with an acetate buffer. In some embodiments, the composition is formulated at pH 4.5. In some embodiments, the composition is formulated with mannitol.

[0241] In some embodiments, an additive (e.g., a preservative) is added to a (e.g., subcutaneous) composition having a pH of about 3 to 6 (e.g., 4.5) and comprising at least about 1 millimolar (mM) acetate buffer (e.g., about 5 mM sodium acetate to about 150 mM sodium acetate) and about 10 milligrams per milliliter (mg / mL) to about 100 mg / mL mannitol (e.g., about 43.6 mg / mL mannitol). In some cases, the additive is a preservative. In some cases, a preservative is added to a (e.g., subcutaneous) composition having a pH of about 4.5 and comprising about 10 mM sodium acetate and about 43.6 mg / mL mannitol.

[0242] In some embodiments, provided herein are compositions comprising Compound 1. In some embodiments, the compositions are suitable for subcutaneous administration. In some embodiments, the formulations are suitable for subcutaneous (bolus) injection. In some embodiments, the subcutaneous (bolus) injection is provided to an individual as a single dose (e.g., all at once). In some embodiments, the formulations are suitable for subcutaneous infusion.

[0243] 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 a preservative, a solubilizing agent (e.g., cyclodextrin), a buffering agent, and a chelating agent (e.g., zinc acetate or ethylenediaminetetraacetic acid (EDTA)). In some embodiments, the additive is a preservative.

[0244] In some embodiments, provided herein are subcutaneous formulations comprising a compound having a structure according to Formula I and a preservative.

[0245] 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 greater. In some embodiments, the preservative is present in the composition in an amount of about 50 mg / mL or less. In some embodiments, the preservative is present in the composition in an amount of about 0.1 mg / mL to about 50 mg / mL. In some embodiments, the preservative is present in the composition in an amount of about 1 mg / mL to about 20 mg / mL.

[0246] In some cases, compositions containing the preservatives described herein do not exhibit physical interactions (e.g., aggregation) with any of the preservatives screened (e.g., between the preservative and Compound 1), even at relatively high concentrations of the preservative.

[0247] In some embodiments, provided herein are subcutaneous formulations comprising a compound having a structure according to Formula I and a solubilizing agent.

[0248] In some embodiments, the compositions described herein further comprise a solubilizing agent. In some embodiments, the preservative is any suitable solubilizing agent, such as a cyclodextrin (e.g., sulfobutylether-β-cyclodextrin (SBECD)). In some embodiments, the solubilizing agent is present in the composition in an amount of about 0.1 mg / mL or greater. In some embodiments, the solubilizing agent is present in the composition in an amount of about 500 mg / mL or less. In some embodiments, the solubilizing agent is present in the composition in an amount of about 250 mg / mL or less. In some embodiments, the solubilizing agent is present in the composition in an amount of about 100 mg / mL or less. In some embodiments, the solubilizing agent is present in the composition in an amount of about 0.1 mg / mL to about 250 mg / mL. In some embodiments, the solubilizing agent is present in the composition in an amount of about 0.1 mg / mL to about 100 mg / mL. In some embodiments, the solubilizing agent is present in the composition in an amount of about 1 mg / mL to about 250 mg / mL. In some embodiments, the solubilizing agent is present in the composition in an amount of about 1 mg / mL to about 100 mg / mL, hi some embodiments, the solubilizing agent is present in the composition in an amount of about 60 mg / mL to about 80 mg / mL.

[0249] In some embodiments, the composition further comprises a buffering agent. In some embodiments, the buffering agent has a pKa of about 3.0 to about 6.0, for example, at 25°C. In some embodiments, the buffering agent is selected from the group consisting of acetate buffer, succinate buffer, phosphate buffer, and citrate buffer. In some embodiments, the composition further comprises an acetate buffer. In some embodiments, the acetate buffer is a combination of acetate salt and acetic acid. In some embodiments, the composition further comprises a succinate buffer. In some embodiments, the succinate buffer is a combination of succinate salt and succinic acid. In some embodiments, the composition further comprises a citrate buffer. In some embodiments, the citrate buffer is a combination of citrate salt and citric acid.

[0250] In some embodiments herein, there is provided a subcutaneous formulation comprising a compound having a structure according to Formula I and a buffering agent at a concentration of about 1 millimolar (mM) to about 1 M.

[0251] In some embodiments, the compositions described herein comprise a buffering agent at a concentration of about 1 millimolar (mM) or greater. In some embodiments, the compositions described herein comprise a buffering agent at a concentration of about 1 molar (M) or less. In some embodiments, the compositions described herein comprise a buffering agent at a concentration of about 1 mM to about 1 M. In some embodiments, the compositions described herein comprise a buffering agent at a concentration of about 1 mM to about 500 mM. In some embodiments, the compositions described herein comprise a buffering agent at a concentration of about 1 mM to about 250 mM. In some embodiments, the compositions described herein comprise a buffering agent at a concentration of about 50 mM to about 250 mM. In some embodiments, the compositions described herein comprise a buffering agent at a concentration of about 50 mM to about 150 mM. In some embodiments, the compositions described herein comprise a buffering agent at a concentration of about 100 mM. In some embodiments, the compositions described herein comprise a buffering agent at a concentration of about 1 mM to about 50 mM. In some embodiments, the compositions described herein comprise a buffering agent at a concentration of about 5 mM to about 25 mM. In some embodiments, the compositions described herein comprise a buffering agent at a concentration of about 10 mM.

[0252] In some embodiments, the compositions described herein have a pH sufficient to inhibit (e.g., deactivate or inactivate) proteases (e.g., trypsin), e.g., in the subcutaneous layer of an individual to whom the formulation is administered subcutaneously.

[0253] In some embodiments, the pH of a composition described herein does not change (substantially) when administered subcutaneously to an individual. In some embodiments, the pH of a composition described herein does not change (substantially) when administered subcutaneously to an individual by subcutaneous (bolus) injection. In some embodiments, the pH of a composition described herein does not change (substantially) when administered subcutaneously to an individual by subcutaneous infusion.

[0254] In some embodiments, the compositions described herein have a pH of at least about 3. In some embodiments, the compositions described herein have a pH of about 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, or 4 or less. In some embodiments, the compositions described herein have a pH of about 4 to about 8. In some embodiments, the compositions described herein have a pH of about 4 to about 6. In some embodiments, the compositions described herein have a pH of about 4.5 to about 5. In some embodiments, the compositions described herein have a pH of about 4. In some embodiments, the compositions described herein have a pH of about 4.5.

[0255] In some embodiments, the compositions described herein have an ionic strength of about 1 mM or greater. In some embodiments, the compositions described herein have an ionic strength of about 1 M or less. In some embodiments, the compositions described herein have an ionic strength of about 1 mM to about 500 mM. In some embodiments, the compositions described herein have an ionic strength of about 5 mM to about 200 mM. In some embodiments, the compositions described herein have an ionic strength of about 5 mM to about 10 mM to about 100 mM.

[0256] In some embodiments, the compounds described herein, e.g., compounds having a structure according to Formula I, are relatively (e.g., substantially) resistant to (e.g., protease) degradation. In some embodiments, the compounds described herein, e.g., compounds having a structure according to Formula I, are relatively (e.g., substantially) resistant to (e.g., protease) degradation in the subcutaneous layer of an individual to whom a composition comprising the compound has been subcutaneously administered.

[0257] In some embodiments, the compounds described herein, e.g., 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, e.g., compounds having a structure represented by Formula I, degrade in a vial. In some embodiments, less than 50% of the compounds described herein, e.g., compounds having a structure represented by Formula I, degrade in a vial over a period of at least about one week (e.g., about one week or more, two weeks or more, three weeks or more, or four weeks or more). In some embodiments, less than 50% of the compounds described herein, e.g., compounds having a structure represented by Formula I, degrade subcutaneously. In some embodiments, less than 50% of the compounds described herein, e.g., compounds having a structure represented by Formula I, degrade subcutaneously over a period of at least about one hour (e.g., about one hour or more, six hours or more, 12 hours or more, or 24 hours or more).

[0258] In some embodiments, compositions described herein, e.g., having an acidic pH, a relatively high buffer (e.g., acetate buffer) concentration, and / or a relatively high concentration of a compound described herein (e.g., Compound 1), are well tolerated following subcutaneous (e.g., injection or infusion) administration (see Examples 3 and 4).

[0259] In some embodiments, the compositions described herein comprise a pH and / or buffer (e.g., acetate buffer) concentration sufficient to inhibit, reduce, or eliminate the formation of undesired metabolites of a compound described herein (e.g., Compound 1), e.g., full (V1a) agonists such as M1. In some cases, compositions comprising a relatively high buffer concentration (e.g., 50 mM or higher buffer) extend the amount of time that the local environment (e.g., at or near the injection site) maintains a particular pH (e.g., a pH of about 3 or higher) sufficient to inhibit, reduce, or eliminate the formation of undesired metabolites of a compound described herein (e.g., Compound 1), e.g., full (V1a) agonists such as M1. In some cases, compositions having an acidic pH (e.g., a pH of 1-6) produce undesirable effects when injected (subcutaneously), including burning, stinging, pain, etc., at the injection site. (Subcutaneous) injection of a composition having a relatively acidic pH or buffer concentration that extends the amount of time the local environment (e.g., at or near the injection site) maintains a particular (e.g., acidic) pH would be expected to extend such undesirable effects. In contrast, compositions described herein having a relatively acidic pH (e.g., a pH of 4 or 4.5) and / or buffer concentration that extends the amount of time the local environment (e.g., at or near the injection site) maintains a particular (e.g., acidic) pH do not produce (significant) undesirable effects when administered subcutaneously (e.g., by injection or infusion). In some cases, a higher buffer concentration inhibits, reduces, or eliminates the formation of M1, e.g., due to the extension of the amount of time the pH of the local environment is acidic (e.g., 4.5) after administration, providing a sufficient amount of time for absorption of a compound described herein. In some embodiments, the buffer concentration of a composition provided herein that extends the amount of time the local environment (e.g., at or near the injection site) maintains a particular (e.g., acidic) pH is about 50 mM or greater. In some embodiments, the pH of the compositions provided herein is acidic enough to inhibit, reduce, or eliminate the formation of undesirable metabolic products of a compound described herein (e.g., Compound 1), e.g., a full (V1a) agonist such as M1, when administered subcutaneously (e.g., by injection or infusion).In some embodiments, the pH of the compositions provided herein, when administered subcutaneously (e.g., by injection or infusion), is about 3 or greater to sufficiently inhibit, reduce, or eliminate the formation of undesired metabolic products of a compound described herein (e.g., Compound 1), e.g., full (V1a) agonists such as M1. In some embodiments, the pH of the compositions provided herein, when administered subcutaneously (e.g., by injection or infusion), is about 4 or 4.5 to sufficiently inhibit, reduce, or eliminate the formation of undesired metabolic products of a compound described herein (e.g., Compound 1), e.g., full (V1a) agonists such as M1.

[0260] In some embodiments, compositions described herein (e.g., compositions suitable for intravenous or subcutaneous administration) comprise an acetate buffer at a concentration of about 10 mM or greater, hi some embodiments, compositions described herein comprise an acetate buffer at a concentration of about 50 mM or greater.

[0261] In some embodiments, compositions described herein (eg, compositions suitable for intravenous or subcutaneous administration) have a pH of about 3 or greater.

[0262] In some embodiments, a composition described herein (e.g., a composition suitable for intravenous or subcutaneous administration) comprises an acetate buffer at a concentration of 10 mM and has a pH of 4.5. In some embodiments, the composition is suitable for intravenous administration. In some embodiments, the composition is preservative-free. In some embodiments, the composition is suitable for subcutaneous administration. In some embodiments, the composition is suitable for subcutaneous injection.

[0263] In some embodiments, compositions described herein (e.g., compositions suitable for subcutaneous administration) comprise acetate buffer at a concentration of 100 mM (or greater) and have a pH of about 4 or 4.5. In some embodiments, the compositions are suitable for subcutaneous administration. In some embodiments, the compositions are suitable for subcutaneous (bolus) injection. In some embodiments, the compositions are suitable for subcutaneous infusion.

[0264] In some embodiments, compositions described herein (e.g., compositions suitable for intravenous or subcutaneous administration) comprise an acetate buffer at a concentration of about 10 mM or greater, hi some embodiments, compositions described herein comprise an acetate buffer at a concentration of about 50 mM or greater.

[0265] In some embodiments, the compositions described herein comprise a concentration of a compound described herein (e.g., Compound 1) sufficient to inhibit, reduce, or eliminate the formation of undesired metabolites of the compound, e.g., full (V1a) agonists such as M1. In some cases, a composition comprising a relatively high drug concentration (e.g., 0.1 milligrams per milliliter (mg / mL) or greater) saturates the local environment (e.g., at or near the injection site) with drug, such that more drug is absorbed prior to significant formation of undesired metabolites of the drug, e.g., full (V1a) agonists. In some embodiments, a composition described herein having a relatively high concentration of a compound provided herein, when administered subcutaneously (e.g., by injection or infusion), sufficiently inhibits, reduces, or eliminates the formation of undesired metabolites of a compound described herein (e.g., Compound 1), e.g., full (V1a) agonists such as M1. In some embodiments, the drug concentration in the composition (e.g., the concentration of a compound described herein) is about 0.1 mg / mL or greater.

[0266] In some embodiments, the compositions provided herein have a concentration of a compound described herein of about 0.1 mg / mL or greater. In some embodiments, the compositions provided herein have a concentration of a compound described herein of about 1 mg / mL or greater. In some embodiments, the compositions provided herein have a concentration of a compound described herein of about 100 mg / mL or less. In some embodiments, the compositions provided herein have a concentration of a compound described herein of about 0.1 mg / mL to about 100 mg / mL. In some embodiments, the compositions provided herein have a concentration of a compound described herein of about 0.1 mg / mL to about 10 mg / mL. In some embodiments, the compositions are suitable for subcutaneous administration. In some embodiments, the compositions are suitable for subcutaneous (bolus) injection. In some embodiments, the compositions are suitable for subcutaneous infusion. In some embodiments, the compositions provided herein have a concentration of a compound described herein of about 0.1 mg / mL or less. In some embodiments, the compositions are suitable for intravenous administration.

[0267] In some embodiments, the compositions described herein are suitable for subcutaneous injection. In some embodiments, compositions suitable for subcutaneous injection are administered to an individual in a manner that reduces injury or trauma (at the injection site). In some embodiments, compositions suitable for subcutaneous injection are administered to an individual over a specific (extended) period of time. In some embodiments, compositions suitable for subcutaneous injection are administered to an individual at a specific (relatively slow) rate, e.g., 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 / hour (mL / hour) or less, e.g., over an extended period of time (e.g., a period of about 24 hours or more).

[0268] In some embodiments, provided herein are pharmaceutical compositions comprising an amount of a compound having a structure according to 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.

[0269] In some embodiments, provided herein are pharmaceutical compositions comprising an amount of Compound 1, or a pharmaceutically acceptable salt thereof, wherein the composition is formulated for subcutaneous administration. In some embodiments, the amount of the compound is an effective amount of the compound.

[0270] In some embodiments, the compositions described herein are suitable for systemic delivery of an active agent described herein, e.g., a compound having a structure represented by Formula I. In some embodiments, the compositions described herein are suitable for administration of an active agent described herein, e.g., a compound having a structure represented by Formula I, in an outpatient setting, e.g., at home. In some embodiments, the compositions described herein are suitable for systemic delivery of Compound 1. In some embodiments, the compositions described herein are suitable for administration of Compound 1 in an outpatient setting, e.g., at home.

[0271] In some embodiments herein, a system for regulating mean arterial pressure is provided, the system comprising a composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and a device configured to provide subcutaneous infusion of the composition to an individual when placed on the skin of the individual.

[0272] In some embodiments, the system comprises an adhesive for securing the (subcutaneously injected) device to the surface of the skin of an individual, hi some embodiments, the system comprises an adhesive for reversibly securing the (subcutaneously injected) device to the surface of the skin of an individual.

[0273] In some embodiments, the system includes a chamber body and a hollow tube body. In some embodiments, the composition is configured to be within the chamber body. In some embodiments, the hollow tube body includes a first opening and a second opening. In some embodiments, the first opening is fluidly connected to the chamber body. In some embodiments, the second opening is configured to be subcutaneously within the individual after securing the subcutaneous injection device to the individual's skin. In some embodiments, the hollow tube is a needle, e.g., having any gauge suitable for subcutaneous administration (e.g., subcutaneous injection).

[0274] In some embodiments, the system does not include an adhesive. In some embodiments, the device is not attached to the surface of the individual's skin. In some embodiments, the chamber body is not attached to an injection port. In some embodiments, the system does not include an adhesive and the chamber body is attached to an injection port.

[0275] In some embodiments, the (subcutaneous infusion) device further comprises a pump configured to subcutaneously infuse the composition into the individual at a constant or variable rate (e.g., as described herein). In some embodiments, the system is configured to provide the composition to the individual over a period of about 24 hours or more. In some embodiments, the system is configured to continuously provide the composition to the individual over a period of about 24 hours or more.

[0276] In some embodiments, the device is configured to receive a vial and / or cartridge of the composition.

[0277] In some embodiments, the device is a subcutaneous infusion device. In some embodiments, the device is a pump.

[0278] In some cases, provided herein are pharmaceutical compositions comprising an effective amount of a first compound, or a pharmaceutically acceptable salt thereof, and an effective amount of a second compound, or a pharmaceutically acceptable salt thereof, wherein the first compound is a vasoconstrictor, and the second compound sufficiently blocks the (e.g., local) vasoconstrictor effect of the first compound, for example, providing sufficient uptake of the first compound into the circulatory system and / or internal organs (e.g., kidneys) of an individual (e.g., in need thereof). In some embodiments, the pharmaceutical composition is for injection. 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.

[0279] In some embodiments, a compound described herein (e.g., Compound 1) is safe (e.g., in humans) (see, e.g., Example 1). In some embodiments, a compound described herein (e.g., Compound 1) is well tolerated (e.g., in humans) (see, e.g., Example 1). In some embodiments, a compound described herein (e.g., Compound 1) is safe and well tolerated (e.g., in humans) (see, e.g., Example 1). In some embodiments, a compound described herein (e.g., Compound 1) has a pharmacodynamic profile with submaximal partial agonism consistent with a mixed agonist-antagonist of the V1a receptor.

[0280] In some cases, a compound described herein (e.g., Compound 1) is tested in a Phase 1, double-blind, placebo-controlled, dose-group randomized clinical trial to investigate the safety, tolerability, and pharmacokinetic and pharmacodynamic (PD) profile of the compound administered to healthy adults aged 18-45 years (see Example 1). In some cases, the trial consisted of two treatment periods: Period 1 (a 6-hour intravenous [IV] infusion of compound or placebo over a dose range of 0.1-0.9 mg) and Period 2 (a once-daily subcutaneous [SC] injection of 0.1, 0.3 mg of compound, or placebo for 5 consecutive days). In some cases, Period 1 included 32 men and women. In some cases, 8 men and 5 women continued into Period 2. In some cases, for example, after IV administration, the AUC and C max Exposure as measured by T was approximately dose-proportional over the dose range tested. In some cases, e.g., after SC administration, T max The elimination half-life (t) of the compounds described herein (e.g., Compound 1) was 0.3 hours, exposure was more than proportional, and bioavailability was 18% with no apparent accumulation after repeated dosing. 1 / 2 ) were approximately 1.5 hours and 1.0 hours after IV and SC administration, respectively, indicating, for example, that absorption is not rate-limiting for elimination after SC administration. In some cases, diastolic and, to a lesser extent, systolic blood pressure (BP) increased in subjects treated with a compound described herein (e.g., Compound 1) across all dose groups, while pulse rate decreased. In some cases, the overall change in mean arterial pressure (MAP) after IV and SC administration was similar to the change in diastolic BP. In some cases, absolute changes in cardiac output by echocardiography appeared dose-dependent, with mean decreases of 3% to 12% after a 0.9 mg IV dose and individual decreases of <20% to 25% across any dose. In some cases, adverse events (AEs) included abdominal pain and diarrhea; laboratory tests for mesenteric ischemia were negative and none were reported. In some cases, AEs were treatment-related, generally moderate or mild in severity, and attributed to the expected pharmacological effects.

[0281] In some embodiments, the individual's diastolic blood pressure increases (e.g., compared to a pre-treatment baseline measurement) after administration of a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1). In some embodiments, the individual's diastolic blood pressure increases (e.g., compared to a pre-treatment baseline measurement) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1).

[0282] In some embodiments, the individual's systolic blood pressure increases (e.g., compared to a baseline measurement before treatment) after administration of a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1). In some embodiments, the individual's systolic blood pressure increases (e.g., compared to a baseline measurement before treatment) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1).

[0283] In some embodiments, the individual's diastolic and / or systolic blood pressure increases in a dose-dependent manner (e.g., compared to a pre-treatment baseline measurement) after administration of a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1). In some embodiments, the individual's diastolic and / or systolic blood pressure increases in a dose-dependent manner (e.g., compared to a pre-treatment baseline measurement) after subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1).

[0284] 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, e.g., beyond the maximum therapeutic concentration. In some embodiments, a 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 situations where there is an increase with dose, at least within a certain dose range. For example, a higher dose may not provide a dose-dependent increase or may provide a lower dose-dependent increase.

[0285] In some embodiments, MAP is calculated from measurements of systolic and diastolic blood pressure. In some embodiments, MAP is calculated when taking into account blood pressure during a single cardiac cycle. In some embodiments, MAP is 1 / 3 (systolic blood pressure - diastolic blood pressure) + diastolic blood pressure.

[0286] In some embodiments, the individual's pulse rate is decreased (e.g., compared to baseline measurements before treatment) after administration of a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1). In some embodiments, the individual's peripheral blood flow is decreased (e.g., compared to baseline measurements before treatment) after administration of a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1). In some embodiments, the individual's pulse rate and peripheral blood flow are decreased (e.g., compared to baseline measurements before treatment) after administration of a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1).

[0287] In some embodiments, administration of a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1), to an individual (e.g., as described herein) improves the individual's systemic hemodynamics. In some embodiments, subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1), to an individual (e.g., as described herein) improves the individual's systemic hemodynamics.

[0288] In some embodiments, administering a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1), to an individual (e.g., as described herein) reduces fluid retention in the individual. In some embodiments, administering a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1), to an individual (e.g., as described herein) reduces fluid overload in the individual. In some embodiments, administering a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1), to an individual (e.g., as described herein) reduces fluid retention and overload in the individual. In some embodiments, subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1), to an individual (e.g., as described herein) reduces fluid retention in the individual. In some embodiments, subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1), to an individual (e.g., as described herein) reduces fluid overload in the individual. In some embodiments, subcutaneous administration of a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1) to an individual (e.g., as described herein) reduces fluid retention and overload in the individual.

[0289] In some embodiments, administration (e.g., subcutaneously) of a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1) to an individual (e.g., as described herein) reduces the individual's serum creatinine (sCr) (e.g., compared to a baseline measurement before treatment). In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1) is administered (e.g., subcutaneously) to an individual (e.g., as described herein) at least until the individual has an sCr of 1.5 milligrams (mg) per deciliter (dL) or less. In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1) is administered (e.g., subcutaneously) to an individual (e.g., as described herein) at least until the individual's sCr returns to normal (e.g., baseline).

[0290] In some cases, intravenous (iv) administration of a compound described herein (e.g., Compound 1) provides an elimination half-life of about 1.5 hours with a clearance and distribution volume of about 13 L / h and about 15-20 L, respectively. In some cases, the t after subcutaneous (sc) administration of a compound described herein (e.g., Compound 1) max is about 0.3 hours with an elimination half-life of about 1 hour (e.g., without any accumulation after repeated administration). In some cases, the bioavailability of a compound described herein (e.g., Compound 1) after subcutaneous (sc) administration is about 18%.

[0291] In some cases, the compounds described herein (e.g., Compound 1) exhibit a significant improvement in AUC and C after iv administration. max In some cases, compounds described herein (e.g., Compound 1) have greater than near proportionality after sc administration. In some cases, compounds described herein (e.g., Compound 1) have higher exposure in women than in men, for example, after both iv infusion and subcutaneous injection.

[0292] In some instances, compounds described herein (e.g., Compound 1) are metabolized to the metabolite M1 (see Figure 14). M1 has a structure that is the free form of the circled structure in Figure 14. In some embodiments, M1 is a full (V1A) agonist. In some embodiments, M1 has a molecular weight of 1405.68 g / mol. In some embodiments, M1 is a C 60 H 98 N 19 O 16 S2 + M1 has the chemical formula: M1 is (substantially) less active (against V1a) than compound 1. Specifically, M1 has about 10 times less activity against V1a than compound 1.

[0293] In some cases, for example, in a single subject after iv administration, Ml is found in the plasma of an individual administered Compound 1. In some cases, for example, after sc administration, Ml is found in all subjects surveyed at concentrations equivalent to Compound 1. In some cases, a compound described herein (e.g., Compound 1) is metabolized (e.g., to Ml) during transport into the circulation after sc injection. As discussed herein above, the full agonists described herein are known to be toxic and cause (serious) adverse events when administered subcutaneously. Thus, for example, when a compound described herein is administered by subcutaneous (bolus) injection, the formation of a full agonist (e.g., Ml) is undesirable, for example, when used for the purposes described herein.

[0294] In some cases, a dose-dependent increase in diastolic blood pressure, and to a lesser extent a dose-dependent increase in systolic blood pressure, is more pronounced (e.g., accompanied by a reflex decrease in pulse rate) after sc injection compared to iv infusion of a compound described herein (e.g., Compound 1). In some cases, peripheral blood flow is decreased after intravenous and subcutaneous administration of a compound described herein (e.g., Compound 1).

[0295] In some cases, individuals receiving a dose of a compound described herein (e.g., Compound 1) experienced an adverse event (AE) (e.g., treatment-related). In some cases, the AE occurred at the beginning of the sc treatment period. In some cases, there were more AEs after sc administration compared to iv administration. In some cases, there were more AEs in females than males. In some cases, the AE was mild or moderate in intensity. In some cases, the AE was severe in intensity. In some cases, the severe AE was a mild elevation of troponin I.

[0296] In some cases, compounds described herein (e.g., Compound 1) induce a reversible increase in diastole. In some cases, compounds described herein (e.g., Compound 1) induce a reversible increase in systole. In some cases, compounds described herein (e.g., Compound 1) induce a reversible increase in MAP. In some cases, compounds described herein (e.g., Compound 1) induce a reversible increase in diastole and MAP. In some cases, compounds described herein (e.g., Compound 1) induced a decrease in heart rate and cardiac output. In some cases, evaluation of ECG, clinical chemistry, hematology, hemostasis, and urinalysis parameters did not raise any safety concerns for compounds described herein (e.g., Compound 1).

[0297] In some cases, when administered, for example, as a single iv infusion, a compound described herein (e.g., Compound 1) is safe and well tolerated (e.g., in both men and women) at doses of, for example, about 0.9 mg or less. In some cases, the maximum tolerated sc dose (MTD) is about 0.1 mg of a compound described herein (e.g., Compound 1).

[0298] In some cases, the pharmacokinetic parameters of a compound described herein (e.g., Compound 1) (e.g., in plasma for 0.1-0.9 mg iv dose groups) provide dose proportionality. In some cases, the pharmacokinetic parameters of a compound described herein (e.g., Compound 1) (e.g., in plasma for 0.1-0.9 mg iv dose groups) provide dose-independent PK parameters that are comparable between dose groups (see Example 1). In some cases, males eliminate a compound described herein (e.g., Compound 1) more rapidly than females. In some cases, males administered a compound described herein (e.g., Compound 1) have a lower C of the compound than females. max In some cases, males administered a compound described herein (e.g., Compound 1) have a lower AUC of the compound than females. In some cases, males administered a compound described herein (e.g., Compound 1) have a lower C of the compound than females. max and AUC.

[0299] In some cases, for example, after sc administration of a compound described herein (e.g., Compound 1), t max is consistent between the first and fifth doses. In some cases, for example, after sc administration of a compound described herein (e.g., Compound 1), t 1 / 2 is consistent between the first and fifth doses. In some cases, for example, after sc administration of a compound described herein (e.g., Compound 1), t max and t 1 / 2 is consistent between the first and fifth doses. In some cases, for example, after sc administration of a compound described herein (e.g., Compound 1), the AUC is variable between the first and fifth doses. In some cases, for example, after sc administration of a compound described herein (e.g., Compound 1), the C max is variable between the first and fifth doses. In some cases, for example, after sc administration of a compound described herein (e.g., Compound 1), AUC and C max is variable between the first and fifth doses. In some cases, AUC and C maxThe dose proportionality of the C max About).

[0300] In some cases, the elimination half-life of a compound described herein (e.g., Compound 1) is about 1.5 hours after intravenous administration. In some cases, the elimination half-life of a compound described herein (e.g., Compound 1) is about 1 hour after intravenous administration. In some cases, the elimination half-life of a compound described herein (e.g., Compound 1) is similar in men and women (e.g., C s after subcutaneous administration is similar in both men and women, suggesting that absorption is not rate-limiting for elimination after sc administration). max (This is also supported by the short time to release, about 0.3 hours, of the compound described herein). In some cases, the bioavailability of a compound described herein (e.g., Compound 1) is about 18%. In some cases, the formation of metabolites after sc administration, resulting in comparable concentrations of metabolites and compound, provides a bioavailability of about 18%. In some cases, the fraction of the unchanged excreted dose in urine is about <10% after iv administration. In some cases, the fraction of the unchanged excreted dose of a compound described herein (e.g., Compound 1) in urine is about <5% after sc administration. In some cases, the fraction of the unchanged excreted dose of a compound described herein (e.g., Compound 1) in urine is constant over the entire dose range (e.g., in the study provided in Example 1).

[0301] The presence of metabolite M1 (full agonist) in plasma after subcutaneous administration (but only very low concentrations (<1% of Compound 1) after intravenous administration) indicates that Compound 1 is metabolized somewhere along the pathway between the subcutaneous tissue and the systemic circulation. In some cases, the half-life of M1 is longer than that of Compound 1 after iv and sc administration. In some cases, the half-life of Compound 1 is shorter after sc administration compared to iv administration (e.g., about 4 hours and 2 hours, respectively). In some cases, compounds described herein (e.g., Compound 1) are metabolized in the kidney.

[0302] In some cases, the pharmacodynamic effects of a compound described herein (e.g., Compound 1) on blood pressure and heart rate are as expected for a vasopressin V1a-specific agonist. In some cases, administration of a compound described herein (e.g., Compound 1) to an individual provides an increase in the individual's diastolic blood pressure. In some cases, administration of a compound described herein (e.g., Compound 1) to an individual provides an increase in the individual's systolic blood pressure. In some cases, administration of a compound described herein (e.g., Compound 1) to an individual provides an increase in the individual's MAP. In some cases, administration of a compound described herein (e.g., Compound 1) to an individual provides a decrease in the individual's pulse rate. In some cases, administration of a compound described herein (e.g., Compound 1) to an individual provides a decrease in the individual's peripheral blood flow. In some cases, the effects on blood pressure and heart rate are dose-independent (e.g., changes seen in the lowest dose group were similar to those seen in higher dose groups). In some cases, sc injection provided a more pronounced PD effect compared to the same dose given iv (e.g., approximately 50% lower C after sc administration). max Nevertheless, in some cases, the active metabolite M1 (e.g., a full V1a agonist) in plasma after sc administration contributes (significantly) to the total (e.g., local and / or systemic) V1a vasoconstrictor activity, e.g., in individuals who have a (serious) adverse event after receiving a compound described herein by subcutaneous (bolus) injection. In some cases, increased M1 formation, e.g., after subcutaneous (bolus) injection, can provide a substantial decrease in the (systemic) delivery of Compound 1, resulting in, e.g., undesirable effects (e.g., due to lower delivery of the active agent (e.g., M1 or a mixed V1a agonist-antagonist described herein) and / or an increased amount of vasoconstriction, which may increase the risk of developing ischemia, cyanosis, pain, inflammation, and / or necrosis).

[0303] In some cases, safety evaluation of a compound described herein (e.g., Compound 1) provided an improved profile compared to other (e.g., non-selective) vasopressin receptor agonists described herein. In some cases, absolute changes in mean cardiac output were dose-dependent. In some cases, relative changes in mean cardiac output were comparable between doses (e.g., and well removed from placebo). In some cases, individual decreases in cardiac output were approximately 20-25% (e.g., observed in all active treatment groups, including the placebo group, after both iv and sc administration). In some cases, decreases in cardiac output were secondary to decreases in heart rate. In some cases, ECG evaluations showed no effects of a compound described herein (e.g., Compound 1). In some cases, clinical laboratory parameters showed no signs of cardiac or mesenteric ischemia (e.g., or negative effects on the liver or kidneys).

[0304] In some cases, adverse events in individuals receiving (e.g., intravenously or subcutaneously) a partial agonist described herein (e.g., Compound 1) are comparable to the pharmacological vasoconstrictor activity of a compound described herein (e.g., Compound 1 or vasopressin). For example, subcutaneous administration of a compound described herein (e.g., Compound 1) provided (substantially) more AEs than intravenous administration (see Example 1). Furthermore, the frequency of AEs after subcutaneous administration of a compound described herein (e.g., Compound 1) decreased over the 5 days of treatment. For example, in some cases, sc administration provided about 0.5-fold more AEs per dose than iv administration on day 1 (e.g., despite only 3 subjects receiving 0.3 mg sc compared to 35 subjects receiving doses of 0.45 mg or higher intravenously). In addition, sc administration of a partial agonist described herein (e.g., Compound 1) provided about 3-fold more AEs per dose than iv administration of the same compound (see Example 1). (1) Ml (a full (Vla) agonist) forms after subcutaneous administration of Compound 1; (2) full vasopressin agonists are known to be toxic and cause adverse events; (3) Compound 1 and Ml are present in approximately equimolar concentrations after subcutaneous administration of Ml; and (4) the exposure of Compound 1 after sc administration (C maxConsidering that the V1a vasoconstrictor activity (by s.c. and AUC) was lower than after iv infusion, the presence of Ml (but not Compound 1) in plasma after sc administration contributes to the total V1a vasoconstrictor activity and (e.g., worsened) pharmacological effects and / or AE profile after sc administration of Compound 1.

[0305] Furthermore, given that the presence of the vasopressin receptor full agonist, M1, contributed to an increased number of AE-related vasoconstrictions compared to much higher concentrations of Compound 1, this (combined with the similar pharmacodynamic and adverse effects of Compound 1 across a wide concentration range) further indicates that Compound 1 is a partial agonist and / or mixed agonist-antagonist. Furthermore, the observations from the studies in Example 1 also indicate that a mixed agonist-antagonist mechanism of action limits individual (local vasoconstriction) effects (and limits such effects below the maximal possible level). In further support of this explanation, studies with terlipressin, a V1A receptor full agonist, showed greater increases in blood pressure than those provided in Example 1 (e.g., there is an "upper limit" to the maximum pharmacodynamic effect of Compound 1, further supporting that Compound 1 is a V1A receptor partial agonist and / or mixed agonist-antagonist).

[0306] In some cases, the pharmacological effects of the compounds described herein (e.g., Compound 1) are due to vasopressin V1a-receptor agonism. In some cases, the absence of effects on diuresis and hemostasis indicates a high degree of specificity for the V1a-receptor (e.g., providing a desirable pharmacological profile).

[0307] In some cases, the elimination half-life of a compound described herein (eg, Compound 1) is about 1.5 hours (after iv administration).

[0308] In some cases, the total clearance of a compound described herein (eg, Compound 1) is about 13 L / h (after iv administration).

[0309] In some cases, the elimination half-life of a compound described herein (e.g., Compound 1) is about 1 hour (after sc administration). In some cases, the t max is about 0.3 hours (after sc administration). In some cases, the bioavailability of a compound described herein (e.g., Compound 1) is about 18% (e.g., after repeated subcutaneous administration, without any appreciable accumulation of a compound described herein (e.g., Compound 1)).

[0310] In some cases, increased exposure (e.g., AUC and C max (according to the AUC and C) after intravenous administration of a compound described herein (e.g., Compound 1). max is roughly proportional to

[0311] In some cases, the exposure (AUC and C) of a compound described herein (e.g., Compound 1) max (by IL-1) is higher in women than in men after intravenous injection of a compound described herein (e.g., Compound 1).

[0312] In some cases, administration of a compound described herein (e.g., Compound 1) provided 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) provided 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) provided an increase in MAP in an individual receiving the compound. In some cases, administration of a compound described herein (e.g., Compound 1) provided a reflex decrease in pulse rate (e.g., in a clear dose-independent manner) in an individual receiving the compound.

[0313] In some cases, peripheral blood flow was reduced following intravenous and subcutaneous administration of compounds described herein (eg, Compound 1).

[0314] In some cases, for example, during subcutaneous administration of a compound described herein (e.g., Compound 1), the active metabolite (full (V1a) agonist) M1 is produced at concentrations comparable to, for example, Compound 1.

[0315] In some embodiments, e.g., as described in the studies provided in Example 6, a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) reduces portal venous pressure (PP) (following subcutaneous administration), e.g., over a wide dose range (e.g., 10 μg / kg to 500 μg / kg of Compound 1) without excessive vasoconstriction. See Figures 16 and 18. In some embodiments, e.g., as described in the studies provided in Example 6, a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) reduces PP (following subcutaneous administration), e.g., over a wide dose range (e.g., 10 μg / kg to 500 μg / kg of Compound 1). See Figures 16 and 18.

[0316] In some embodiments, the methods provided herein further comprise evaluating a biological sample (e.g., of an individual). In some embodiments, the methods further comprise evaluating the individual's biological sample for a biomarker, e.g., a 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).

[0317] In some embodiments, biomarkers described herein, e.g., biomarkers described in Example 6, are assessed at a first time point and a second time point. In some embodiments, the second time point is used to determine the responsiveness or efficacy of, for example, a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1). In some embodiments, the second time point is an endpoint. In some cases, the endpoint is used to determine the amount or level of the biomarkers sufficient to achieve the desired responsiveness or efficacy of a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1). In some embodiments, the methods provided herein further include administering to the individual a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) until at least the level or amount of the biomarkers (in the individual) reaches the endpoint. In some embodiments, the method includes continuing administration of the compound after the level or amount of the biomarkers (in the individual) reaches the endpoint.

[0318] In some embodiments, the level or amount of a biomarker described herein, e.g., a biomarker described in Example 6, is higher (e.g., at least 5% higher, at least 15% higher, at least 25% higher, at least 35% higher, at least 45% higher, at least 55% higher, at least 65% higher, at least 75% higher, at least 85% higher, at least 95% higher, or more) at the second time point compared to the first time point.

[0319] In some embodiments, the level or amount of a biomarker described herein, e.g., a biomarker described in Example 6, is lower (e.g., up to 95% lower, up to 85% lower, up to 75% lower, up to 65% lower, up to 55% lower, up to 45% lower, up to 35% lower, up to 25% lower, up to 15% lower, up to 5% lower, or more) at the second time point compared to the first time point.

[0320] In some embodiments, e.g., as described in the study provided in Example 6, a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) increases mean arterial pressure (MAP) (following subcutaneous administration), e.g., over a wide dose range (e.g., 10 μg / kg to 500 μg / kg of Compound 1). See Figure 17. In some embodiments, e.g., as described in the study provided in Example 6, the increase in MAP reaches a peak plateau or upper therapeutic limit (e.g., an increase in MAP of about 10 to about 15 mmHg). See Figure 17. In some embodiments, e.g., as described in the study provided in Example 6, the increase in MAP reaches a peak plateau or upper therapeutic limit (e.g., an increase in MAP of about 10 to about 15 mmHg) in parallel with a decrease in PP (of about 2 to about 14 mmHg). See Figure 17. In some cases, even after a five-fold increase in dose (e.g., 100 μg / kg or 500 μg / kg of Compound 1), a compound described herein does not produce any meaningful additional effect, such as an increase in MA. See Figure 17.

[0321] In other cases, administration of a full V1a receptor agonist, e.g., terlipressin, provides a significantly higher increase in MAP (and beyond the therapeutic window of 10-15 mmHg), despite, for example, a reduction in PP similar to that of a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1). See Figure 17.

[0322] Some embodiments herein provide a method for treating a complication of end-stage liver disease, such as HRS-AKI, 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 salt).

[0323] In some embodiments, the individual described herein has cirrhosis portal hypertension. In some embodiments, the individual described herein has end-stage liver disease (ESLD). In some embodiments, the individual described herein has HRS-AKI. In some embodiments, the individual described herein develops HRS-AKI as a complication of ESLD.

[0324] In some embodiments, a compound described herein (e.g., Compound 1) provides a substantially improved therapeutic index (e.g., resulting from a lower maximal vasoconstriction effect and a lower risk of tissue hypoxia), e.g., when compared to a full V1A receptor agonist. In some embodiments, a compound described herein (e.g., Compound 1) provides about half the maximal vasoconstriction produced by a full agonist, e.g., without concomitant signs of ischemia. In some embodiments, a compound described herein (e.g., Compound 1) is a (clinically) effective vasoconstrictor (e.g., with a favorable benefit / risk profile, e.g., with low or no organ toxicity).

[0325] In some embodiments herein, there is provided a method of treating hepatorenal syndrome with acute kidney injury (HRS-AKI) 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 salt).

[0326] In some embodiments herein, there is provided a method for treating hepatorenal syndrome associated with acute kidney injury (HRS-AKI) in an individual, for example, an individual who has developed HRS-AKI as a complication of cirrhosis with ascites, 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) thereof.

[0327] In some embodiments, the individual has end-stage liver disease (ESLD). In some embodiments, the individual has HRS-AKI as a complication of end-stage liver disease (ESLD). In some embodiments, the individual develops HRS-AKI as a complication of end-stage liver disease (ESLD).

[0328] 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.

[0329] In some embodiments, a therapeutically effective amount of a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate) is about 5 μg to about 55 μg. In some embodiments, a therapeutically effective amount of a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate) is about 8 μg to about 50 μg. In some embodiments, a therapeutically effective amount of a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate) is about 20 μg to about 35 μg. In some embodiments, a therapeutically effective amount of a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate) is about 25 μg to about 35 μg. In some embodiments, a therapeutically effective amount of a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate) is about 30 μg. In some embodiments, a therapeutically effective amount of a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate salt) is administered over a period of time, such as over several hours (e.g., continuously for up to 24 hours) for several days (e.g., up to 10 days).

[0330] In some embodiments, a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate) is administered to an individual intravenously. In some embodiments, Compound 1, or a pharmaceutically acceptable salt (e.g., acetate) is administered to an individual by intravenous infusion.

[0331] In some embodiments, a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate) is administered to an individual subcutaneously. In some embodiments, Compound 1, or a pharmaceutically acceptable salt (e.g., acetate) is administered to an individual by subcutaneous injection.

[0332] In some embodiments, the therapeutically effective amount of a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate) is about 5 μg / hour or greater. In some embodiments, the therapeutically effective amount of a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate) is about 55 μg / hour or less. In some embodiments, the therapeutically effective amount of a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate) is about 5 μg / hour to about 55 μg / hour. In some embodiments, the therapeutically effective amount of a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate) is about 8 μg / hour to about 50 μg / hour. In some embodiments, the therapeutically effective amount of a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate) is about 20 μg / hour to about 35 μg / hour. In some embodiments, the therapeutically effective amount of a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate) is about 25 μg / hour to about 35 μg / hour. In some embodiments, the therapeutically effective amount of a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate) is about 30 μg / hour.

[0333] In some embodiments, a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate) is administered to an individual on days 1 and 2. In some embodiments, a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate) is administered to an individual (e.g., subcutaneously) on one or more days after day 1. In some embodiments, an individual receives an initial (e.g., intravenous infusion) dose of a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate) on day 1. In some embodiments, an individual receives an initial (e.g., intravenous infusion) dose of a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate) on day 1 to acclimate the individual to vasoconstriction before receiving the first assigned (e.g., subcutaneous) therapeutic dose (e.g., on day 2).

[0334] In some embodiments, a compound provided herein is administered to an individual (e.g., in need thereof) in an amount of about 0.01 milligrams (mg) or more. In some embodiments, a compound provided herein is administered to an individual (e.g., in need thereof) in an amount of about 0.1 mg or more. In some embodiments, a compound provided herein is administered to an individual (e.g., in need thereof) in an amount of about 0.3 mg or more. In some embodiments, a compound provided herein is administered to an individual (e.g., in need thereof) in an amount of about 0.45 mg or more. In some embodiments, a compound provided herein is administered to an individual (e.g., in need thereof) in an amount of about 0.6 mg or more. In some embodiments, a compound provided herein is administered to an individual (e.g., in need thereof) in an amount of about 0.9 mg or more. In some embodiments, a compound provided herein is administered to an individual (e.g., in need thereof) in an amount of about 10 mg or more. In some embodiments, a compound provided herein is administered to an individual (e.g., in need thereof) in an amount of about 20 mg or more. In some embodiments, a compound provided herein is administered to an individual (e.g., in need thereof) in an amount of about 30 mg or more. In some embodiments, a compound provided herein is administered to an individual (e.g., in need thereof) in an amount of about 40 mg or more. In some embodiments, a compound provided herein is administered to an individual (e.g., in need thereof) in an amount of about 50 mg or more. In some embodiments, a compound provided herein is administered to an individual (e.g., in need thereof) in an amount of about 0.01 mg to about 50 mg. In some embodiments, a compound provided herein is administered to an individual (e.g., in need thereof) in an amount of about 0.01 mg to about 10 mg. In some embodiments, a compound provided herein is administered to an individual (e.g., in need thereof) in an amount of about 0.01 mg to about 1 mg.

[0335] In some embodiments, the initial (e.g., intravenous infusion) dose is about 0.01 milligrams (mg) or greater. In some embodiments, the initial (e.g., intravenous infusion) dose is about 0.1 mg or greater. In some embodiments, the initial (e.g., intravenous infusion) dose is about 0.3 mg or greater. In some embodiments, the initial (e.g., intravenous infusion) dose is about 0.45 mg or greater. In some embodiments, the initial (e.g., intravenous infusion) dose is about 0.6 mg or greater. In some embodiments, the initial (e.g., intravenous infusion) dose is about 0.9 mg or greater. In some embodiments, the initial (e.g., intravenous infusion) dose is about 10 mg or greater. In some embodiments, the initial (e.g., intravenous infusion) dose is about 20 mg or greater. In some embodiments, the initial (e.g., intravenous infusion) dose is about 30 mg or greater. In some embodiments, the initial (e.g., intravenous infusion) dose is about 40 mg or greater. In some embodiments, the initial (e.g., intravenous infusion) dose is about 50 mg or greater. In some embodiments, the initial (e.g., intravenous) dose is about 0.01 mg to about 50 mg. In some embodiments, the initial (e.g., intravenous) dose is about 0.01 mg to about 10 mg. In some embodiments, the initial (e.g., intravenous) dose is about 0.01 mg to about 1 mg.

[0336] In some embodiments, the dose administered subsequent to the initial dose (e.g., subcutaneously) is about 0.01 milligrams (mg) or greater. In some embodiments, the dose administered subsequent to the initial dose (e.g., subcutaneously) is about 0.1 mg or greater. In some embodiments, the dose administered subsequent to the initial dose (e.g., subcutaneously) is about 0.3 mg or greater. In some embodiments, the dose administered subsequent to the initial dose (e.g., subcutaneously) is about 0.45 mg or greater. In some embodiments, the dose administered subsequent to the initial dose (e.g., subcutaneously) is about 0.6 mg or greater. In some embodiments, the dose administered subsequent to the initial dose (e.g., subcutaneously) is about 0.9 mg or greater. In some embodiments, the dose administered subsequent to the initial dose (e.g., subcutaneously) is about 10 mg or greater. In some embodiments, the dose administered subsequent to the initial dose (e.g., subcutaneously) is about 20 mg or greater. In some embodiments, the dose administered subsequent to the initial dose (e.g., subcutaneously) is about 30 mg or greater. In some embodiments, the dose administered (e.g., subcutaneously) following the initial dose is about 40 mg or more. In some embodiments, the dose administered (e.g., subcutaneously) following the initial dose is about 50 mg or more. In some embodiments, the dose administered (e.g., subcutaneously) following the initial dose is about 0.01 mg to about 50 mg. In some embodiments, the dose administered (e.g., subcutaneously) following the initial dose is about 0.01 mg to about 10 mg. In some embodiments, the dose administered (e.g., subcutaneously) following the initial dose is about 0.01 mg to about 1 mg.

[0337] In some embodiments, the initial (e.g., intravenous infusion) dose of a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate) is low. In some embodiments, the initial (e.g., intravenous infusion) dose of a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate) is about 5 μg / hour to about 15 μg / hour. In some embodiments, the initial (e.g., intravenous infusion) dose of a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate) is about 8 μg / hour.

[0338] In some embodiments, a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., the acetate salt) is administered to an individual (e.g., by intravenous infusion) for a period of about 4 hours to about 8 hours on Day 1. In some embodiments, a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., the acetate salt) is administered to an individual (e.g., by intravenous infusion) for a period of about 6 hours on Day 1.

[0339] In some embodiments, a first dose of the compound, or a pharmaceutically acceptable salt thereof, is administered to the individual on day 1, and a second dose is administered to the individual on day 2. In some embodiments, the first dose and the second dose comprise the same amount of the compound, or a pharmaceutically acceptable salt thereof.

[0340] In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1), is administered (e.g., subcutaneously) to an individual (e.g., as described herein) in an amount of about 0.01 milligram (mg) per day or more. In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1), is administered (e.g., subcutaneously) to an individual (e.g., as described herein) in an amount of about 0.1 mg per day or more. In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1), is administered (e.g., subcutaneously) to an individual (e.g., as described herein) in an amount of about 0.3 mg per day or more. In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1), is administered (e.g., subcutaneously) to an individual (e.g., as described herein) in an amount of about 0.45 mg per day or more. In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1), is administered (e.g., subcutaneously) to an individual (e.g., as described herein) in an amount of about 0.6 mg / day or more. In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1), is administered (e.g., subcutaneously) to an individual (e.g., as described herein) in an amount of about 0.9 mg / day or more. In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1), is administered (e.g., subcutaneously) to an individual (e.g., as described herein) in an amount of about 10 mg / day or more. In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1), is administered (e.g., subcutaneously) to an individual (e.g., as described herein) in an amount of about 50 mg / day or more. In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1), is administered (e.g., subcutaneously) to an individual (e.g., as described herein) in an amount of about 100 mg / day or more. In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1), is administered (e.g., subcutaneously) to an individual (e.g., as described herein) in an amount of about 100 mg / day or less.In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1), is administered (e.g., subcutaneously) to an individual (e.g., as described herein) in an amount of about 50 mg / day or less. In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1), is administered (e.g., subcutaneously) to an individual (e.g., as described herein) in an amount of about 10 mg / day or less. In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1), is administered (e.g., subcutaneously) to an individual (e.g., as described herein) in an amount of about 1 mg / day or less. In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1), is administered (e.g., subcutaneously) to an individual (e.g., as described herein) in an amount of about 0.1 mg / day or less. In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1), is administered (e.g., subcutaneously) to an individual (e.g., as described herein) in an amount of about 0.01 mg / day to about 100 mg / day. In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1), is administered (e.g., subcutaneously) to an individual (e.g., as described herein) in an amount of about 0.01 mg / day to about 10 mg / day. In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1), is administered (e.g., subcutaneously) to an individual (e.g., as described herein) in an amount of about 0.01 mg / day to about 1 mg / day.

[0341] In some embodiments, a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate salt) is administered (e.g., subcutaneously) to an individual on multiple days (e.g., 5 days). In some embodiments, a method comprises administering a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate salt) to an individual on one or more days (e.g., subcutaneously). In some embodiments, a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate salt) is administered to an individual the next day (e.g., subcutaneously). In some embodiments, a method comprises administering a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate salt) to an individual on consecutive and / or non-consecutive days (e.g., subcutaneously). In some embodiments, a method comprises administering a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate salt) to an individual on one or more consecutive days (e.g., subcutaneously). In some embodiments, the method comprises administering (e.g., subcutaneously) to the individual a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate) on one or more non-consecutive days. In some embodiments, the method comprises administering (e.g., subcutaneously) to the individual a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate) on one or more consecutive days after day 1. In some embodiments, the method comprises administering (e.g., subcutaneously) to the individual a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate) on one or more non-consecutive days after day 1.

[0342] In some embodiments, the method comprises administering (e.g., subcutaneously) to an individual a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate) for at least two days. In some embodiments, the method comprises administering (e.g., subcutaneously) to an individual a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate) for five or more days. In some embodiments, the method comprises administering (e.g., subcutaneously) to an individual a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate) for ten or more days.

[0343] In some embodiments, the method includes administering (e.g., subcutaneously) to an individual a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate) for one week or more.

[0344] In some embodiments, the method includes administering (e.g., subcutaneously) a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate) to an individual for one month or more.

[0345] In some embodiments, the method includes administering (e.g., subcutaneously) a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate) to the individual for one year or more.

[0346] In some embodiments, the method involves administering (e.g., subcutaneously) to the individual a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate) for up to 11 days, for example, up to 10 days after day 1. In some embodiments, the method involves administering (e.g., subcutaneously) to the individual a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate) for 4 to 10 days. In some embodiments, the method involves administering (e.g., subcutaneously) to the individual a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate) for 4 to 10 days after day 1. In some embodiments, the method involves administering (e.g., subcutaneously) to the individual a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate) for up to 9 days. In some embodiments, the days are consecutive days. In some embodiments, the days are non-consecutive days. In some embodiments, the method includes administering to an individual (e.g., via continuous intravenous infusion) a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate) over a 24-hour period.

[0347] In some embodiments, the method includes administering a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate) to an individual via continuous intravenous infusion over a 24-hour period per day (for up to 9 days). In some embodiments, the method includes subcutaneously administering a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate) to an individual (for up to 5 days). In some embodiments, the compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate) is administered to an individual in an amount of up to about 2 milligrams (mg) per day. In some embodiments, the compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate) is administered to an individual in an amount of about 0.2 mg / day to about 2 mg / day. In some embodiments, the compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate) is administered to an individual in an amount of about 0.5 mg / day to about 1.5 mg / day. In some embodiments, a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate) is administered to an individual in an amount of about 1.2 mg / day.

[0348] In some embodiments, an individual (e.g., as described herein) receives repeated subcutaneous injections of a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1). In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1), is administered subcutaneously to an individual (e.g., as described herein) once daily. In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1), is administered subcutaneously to an individual (e.g., as described herein) once daily for two or more consecutive days. In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1), is administered subcutaneously to an individual (e.g., as described herein) once daily for three or more consecutive days. In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1), is administered subcutaneously to an individual (e.g., as described herein) once daily for four or more consecutive days. In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1), is administered subcutaneously to an individual (e.g., as described herein) once daily for five or more consecutive days.

[0349] In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1), is administered to an individual (e.g., as described herein) via subcutaneous bolus injection.

[0350] In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1), is administered to an individual (e.g., as described herein) via subcutaneous infusion. In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1), is administered to an individual (e.g., as described herein) via continuous subcutaneous infusion.

[0351] Unless otherwise specified, a composition for subcutaneous administration means a composition that is suitable for systemic delivery of an active agent or API (e.g., Compound 1) when administered subcutaneously.

[0352] Unless otherwise specified, formulated means a composition that includes excipients such as stabilizers or diluents.

[0353] Unless otherwise specified, weights (e.g., dosages) provided herein for compounds described herein (e.g., Compound 1) are calculated based on the free base of the compound (e.g., not a pharmaceutically acceptable salt of the compound). In some cases, an acetate salt of a compound described herein (e.g., Compound 1) is administered to an individual receiving a treatment provided herein.

[0354] In some cases, a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) has an effect (e.g., an increase or decrease) on the level of a biomarker described herein, such as a biomarker described in Example 5 or 6. In some embodiments, the biomarker described herein is selected from the group consisting of mean arterial pressure (MAP), (plasma) aldosterone, (plasma) renin, ascites volume, body weight, urine volume, (net) fluid balance, urinary sodium, urinary potassium, portal pressure, cardiac output, systemic vascular resistance, BUN, BUN / CREA, PHOS, spleen weight, skin blood flow (SBF), blood lactate concentration, heart rate, systolic arterial pressure, diastolic arterial pressure, and blood pH. In some embodiments, the biomarker described herein is mean arterial pressure (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 systolic arterial pressure. In some embodiments, the biomarker described herein is diastolic arterial pressure. In some embodiments, the biomarker described herein is heart rate. In some embodiments, the biomarker described herein is portal 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 heart rate. In some embodiments, the biomarker described herein is systolic arterial pressure.In some embodiments, the biomarker described herein is diastolic arterial pressure.

[0355] In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) increases mean arterial blood pressure, systolic arterial blood pressure, and diastolic arterial blood pressure in an individual (e.g., a mammal), e.g., after subcutaneous administration (see, e.g., Figures 24A-C). In some cases, the occurrence and amplitude of the maximum increase in blood pressure is related to the dose of a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) in an individual (e.g., a mammal), e.g., after subcutaneous administration. In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) increases mean arterial blood pressure (MAP) in an individual (e.g., a mammal) by at least about 10 mmHg (e.g., at least 15 mmHg, at least 20 mmHg, at least 30 mmHg, at least 40 mmHg), e.g., after subcutaneous administration (see, e.g., Figure 26A). In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) increases mean arterial blood pressure (MAP) in an individual (e.g., a mammal) by up to about 50 mmHg (e.g., up to 40 mmHg, up to 30 mmHg, up to 20 mmHg, up to 10 mmHg), e.g., after subcutaneous administration. In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) increases mean arterial blood pressure (MAP) in an individual (e.g., a mammal) by about 10 mmHg to about 50 mmHg, e.g., after subcutaneous administration. In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) increases mean arterial blood pressure (MAP) in an individual (e.g., a mammal) by about 20 mmHg, e.g., after subcutaneous administration. In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) increases mean arterial blood pressure (MAP) in an individual (e.g., a mammal) by about 40 mmHg, e.g., after subcutaneous administration.In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) increases mean arterial blood pressure (MAP) in an individual (e.g., a mammal) by about 25 mmHg, for example, after subcutaneous administration. In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) increases mean arterial blood pressure (MAP) in an individual (e.g., a mammal) after subcutaneous administration, and the increase persists for at least 75 minutes (e.g., at least 150 minutes, at least 300 minutes). In some cases, a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) provides a change in mean arterial blood pressure (MAP) in an individual (e.g., a mammal) that is statistically different from vehicle, for example, after subcutaneous administration. In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) increases MAP, e.g., after subcutaneous administration, and MAP does not return to baseline values ​​in an individual (e.g., a mammal).

[0356] In some embodiments, a full antagonist such as terlipressin increases mean arterial pressure (MAP) in an individual (e.g., a mammal) (see, e.g., Figure 26B). In some embodiments, a full antagonist such as terlipressin increases mean arterial pressure (MAP), and the effect lasts for only a short time, e.g., less than 90 minutes (e.g., 30, 75, or 90 minutes or less), following intravenous administration (see, e.g., Figure 26B). In some embodiments, a full antagonist such as terlipressin provides a transient effect on MAP (see, e.g., Figure 26B). In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) provides an increase in MAP in an individual (e.g., a mammal) over a 50-fold dose range, which may represent the maximum effect on arterial pressure in some cases.

[0357] In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) reduces the heart rate in an individual (e.g., a mammal) after, for example, subcutaneous administration (see Figure 24D). In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) reduces the heart rate in an individual (e.g., a mammal) by at least 2% (e.g., at least 5%, at least 10%, at least 15%) after, for example, subcutaneous administration (see Figure 24D). In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) reduces the heart rate in an individual (e.g., a mammal) by at most 20% (e.g., at most 15%, at most 10%, at most 5%) after, for example, subcutaneous administration (see Figure 24D). In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) reduces heart rate in an individual (e.g., a mammal) by about 5%, e.g., after subcutaneous administration (see, e.g., Figure 24D). In some cases, a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) provides a change in MAP that correlates with a measurable reduction in heart rate in an individual (e.g., a mammal), e.g., after subcutaneous administration (see, e.g., Figures 24D, 26A). In some cases, changes in systolic blood pressure and diastolic blood pressure after, e.g., subcutaneous administration of a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) correlate with changes in MAP in an individual (e.g., a mammal) (see, e.g., Figures 24A-C).

[0358] In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) has an elimination half-life (t) of at least 50 minutes (e.g., at least 70 minutes, at least 90 minutes, at least 110 minutes, at least 130 minutes) in an individual (e.g., a mammal), e.g., after subcutaneous administration. 1 / 2termIn some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) has an elimination half-life (t) 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), e.g., after subcutaneous injection. 1 / 2term In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) has an elimination half-life (t) of about 50 to about 150 minutes in an individual (e.g., a mammal), e.g., after subcutaneous injection. 1 / 2term In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) has an elimination half-life (t) of about 110 minutes in an individual (e.g., a mammal), e.g., after subcutaneous injection. 1 / 2term In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) has an elimination half-life (t) of at least 1 minute (e.g., at least 5 minutes, at least 10 minutes, at least 15 minutes, at least 20 minutes) in an individual (e.g., a mammal), e.g., after intravenous administration. 1 / 2elim In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) has an elimination half-life (t) of at most 60 minutes (e.g., at most 40 minutes, at most 20 minutes, at most 10 minutes) in an individual (e.g., a mammal). 1 / 2elim In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) has an elimination half-life (t) of about 1 minute to about 40 minutes in an individual (e.g., a mammal). 1 / 2elim In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) has an elimination half-life (t) of about 20 minutes in an individual (e.g., a mammal). l / 2elim In some embodiments, the compound has an elimination half-life (t l / 2term ) is the elimination half-life (t l / 2elim ) is greater than

[0359] In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) has a bioavailability in an individual (e.g., a mammal) of at least 40% (e.g., at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%), e.g., after subcutaneous administration. In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) has a bioavailability in an individual (e.g., a mammal) of at most 75% (e.g., at most 70%, at most 60%, at most 50%, at most 40%). In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) has a bioavailability in an individual (e.g., a mammal) of about 40% to about 70%. In some embodiments, a compound described herein (eg, a mixed V1AR agonist-antagonist, such as Compound 1) has a bioavailability in an individual (eg, a mammal) of about 60%.

[0360] In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) has a clearance rate in an individual (e.g., a mammal) similar to the glomerular filtration rate (e.g., 5-15 mL / min / kg), e.g., after subcutaneous administration. In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) has a filtration rate of at least 5 mL / min / kg (e.g., at least 7 mL / min / kg, at least 10 mL / min / kg, at least 13 mL / min / kg). In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) has 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, a compound described herein (e.g., a mixed V1AR agonist-antagonist, such as Compound 1) has a filtration rate of about 20 mL / min / kg. In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist, such as Compound 1) has a filtration rate of about 10 mL / min / kg.

[0361] In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) reduces cutaneous blood flow in an individual (e.g., a mammal), e.g., after intravenous administration (see, e.g., Figure 23A). In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) reduces 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, a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) reduces 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, a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) reduces cutaneous blood flow in an individual (e.g., a mammal) by about 20% to about 60%. In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) reduces cutaneous blood flow in an individual (e.g., a mammal) by about 40%. In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1), e.g., after intravenous administration, reduces cutaneous blood flow in an individual (e.g., a mammal) more than vasopressin reduces cutaneous blood flow in an individual (e.g., a mammal). See, e.g., Figure 23A. In some cases, a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) reduces 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, indicating that a mixed V1AR agonist-antagonist described herein, e.g., Compound 1, is more suitable for intravenous administration than a fully non-selective (V2, V1a) agonist (e.g., vasopressin or terlipressin), for example, by reducing (significant) injection site reactions (e.g., local vasoconstriction) that make the drug unsuitable for systemic delivery.In some cases, a smaller decrease in cutaneous blood flow with a compound provided herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) compared to vasopressin indicates less local vasoconstriction compared to vasopressin.

[0362] In some cases, an increase in serum lactate levels is a clinical marker of anaerobic metabolism and tissue hypoxia, and is used as a surrogate marker for the development of vasoconstriction and tissue ischemia. In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) does not (significantly) increase blood lactate levels in an individual, for example, after intravenous administration (see, e.g., Figure 23B). In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) does not (significantly) increase blood lactate levels in an individual, while a similar dose of vasopressin significantly increases blood lactate levels in an individual, for example, after intravenous administration (see, e.g., Figure 23B-C). In some cases, vasopressin increases blood lactate levels in an individual by at least twofold (e.g., threefold, fourfold), for example, after intravenous administration (see, e.g., Figure 23B).

[0363] In some embodiments, a compound described herein (e.g., a mixed Vi1AR agonist-antagonist, e.g., Compound 1) reduces plasma concentrations (e.g., linearly) (see, e.g., Figures 22A-B, 25A-B).

[0364] In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) increases the blood pH of an individual, e.g., after intravenous administration. In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) decreases the blood pH of an individual, e.g., after intravenous administration.

[0365] In some cases, a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) may be administered, for example, after intravenous administration, to an individual (e.g., a mammal) in the central compartment (V1AR) 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). c In some cases, a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) provides an initial apparent volume of the central compartment (V) in an individual (e.g., a mammal) of up to 150 mg / kg (e.g., up to 130 mg / kg, up to 110 mg / kg, up to 90 mg / kg), e.g., after intravenous administration. c ) provides the initial apparent volume.

[0366] In some cases, a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) has a steady-state volume of distribution (V) in an individual (e.g., a mammal) of at least 120 mL / kg (e.g., at least 130 mL / kg, at least 140 mL / kg, at least 150 mL / kg), e.g., after intravenous administration. ss In some cases, a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) has a steady-state volume of distribution (V) in an individual (e.g., a mammal) of at most 200 mL / kg (e.g., at most 180 mL / kg, at most 160 mL / kg, at most 140 mL / kg), e.g., after intravenous administration. ss ) is provided.

[0367] In some cases, a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) may have a maximum plasma concentration per unit dose (C) in an individual (e.g., a mammal) of at least 200 ng / mL per mg / kg (e.g., at least 300 ng / mL per mg / kg, at least 500 ng / mL per mg / kg, at least 600 ng / mL per mg / kg, at least 700 ng / mL per mg / kg), e.g., after subcutaneous administration. max In some cases, a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) provides a maximum plasma concentration (C) per unit dose in an individual (e.g., a mammal) of at most 1000 ng / mL per mg / kg (e.g., at most 900 ng / mL per mg / kg, at most 700 ng / mL per mg / kg, at most 500 ng / mL per mg / kg, at most 400 ng / mL per mg / kg), e.g., after subcutaneous administration. max In some cases, a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) provides a maximum plasma concentration (T) in an individual (e.g., a mammal) of at least 5 minutes (e.g., at least 10 minutes, at least 20 minutes, at least 30 minutes), e.g., after subcutaneous administration. max In some cases, a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) provides a maximum plasma concentration (T) in an individual (e.g., a mammal) of up to 60 minutes (e.g., up to 50 minutes, up to 40 minutes, up to 30 minutes, up to 20 minutes), e.g., after subcutaneous administration. max ) time.

[0368] In some cases, a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) provides an area under the curve (AUC) per unit dose in an individual (e.g., a mammal) of at least 40,000 min ng / mL per mg / kg (e.g., at least 45,000 min ng / mL per mg / kg, at least 50,000 min ng / mL per mg / kg, at least 55,000 min ng / mL per mg / kg, at least 60,000 min ng / mL per mg / kg), for example, after subcutaneous administration. In some cases, a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) provides an area under the curve (AUC) per unit dose in an individual (e.g., a mammal) of up to 70,000 min ng / mL per mg / kg (e.g., 65,000 min ng / mL per mg / kg, 60,000 min ng / mL per mg / kg, 55,000 min ng / mL per mg / kg, 50,000 min ng / mL per mg / kg), for example, after subcutaneous administration.

[0369] In some cases, a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) provides an apparent total body clearance (CL / F) in an individual (e.g., a mammal) of at least 10 mL / min / kg (e.g., at least 12 mL / min / kg, at least 15 mL / min / kg, at least 18 mL / min / kg), for example, after subcutaneous administration. In some cases, a compound described herein (e.g., a mixed V1AR agonist-antagonist, e.g., Compound 1) provides an apparent total body clearance (CL / F) in an individual (e.g., a mammal) of at most 30 mL / min / kg (e.g., at most 28 mL / min / kg, at most 25 mL / min / kg, at most 22 mL / min / kg, at most 20 mL / min / kg), for example, after subcutaneous administration.

[0370] In some cases, an individual receiving a treatment described herein achieves one or more outcome measures described herein, e.g., as described in the Examples, during and / or after receiving the treatment. In some cases, an individual receiving a treatment described herein meets one or more inclusion criteria provided in the Examples. In some cases, an individual receiving a treatment described herein meets each of the inclusion criteria provided in the Examples. In some cases, an individual receiving a treatment described herein fails to meet one or more exclusion criteria provided in the Examples. In some cases, an individual receiving a treatment described herein fails to meet each of the exclusion criteria provided in the Examples. In some embodiments, an individual receiving a treatment described herein is administered a compound described herein (e.g., Compound 1) until one or more primary and / or secondary outcome measures are met, e.g., the primary and / or secondary outcome measures provided in the Examples. In some cases, an individual is administered a compound described herein (e.g., Compound 1) until the individual has an sCr value of 1.5 milligrams (mg) / deciliter (dL) or less on (e.g., two or more) consecutive days. In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof (e.g., Compound 1), is administered (e.g., subcutaneously) to an individual (e.g., as described herein) at least until the individual's sCr value returns to normal (e.g., baseline).

[0371] Unless otherwise specified, the measurements described herein (e.g., measurements of sCr, MAP, etc.) can be measured immediately before, hours, days, or weeks before a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate salt) is administered to an individual undergoing a treatment described herein.

[0372] In some embodiments, an individual undergoing a treatment described herein has a decrease in sCr. In some embodiments, an individual undergoing a treatment described herein has a substantial decrease in sCr. In some embodiments, an individual undergoing a treatment described herein has a significant decrease in sCr. In some embodiments, an individual undergoing a treatment described herein has a decrease in sCr levels of about 10% or more, e.g., compared to a baseline measurement before treatment. In some embodiments, an individual undergoing a treatment described herein has a decrease in sCr levels of about 50% or less, e.g., compared to a baseline measurement before treatment. In some embodiments, an individual undergoing a treatment described herein has a decrease in sCr levels of about 10% to about 50%, e.g., compared to a baseline measurement before treatment. In some embodiments, an individual undergoing a treatment described herein has a decrease in sCr levels of about 20% to about 50%, e.g., compared to a baseline measurement before treatment. In some embodiments, an individual undergoing a treatment described herein has a decrease in sCr levels of about 30% to about 50%, e.g., compared to a baseline measurement before treatment. In some embodiments, an individual undergoing a treatment described herein has a decrease in sCr levels of about 40% to about 50%, e.g., compared to a baseline measurement before treatment. In some cases, the reduction in sCr levels following treatment with a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., acetate), is significantly greater than the reduction in sCr levels following treatment with other treatment options.

[0373] In some embodiments, an individual undergoing a treatment described herein is administered a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., the acetate salt), until the individual has an sCr level of 1.5 milligrams (mg) per deciliter (dL) or less on consecutive days. In some embodiments, an individual undergoing a treatment described herein is administered a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., the acetate salt), until the individual has an sCr level of 1.5 mg / dL or less on two or more consecutive days.

[0374] In some embodiments, the mean arterial pressure (MAP) of an individual undergoing a treatment described herein is increased. In some embodiments, the MAP of an individual undergoing a treatment described herein is increased compared to a baseline measurement before treatment. In some embodiments, the MAP of an individual undergoing a treatment described herein is increased by about 15 mmHg or less (e.g., compared to a baseline measurement before treatment).

[0375] In some embodiments, the mean arterial pressure (MAP) of an individual receiving a treatment described herein is reduced. In some embodiments, the MAP of an individual receiving a treatment described herein is reduced compared to a baseline measurement before treatment. In some embodiments, the MAP of an individual receiving a treatment described herein is reduced by about 15 mmHg or less (e.g., compared to a baseline measurement before treatment).

[0376] In some embodiments, the MAP of an individual undergoing a treatment described herein remains largely (e.g., significantly) unchanged (e.g., compared to a baseline measurement before treatment). In some embodiments, the MAP of an individual undergoing a treatment described herein remains largely (e.g., significantly) unchanged compared to a baseline measurement before treatment.

[0377] In some cases herein, provided are methods for regulating mean arterial pressure (MAP) in an individual (e.g., in need thereof), the methods comprising: (a) administering (e.g., intravenously or subcutaneously) an effective amount of a first compound, or a pharmaceutically acceptable salt thereof, where the first compound is a vasoconstrictor (e.g., a vasopressin receptor 1A (V1AR) agonist (e.g., a selective V1AR agonist)); and (b) administering (e.g., intravenously or subcutaneously) a second compound (e.g., a V1AR antagonist (e.g., a selective V1AR antagonist) or a vasodilator), or a pharmaceutically acceptable salt thereof, where the second compound sufficiently blocks the (local) vasoconstrictor effect (on the individual) of the first compound, thereby providing sufficient uptake of the first compound into the individual's circulatory system and / or internal organs (e.g., the kidneys). In some cases, for example, following administration, the first compound constricts blood vessels near or at the administration site, thereby preventing sufficient uptake of the first compound into the individual's internal organs (e.g., kidneys). In some cases, the first compound and the second compound are administered to the individual simultaneously. In some cases, administration of the second compound reduces the local vasoconstrictor effect of the first compound, but does not reduce the vasoconstrictor effect of the first compound on the individual's internal organs (e.g., kidneys). In some cases, administration of the second compound reduces the local vasoconstrictor effect of the first compound so that a therapeutically effective amount of the first compound is delivered to the individual's internal organs (e.g., kidneys). In some cases, the individual has HRS-AKI.

[0378] In some embodiments, an individual undergoing a treatment described herein has a Model for End-Stage Liver Disease (MELD) score of up to 35 prior to treatment, e.g., at the time of randomization, e.g., several days prior to treatment.

[0379] In some embodiments, an individual undergoing a treatment described herein has proteinuria of up to about 500 mg / dL prior to treatment, eg, at the time of randomization, eg, several days before treatment.

[0380] In some embodiments, an individual undergoing a treatment described herein has an oxygen flow of at least about 90% at or below 2 liters (L) prior to treatment, e.g., at the time of randomization, e.g., several days prior to treatment.

[0381] In some embodiments, an individual undergoing a treatment described herein has a pulse oximeter reading of at least about 90% at 2 liters (L) prior to treatment, e.g., at the time of randomization, e.g., several days prior to treatment.

[0382] In some embodiments, an individual receiving a treatment described herein has a systolic blood pressure of up to 140 mmHg. In some embodiments, an individual receiving a treatment described herein has a diastolic blood pressure of up to 100 mmHg. In some embodiments, an individual receiving a treatment described herein has a systolic blood pressure of 140 mmHg or less and a diastolic blood pressure of 100 mmHg or less. In some cases, the individual's systolic and / or diastolic blood pressure is measured prior to treatment, e.g., at the time of randomization, e.g., several weeks prior to treatment.

[0383] In some embodiments, the individual receiving the treatment described herein is receiving albumin. In some embodiments, the individual receiving the treatment described herein is receiving albumin and has had adequate diuretic withdrawal prior to treatment. In some embodiments, the individual receiving the treatment described herein is receiving albumin and has had adequate diuretic withdrawal several days prior to treatment. In some embodiments, the individual receiving the treatment described herein is receiving albumin and has had adequate diuretic withdrawal at least 48 hours prior to treatment.

[0384] In some embodiments, an individual undergoing a treatment described herein has a lack of sustained improvement in renal function. In some embodiments, an individual undergoing a treatment described herein has a lack of sustained improvement in renal function after diuretic withdrawal. In some embodiments, an individual undergoing a treatment described herein has a lack of sustained improvement in renal function after plasma volume expansion with albumin. In some embodiments, an individual undergoing a treatment described herein has a lack of sustained improvement in renal function after diuretic withdrawal and plasma volume expansion with albumin.

[0385] In some cases, the individual receiving the treatment described herein is in need of the treatment described herein.

[0386] While preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous modifications, changes, and substitutions will occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. The following claims define the scope of the invention, and it is intended that methods and structures within the scope of these claims and their equivalents be covered thereby. [Example]

[0387] Example 1: Tolerability, Pharmacokinetic (PK), and Pharmacodynamic (PD) Profiles of a Mixed V1AR Agonist-Antagonist in Healthy Humans and Rats After Intravenous (IV) and Subcutaneous (SC) Administration In summary, the systemic exposure of compounds described herein (e.g., mixed V1AR agonist-antagonist, e.g., Compound 1) was measured after administering a composition containing the compound by IV infusion and SC (bolus) injection to healthy rats and humans. In addition, systemic effects such as the regulation of mean arterial pressure (MAP) were measured after administering the composition by IV infusion and SC (bolus) injection to healthy rats and humans.

[0388] The systemic effects observed after IV infusion and SC (bolus) injection were comparable, although more adverse events were observed in individuals receiving SC (bolus) injection of the composition. In general, the compounds were well tolerated by individuals receiving the composition by IV infusion.

[0389] Substantial amounts of metabolites (Ml - full (V1a) agonists) were measured in healthy humans and rats after subcutaneous (bolus) injection of the compositions. Specifically, approximately 80-90% of metabolite Ml was measured after subcutaneous (bolus) injection of the compositions in both healthy humans and rats. In contrast, little or no Ml was measured after intravenous infusion of the compositions. As discussed herein, full vasopressin receptor agonists described herein (e.g., terlipressin) are known to cause (serious) adverse events when administered subcutaneously. Therefore, substantial metabolic conversion of the compounds to full agonists (Ml) after SC (bolus) injection provides an explanation for the differences between the tolerability profiles of the compositions in healthy individuals after IV infusion and SC bolus injection. Additional studies described below demonstrate methods for reducing full agonist (Ml) formation after SC administration of compositions containing the mixed V1AR agonist-antagonists described herein, such as Compound 1.

[0390] Clinical trial design overview A double-blind, placebo-controlled, dose-group randomized clinical trial investigating the safety, tolerability, pharmacokinetics, and pharmacodynamics of Compound 1 administered as an intravenous infusion and multiple subcutaneous injections in healthy men and women. The trial consisted of two treatment periods, Treatment Period 1 and Treatment Period 2 (see Figure 1).

[0391] The study was conducted in two periods, with treatment in Period 1 administered as an intravenous infusion and treatment in Period 2 administered as a subcutaneous injection. The trial consisted of five ascending dose panels, each containing eight healthy subjects (six active, two placebo). A new cohort of subjects was used for each dose panel.

[0392] Treatment Period 1: Subjects received a 6-hour intravenous infusion of Compound 1 or placebo. At each dose level, the first two subjects to receive an infusion were randomized to receive either Compound 1 or placebo, with a minimum observation period of 24 hours. If no safety concerns arose as determined by the investigator, the remaining subjects in that dose group were randomized and treated with a staggered dosing schedule as per the randomization and protocol. Dose escalation included Compound 1 at 0.1, 0.3, 0.45, 0.6, and 0.9 milligrams (mg).

[0393] Treatment Period 2: After a 2- to 18-day rest period, each subject received a single subcutaneous dose of the same treatment as in Period 1 for 5 days. Doses were selected to prevent exposure from exceeding intravenous exposure. Dose escalation was stopped after the 0.3 mg dose panel due to the risk of exceeding the maximum tolerated dose with higher doses. For each subject, the treatment period was 2 + 6 days, and the total time from the screening visit to the post-treatment follow-up visit did not exceed 8 weeks. The SRC evaluated the safety and tolerability of the compound after completion of all subjects in a dose group.

[0394] All subjects were assigned to active treatment or placebo in a double-blind setting, i.e., the active or placebo treatment was not revealed to the subjects or study personnel. Randomization and blinding were used to reduce bias, for example, regarding reporting of AEs.

[0395] A single intravenous infusion over 6 hours and a once-daily subcutaneous dose for 5 days were chosen as the routes of administration and duration of treatment (e.g., to explore the full interim dose range of Compound 1). The continuation of intravenous to subcutaneous dosing in the same subjects was chosen to obtain the most reliable possible estimate of bioavailability (F) in the outlined subgroups.

[0396] The first two subjects to be infused at each dose level, one receiving Active Compound 1 and one receiving placebo, had a minimum observation period of 24 hours to reduce the risks associated with exposure to substances in early clinical development. Considering the safety of the study subjects, a sequential dose escalation design with safety assessment of the previous dose level was selected.

[0397] The originally planned escalating doses were 0.1, 0.3, 1, 3, 6, and 10 mg, respectively. In previous studies, administration of 0.3 mg as a 6-hour intravenous infusion resulted in C up to approximately 6 ng / mL. max Based on data from previous studies, the planned subcutaneous (sc) doses (0.1, 0.3, 1, 3, 6, and 10 mg) were expected to yield C concentrations comparable to those obtained with the corresponding intravenous infusions. max It was estimated that the 0.3 mg dose as a sc injection would reach but not exceed C levels of approximately 2.5 ng / mL. max The dose and / or infusion rate could be adjusted based on recommendations from the SRC.

[0398] Injection site reactions were assessed by the investigator immediately, 0.5, 4, and 24 hours after subcutaneous administration of study drug on days 1 to 5 during treatment period 2 only. The following injection site reactions were assessed: erythema, pain, pruritus, edema, bruising, and pallor, each of which was rated as none, mild, moderate, or severe. Injection site reactions other than those listed above or lasting more than 24 hours were classified as adverse events (AEs).

[0399] In Period 1, blood samples for safety laboratory evaluation of clinical chemistry parameters were collected at screening, Day -1, pre-dose, and 1, 2, 4, 6, 8, 12, and 24 hours after initiation of intravenous administration of Compound 1. Blood samples for hematology and hemostatic parameters were collected at screening, Day -1, and 6, 12, and 24 hours after initiation of intravenous administration of Compound 1.

[0400] For subcutaneous administration in Period 2, samples for clinical chemistry parameters were collected on Day -1, pre-dose, and 2 and 6 hours after administration of Compound 1, and at follow-up. Blood samples for hematology and hemostatic parameters were collected on Day -1, and 2 and 4 hours after administration on Day 1, pre-dose, and 3 hours after administration on Days 2-4, pre-dose, and 2 and 6 hours after administration on Day 5, and at follow-up. Actual sampling times were recorded.

[0401] Urine samples for safety laboratory evaluation of urinalysis parameters were collected in Period 1 at screening, Day -1, predose, and collection periods 0-4 hours, 4-8 hours, 8-12 hours, and 12-24 hours after the start of intravenous Compound 1 administration. For subcutaneous administration in Period 2, urine samples were collected on Day -1, predose, 2 and 6 hours after Compound 1 administration on Days 1-5, and at follow-up. Urinalysis was performed on-site by dipstick. Abnormal dipstick results led to a new urine test. Abnormal dipstick results, both clinically significant and clinically significant, led to a new urine test. If abnormal results were confirmed, further testing could be initiated at the investigator's discretion. Clinically significant abnormal findings were reported as AEs. Metabolite patterns of Compound 1 were measured in plasma and urine.

[0402] Similar studies in healthy rats were used to assess the differences between metabolite formation of Compound 1 after IV bolus and SC (bolus) injection.

[0403] Eligibility Individuals in the study met the inclusion criteria provided in Table 1.

[0404] [Table 1]

[0405] Individuals with any one of the exclusion criteria provided in Table 2 were excluded from the study.

[0406] [Table 2]

[0407] Dose escalation was terminated when one or more of the predefined criteria provided in Table 3 were met in at least two subjects on active treatment in the dose panel, as confirmed by a second measurement.

[0408] [Table 3]

[0409] subject Eighty-five subjects were screened for this trial, of whom 64 were randomized and administered. In Period 1, there were five dose groups for intravenous (iv) administration: 0.1, 0.3, 0.45, 0.6, and 0.9 mg. In Period 2, there were two dose groups for subcutaneous (sc) administration: 0.1 and 0.3 mg. The 0.1 mg and 0.3 mg dose groups (iv infusion followed by sc administration) initially consisted of eight subjects, six of whom received the active treatment and two of whom received a placebo. All subjects in the 0.1 mg dose group received both iv and sc administration, while in the 0.3 mg dose group, only three of the six infused subjects continued on with the sc administration. The 0.45, 0.6, and 0.9 mg dose groups (iv administration) each consisted of 16 subjects, 12 of whom received the active treatment and four of whom received a placebo. All active-treatment subjects in the 0.1, 0.45, 0.6, and 0.9 mg dose groups completed the study, while one active-treatment subject in the 0.3 mg dose group discontinued the study due to an AE (single event of elevated troponin I levels) after the first subcutaneous dose. The decision to terminate sc dosing after three subjects in the 0.3 mg dose group meant the remaining three subjects were defined as completers. All subjects receiving placebo completed the study.

[0410] treatment In Period 1, subjects received a single 6-hour intravenous infusion of either Compound 1 or placebo at a constant rate. The intravenous dose for the first dose panel was the lowest dose that gave a clear signal of pharmacological activity in previous trials. The planned and actual doses of Compound 1 during the intravenous infusion are provided in Table 4. Administration was performed using a piston-driven syringe auto-infusion pump. The volume administered was recorded for each subject.

[0411] [Table 4]

[0412] In Period 2, subjects received once-daily subcutaneous injections of the same treatment as in Period 1 for 5 days at different locations in the abdomen (Table 5). The subcutaneous dose was selected based on data from previous clinical trials.

[0413] [Table 5]

[0414] formulation In some cases, Compound 1 was formulated as a sterile aqueous solution of 1 mg / mL to about 10 mg / mL of Compound 1 in 10 mM acetate buffer, pH 4.5, with mannitol (e.g., for isotonicity). In some cases, the Compound 1-containing formulation was filled into glass vials (1.5 mL drawable volume) and sealed with rubber stoppers and plastic caps. In some cases, the Compound 1-containing formulation was diluted to the appropriate concentration with 0.9% sodium chloride injection prior to administration.

[0415] In some cases, Compound 1 was formulated into an investigational medicinal product (IMP) as shown in Table 6. In some cases, Compound 1 was diluted to the desired concentration with 5% dextrose, and placebo was diluted to the same extent for each dose group.

[0416] [Table 6]

[0417] Objectives and Endpoints In some cases, the purpose of the study was to characterize differences between intravenous and subcutaneous administration (administration). In previous single-blind studies, differences in adverse events (AEs) and pharmacodynamic cardiovascular changes were observed after subcutaneous compared with intravenous administration, despite administration of the same dose and similar exposure.

[0418] In some cases, the purpose of the studies was to obtain general data on the safety, tolerability, pharmacokinetics, and pharmacodynamics of Compound 1 in healthy subjects.

[0419] In some cases, the objective of the studies was to determine the safety and tolerability of a single dose of Compound 1 administered as a continuous intravenous infusion.

[0420] In some cases, the objective of the studies was to determine the safety and tolerability of multiple doses of Compound 1 administered as daily subcutaneous injections.

[0421] In some cases, the objective of the study was to determine the single-dose intravenous and multiple-dose subcutaneous pharmacokinetics of Compound 1.

[0422] In some cases, the purpose of the studies was to investigate the metabolite patterns of Compound 1 in plasma and urine.

[0423] In some cases, the purpose of the studies was to examine the relationship between the pharmacokinetics and pharmacodynamics of Compound 1 in healthy subjects.

[0424] In some cases, study endpoints include: vital signs (e.g., supine blood pressure, pulse, and temperature), electrocardiogram (ECG) (e.g., interval, rhythm, and morphology), cardiac function (e.g., cardiac output using echocardiography), peripheral blood flow / tissue perfusion (e.g., by skin color), venous blood gases (e.g., lactate), urine output, clinical chemistry, hematology, hemostasis, and urinalysis, adverse events (AEs) (e.g., type, frequency, and intensity), pharmacokinetics (e.g., AUC, AUC t, AUCτ, % Extrap AUC, C max , t max , C.L., V. z , t 1 / 2 , MRT, V ss , F, Ae, and CLR), and the metabolite patterns in plasma and urine.

[0425] result In general, compound 1 was delivered systemically and produced systemic effects when administered to healthy individuals via IV infusion and SC (bolus) injection. However, there was little (e.g., approximately 0-15%) formation of Ml after compound 1 was administered to healthy humans via intravenous infusion (Figure 44, panel A), whereas the concentrations of compound 1 and Ml were nearly equimolar after compound 1 was administered to healthy humans via subcutaneous (bolus) injection (Figure 44, panel B). Specifically, both human and rat data indicate that after SC (bolus) injection, approximately 80-90% of compound 1 was converted to Ml (e.g., within the subcutaneous space). These results indicate that a significant amount of Ml (a full (Vl) agonist) was formed after SC (bolus) injection but not after IV infusion, providing an explanation for why healthy humans administered compound 1 via SC (bolus) injection experience more adverse events than healthy humans receiving compound 1 via IV infusion.

[0426] Summary of tolerability and adverse events (AEs): After intravenous infusion in Period 1, 94 treatment-emergent adverse events (TEAEs) occurred in 35 of 48 active-treatment subjects and 8 TEAEs occurred in 5 of 16 placebo subjects. After subcutaneous administration in Period 2, 87 TEAEs occurred in 9 active-treatment subjects and 4 TEAEs occurred in 3 of 4 placebo subjects. In Period 1, 87 TEAEs reported by 34 active-treatment subjects and 6 TEAEs reported by 3 placebo subjects were considered adverse drug reactions (ADRs) (e.g., reasonably assessed as possibly related to treatment). One AE reported by one subject in the 0.1 mg dose group was judged to be severe. No serious AEs occurred, and none of the AEs led to death or study discontinuation. In Period 2, all 87 TEAEs reported by nine subjects in the active treatment group and all four TEAEs reported by three subjects in the placebo group were considered ADRs. Three AEs reported by three subjects in the 0.1 mg dose group and two AEs reported by one subject in the 0.3 mg group were judged to be severe, and one AE reported by one subject in the 0.3 mg group was judged to be serious and led to discontinuation of the study for that subject. None of the AEs resulted in death. The majority of TEAT events during intravenous and subcutaneous administration in women and men were mild or moderate in intensity. Six events were reported as severe in intensity: one event of bradycardia reported after intravenous injection of 0.1 mg, three events of abdominal pain reported after subcutaneous administration of 0.1 mg, and one event of abdominal pain and one event of back pain, both reported by the same subject after subcutaneous administration of 0.3 mg. One event of elevated troponin I levels reported after a subcutaneous dose of 0.3 mg was reported as serious.

[0427] Pharmacokinetics: The median time to reach maximum serum concentration after 6-hour intravenous infusion was 5 to 6 hours for all dose groups (see Figure 2). AUC and C max increased with increasing dose, and AUC and C maxAnalysis of dose proportionality for 0.6 mg and 0.9 mg showed proportionality for both parameters over the dose range of 0.1 to 0.9 mg. The harmonic mean elimination half-lives were slightly longer in the 0.6 and 0.9 mg dose groups compared to the other dose groups, at approximately 1.5 and 1.7 hours, respectively, which had similar mean t 1 / 2 Other dose-independent pharmacokinetic parameters were comparable among the five doses.

[0428] Pharmacokinetic results for Compound 1 iv infusion are shown in Table 7.

[0429] [Table 7]

[0430] sc:AUC and C max increased with increasing dose after both the first and fifth doses (see Figures 3A and 3B), with a slightly longer elimination half-life in the 0.3 mg dose group (see Table 8). There was no evidence of accumulation of Compound 1 after repeated administration of any of the dose groups (see Table 8). After the first and fifth subcutaneous doses, the median t max The time to release was approximately 0.3-0.4 hours for both the 0.1 and 0.3 mg dose groups (see Table 8). The absolute subcutaneous bioavailability of Compound 1 was estimated from the intravenous data in Period 1 and the repeated subcutaneous administration in Period 2. The bioavailability of Compound 1 after repeated subcutaneous injections was estimated to be 18%. The pharmacokinetic results of Compound 1 sc injection are shown in Table 8. The AUC and C after the first and fifth administered subcutaneous doses were max The dose proportionality analysis of C was performed only after the fifth dose. max While possible dose proportionality was observed for AUC after both the first and fifth doses and C after the first dose, max was shown to be greater than proportional and higher.

[0431] [Table 8]

[0432] Pharmacodynamics: Diastolic Blood Pressure (iv): Diastolic blood pressure increased during the intravenous infusion in response to all five doses of Compound 1 (Figures 4A and 4B), reaching a plateau after approximately 2 hours. Absolute and relative increases were comparable across doses, with maximum mean increases of 15 (25%), 16 (24%), 12 (17%), 13 (19%), and 12 (19%) mmHg for the 0.1, 0.3, 0.45, 0.6, and 0.9 mg doses, respectively, with large interindividual variability. After completion of the infusion, diastolic blood pressure returned to near baseline values ​​within approximately 2 hours.

[0433] Diastolic Blood Pressure (sc): After subcutaneous administration, there was a similar reversible increase in diastolic blood pressure across all doses in both the 0.1 and 0.3 mg dose groups (Figures 5A and 5B). The maximum mean increase over 5 days of dosing was 16-21 (30-40%) and 8-16 (10-22%) mmHg for the 0.1 and 0.3 mg doses, respectively (Figures 5A and 5B), although there was large interindividual variability. The mean absolute levels and mean changes after each of the 5 doses were similar, indicating no evidence of cumulative effects or sensitization / desensitization of this pharmacodynamic effect.

[0434] Systolic Blood Pressure (iv): The effect of Compound 1 on systolic blood pressure was not significant compared to diastolic blood pressure, either absolutely or relatively, with maximum mean increases after intravenous infusion of 13 (13%), 12 (11%), 12 (11%), 12 (11%), and 13 (13%) mmHg for the 0.1, 0.3, 0.45, 0.6, and 0.9 mg doses, respectively (Figures 6A and 6B), and increases were comparable across all doses.

[0435] Systolic Blood Pressure (sc): After subcutaneous administration of the 0.1 and 0.3 mg doses, there was a reversible increase in systolic blood pressure, but it was not significant compared with diastolic blood pressure (Figures 7A and 7B). The maximum mean increase over 5 days of administration was 10-17 (11-18%) and 4-19 (4-17%) mmHg for the 0.1 and 0.3 mg doses, respectively, although there was large interindividual variability. Similar mean absolute levels and mean changes after each of the five doses indicated no cumulative effect or sensitization / desensitization of this pharmacodynamic effect.

[0436] Mean arterial pressure: The overall changes in mean arterial pressure after intravenous and subcutaneous injections were similar to those for diastolic blood pressure (Figures 8A and 8B) (e.g., because the latter parameter has a greater weight in the calculation than systolic pressure). The maximum mean increases after intravenous infusion were 13 (18%), 14 (18%), 12 (14%), 13 (15%), and 12 (16%) mmHg for the 0.1, 0.3, 0.45, 0.6, and 0.9 mg doses, respectively, and 14–18 (21–27%) and 6–18 (6–21%) mmHg for the 0.1 and 0.3 mg subcutaneous doses over the 5 days of subcutaneous administration.

[0437] Pulse Rate: Reversible decreases in pulse rate were observed after intravenous infusion and repeated subcutaneous administration (Figures 9A, 9B, 10A, and 10B). The maximum mean decreases after intravenous infusion were 17 (25%), 17 (21%), 17 (23%), 13 (19%), and 14 (21%) bpm for the 0.1, 0.3, 0.45, 0.6, and 0.9 mg doses, respectively. Over 5 days of subcutaneous administration, the decreases were 18–20 (26–29%) and 16–21 (22–28%) bpm for the 0.1 and 0.3 mg doses, respectively. After the end of the infusion, pulse rate rapidly returned to baseline. Placebo-treated subjects also showed a small decrease in pulse rate during the infusion (Figures 9A, 9B, 10A, and 10B).

[0438] Peripheral Blood Flow: Pallor was reported in 18 active-treatment subjects after intravenous infusion, primarily in the 0.45, 0.6, and 0.9 mg dose groups. Skin color generally returned to normal approximately 4 to 6 hours after completion of the intravenous infusion. Hyperemia was reported in one subject in the 0.45 mg dose group at 30 and 90 minutes after intravenous infusion. Approximately 30% of subjects in the 0.1 and 0.3 mg subcutaneous dose groups reported pallor after the first dose, with skin color returning to normal 4 hours after administration. Pallor was also reported by one subject in both dose groups during the first 2 hours after administration of the second and third doses, but not after the fourth and fifth doses.

[0439] Cardiac Output: Cardiac output following intravenous infusion during Period 1 was decreased in active-treated subjects compared with placebo, except for subjects in the 0.1 mg dose group, with no apparent dose-related trends or changes in the echocardiographic parameters evaluated. One event of a moderate decrease in cardiac output was reported as an AE following intravenous infusion in the 0.1 mg dose group. None of the changes in cardiac output met the predefined stopping criteria. Similarly, after subcutaneous administration, slight decreases in cardiac output parameters were observed in active-treated subjects in both dose groups. No abnormal values ​​were reported for any of the echocardiographic parameters evaluated after repeated subcutaneous administration.

[0440] Urine Volume: There were no clear dose-related trends or changes in urine volume after intravenous or subcutaneous injection in any dose group. Large interindividual differences in urine volume were seen in both females and males within the dose groups.

[0441] Urinary Compound 1 Excretion (iv): Compound 1 was excreted in urine by 24 hours after intravenous infusion in all five dose groups. The largest amounts of Compound 1 (approximately 3, 9, 16, 24, and 37 μg, respectively) were excreted between 4 and 8 hours after the start of infusion in each dose group (FIG. 11). Overall, less than 10% of the dose was excreted unchanged in urine after iv administration.

[0442] Injection site reactions: Erythema, pallor, and pruritus of mild severity were reported by several subjects in the active treatment group, with the majority of events occurring immediately after subcutaneous (bolus) injection. Moderate edema and mild pain were reported by one subject in the 0.1 mg dose group 30 minutes after administration.

[0443] Excretion of Compound 1 in urine (sc): After subcutaneous injection, Compound 1 was excreted in urine by 8 hours after injection of the first and fifth 0.1 mg doses, and by 24 hours after the first and fifth 0.3 mg doses. The maximum amount of Compound 1 was excreted during the first 4 hours after both the first and fifth doses in both dose groups (Figures 12A and 12B). After the first dose, approximately 2 and 3 μg of Compound 1 were excreted, respectively, and after the fifth dose, approximately 0.3 and 1.5 μg were excreted (Figures 12A and 12B). Overall, less than 5% of the dose was excreted unchanged in urine.

[0444] Metabolism: Analysis of human plasma from the 0.1, 0.6, and 0.9 mg iv dose groups and both sc groups using high-resolution mass spectrometry showed the presence of the active metabolite M1 (a full (V1a) agonist) after both iv and sc administration, with only one observation of metabolite M5. Analysis of metabolites in human urine was not possible due to interference with the analytical method. After iv administration, metabolite M1 was present at only low concentrations in one male subject and four female subjects in the 0.6 mg dose group, while it was present in all females and five of six males in the 0.9 mg dose group, with some exceptions below the LOQ (Figure 27, Panel A). Mean C max was just above the LOQ in the range 0.1-0.25 ng / mL, occurred at approximately 5 hours, corresponded to approximately 1-2% of the concurrent Compound 1 concentration, and had a harmonic mean elimination half-life of approximately 4 hours. In contrast, after sc administration of 0.1 mg and 0.3 mg Compound 1, Ml concentrations and exposures were comparable to Compound 1 in both dose groups after the first and final doses (Figure 27, panel B) (Figures 13A, 13B, 3A, 3B; Table 9, cf. Table 7). max The mean elimination half-life was approximately 0.5 to 1.5 hours, and the harmonic mean elimination half-life was approximately 1.5 to 2 hours. The PK summary for metabolite M1 (sc injection) is shown in Table 9.

[0445] [Table 9]

[0446] Example 2: Potent and selective mixed V1AR agonist-antagonists In some cases, the binding data provided herein below show that Compound 1 binds to a given receptor with either its agonist portion or its antagonist portion, and across the population of vasopressin receptors occupied by Compound 1, some portions are occupied by the agonist portion while other portions are occupied by the antagonist portion, resulting in, for example, effective partial agonism of the receptor and limiting the maximum vasoconstriction observed.

[0447] Methods and Materials Cell Lines. Tests were performed using cell lines expressing rat (r) or human (h) V1a, V1b, V2, or OT receptors. For experiments with human receptors, human embryonic kidney (HEK)-flp-in cells stably expressing a lacZ-Zeocin™ fusion gene were used to express hV1a and hV1b. These cells were designed for use with the Flp-In™ expression vector containing the gene of interest (hV1a or hV1b herein) and the Flp recombinase expression plasmid pOG44. For hV2 and hOTR, HEK-293 cells transiently expressing hV2 were used. For experiments with rat receptors, A7r5 rat thoracic aortic smooth muscle cells endogenously expressing rV1a (ATCC), FLP-In 293 (HEK-293) cells stably expressing rV1b, HEK-293 cells transiently transfected with rV2 (ATCC), and Chinese hamster ovary (CHO)-K1 cells transiently expressing rOTR (ATCC) were used.

[0448] Cell maintenance. HEK-flp-in cells were maintained in Dulbecco's modified Eagle's medium (DMEM) containing 10% (v / v) heat-inactivated fetal bovine serum (FBS), 4 mM GlutaMAX™-I, and 25 μg / mL hygromycin B at 37°C under 5% CO2 in a humidified atmosphere. Culture medium for hV1b-expressing cells also contained 100 U / mL penicillin and 100 μg / mL streptomycin. HEK-293 cells transiently expressing hV2 were maintained in DMEM containing 10% (v / v) heat-inactivated FBS and 4 mM L-glutamine or GlutaMAX-I at 37°C under 5% CO2 in a humidified atmosphere. CHO-K1 cells stably expressing hOTR were maintained in DMEM-F12 supplemented with 5% (v / v) heat-inactivated FBS, 2 mM L-glutamine or GlutaMAX-I, and 900 μg / mL G418 sulfate at 37°C in a humidified atmosphere with 5% CO2. A7r5 cells were maintained in DMEM supplemented with 10% (v / v) heat-inactivated FBS, 4 mM GlutaMAX-I, and 3°C in a humidified atmosphere with 5% CO2. The day before the assay, cells were removed from culture flasks using trypsin-EDTA, collected in the medium used for cell culture, and plated at 7.5 x 10 cells per well in 384-well (for V1a) or 96-well (for other receptors) poly-d-lysine-treated plates at 20 μL / well for rV1a. 4 For cells, hV1a was 2.5x10 in 20µL / well. 4 For cells, all other receptors were 4-5x10 in 100µL / well. 4 were seeded with cells.

[0449] Test Compounds. Compound 1 (97.3% peptide purity) and AVP (reference agonist) were used in functional cell-based assays. Compounds were prepared as 10 mM stock concentrations (or 5 mM in the case of AVP) in 100% DMSO, stored at -20°C, and thawed immediately before assay. Compounds were serially diluted to 10x working solutions in cell culture medium. A blank consisting of dilution medium supplemented with 0.1% (v / v) DMSO was also used as a control in each test. No inhibitory effect of DMSO was observed at 0.1%. For contractility assays, compound 1 was formulated as a 23.5 μM stock solution in physiological saline (PSS; 120 mM NaCl, 4.6 mM KCl, 1.5 mM NaH2PO4·1H2O, 0.7 mM Na2HPO4, 11.5 mM D-glucose, 25 mM NaHCO3, 2.4 mM CaCl2, 1.2 mM MgCl2 [pH 7.35–7.45]). The stock solution was serially diluted in PSS to allow for further 1 / 100 dilutions, such that compound was added cumulatively from lowest to highest concentration to the test apparatus to obtain the final test concentration.

[0450] Functional cell-based assays. Fluorometric Imaging Plate Reader (FL1PR) calcium assays were performed to detect activity generated by binding of test compounds to endogenous rV1a receptors or stably expressed hV1a receptors. Briefly, real-time fluorescence of an intracellular calcium-sensitive dye was measured immediately after the addition of test compounds at various concentrations. The endogenous ligand for V1a, AVP, was used as the reference agonist. Reporter gene assays were used to monitor agonist-induced activity at human and rat V1b, V2, and OT receptors. Cells expressing the receptors of interest were transiently transfected with a luciferase reporter gene under the control of a transcriptional regulatory element responsive to receptor activation. Luciferase gene expression was determined after 5 hours of incubation with various concentrations of test compounds. AVP was used as the reference agonist in the V1b assay, desmopressin (dDAVP) was used as the reference agonist in the V2R assay, and carbetocin was used as the reference agonist in the OT receptor assay. For V1a receptor responses, the area under the curve of the real-time calcium trace, expressed as relative fluorescence units, was determined. For V1b, V2, and OT receptor responses, luciferase activity was expressed as light emissions per second. Compound potency was expressed as the concentration that produced a half-maximal response (EC50), calculated by four-parameter nonlinear regression analysis of concentration-response curves using ActivityBase™ software. Efficacy was expressed relative to the maximal response of the reference agonist for each assay (AVP for V1a and V1b, dDAVP for V2R, and carbetocin for OTR).

[0451] Arterial contractility assay. Resistance arteries were isolated from human mesenteric tissue and dissected under a stereomicroscope while immersed in carbogen-aerated PSS maintained at 37°C. Arterial segments (2 mm) were mounted between two glass cannulae in a 7-mL tissue bath containing aerated PSS within a pressure myograph system. The artery was gradually pressurized to 60 mmHg. Arterial contractility was stabilized by potassium-induced depolarization with three consecutive exposures to a solution with a high potassium concentration (PSS with 124.34 mM KCl and no NaCl; 124K+PSS), each followed by a bath wash with aerated PSS. Cumulative concentration-response curves (CCRCs) were then generated for the compounds. The artery was immersed in aerated PSS containing an initial compound concentration (0.1 nM Compound 1), and each subsequent dose was added without drainage, taking into account the amount of compound already present in the chamber when calculating the final concentration. The concentrations used were 0.1, 0.3, 1, 3, 10, 32, and 100 nM Compound 1. Only a single CCRC was generated in each arterial segment tested. Contractile activity was determined by measuring the arterial outer diameter in response to each 124K+PSS depolarization and each compound concentration using digital video edge detection. Throughout the experiment, vessel diameter data were continuously collected using DMT Vessel Acquisition Suite software. For each 124K+PSS stimulus or compound concentration, data were collected until the vessel diameter was determined to have reached a plateau before proceeding to the next experimental step. The vessel diameter (in milliliters) of each arterial specimen was analyzed using a Microsoft Excel template. Data collected in response to three 124K+PSS depolarization cycles were initially used to determine arterial stability. The contraction induced by the final stimulus (the third 124K+PSS) was then used as each artery's internal reference response (i.e., 100% contraction) for reporting contractile activity. Arteries that failed to stabilize with three cycles of depolarization-induced contraction were excluded from the study.

[0452] result Functional cell-based assay: When examining the effect of Compound 1 on the hV1a receptor, activity was observed with a mean EC 50At 1 nM, Compound 1 reached an average of 39% MPE relative to activity by AVP (Table 14), indicating that Compound 1 acts as a partial agonist at the V1a receptor. The %MPE reached a plateau at a concentration of 1 nM Compound 1, and there was no increase in %MPE in response to further increases in concentration (Figure 19). Partial agonism indicates that treatment with Compound 1 results in vasoconstriction of splanchnic vessels in individuals with portal hypertension, e.g., reducing portal vein blood flow and pressure and improving the patient's systemic hemodynamics, with a lower risk of ischemia than full (V1a) agonists. In addition, Compound 1 is selective for the hV1a receptor over a wide range of concentrations, with much higher EC2s at hV1b, hV2, and hOT receptors than at the V1a receptor. 50 (Table 14). Similar results were observed for potency and activity at rat vasopressin receptors (Table 19). The dose-response curves for Compound 1 activity at hV1a and hV2 receptors were also different, with Compound 1 showing 600-fold higher potency at hV1a than at hV2 (Figure 20). Compound 1 induced a higher maximal response at V2 (74% MPE) than at V1a receptors (39% MPE), but this occurred at a concentration approximately 1000-fold higher than the lowest concentration that induced a maximal response at V1a receptors (no V2 response was observed) (Figure 20). Thus, at clinically relevant concentrations, Compound 1 has little activity at human V2 receptors.

[0453] [Table 10]

[0454] [Table 11]

[0455] Arterial contractility assay: Treatment of human mesenteric resistance arteries with Compound 1 resulted in an attenuated maximal response (40.0%) compared to the maximal depolarization achieved by potassium (expected to approximate the contraction induced by the endogenous ligand, AVP) (Figure 21), helping to confirm that Compound 1 acts as a partial agonist at the V1a receptor.

[0456] Example 3: Ml formation is reduced after SC injection To reduce metabolite (Ml) formation after subcutaneous administration, a compound described herein (e.g., Compound 1) was administered to healthy individuals by subcutaneous injection. In contrast to subcutaneous (bolus) injection, little (e.g., less than 20%) metabolite Ml was formed after subcutaneous injection of a composition containing a compound described herein (e.g., Compound 1) into healthy rats and minipigs. The results provided herein demonstrate that metabolite (Ml) formation can be substantially reduced by subcutaneous injection of a composition containing a compound described herein (e.g., Compound 1).

[0457] Protocol - Single-Dose Subcutaneous Infusion Study in Rats and Minipigs A composition containing 6 milligrams per milliliter (mg / mL) of Compound 1 was continuously infused (subcutaneously via a mini-osmotic pump) into 36 rats over a 24-hour period. Each rat received 200 microliters (μL) of the composition for a total dose of 4.8 mg / kg of Compound 1. The incision for the mini-pump was made on the cranial right side of the spine, and a trocar or hemostat was inserted to form a subcutaneous pocket. The pump was inserted into the pocket with the delivery port facing cranially. The dose was administered to the central dorsal area by surgically implanting a pump filled with the test article. After implantation, a 4 cm x 4 cm area surrounding the pump was demarcated and designated as the test site. Sites were then demarcated and designated as needed.

[0458] Blood samples were collected from each rat at various time points, including 0.25 hours (hr), 1 hour, 3 hours, 7 hours, 24 hours, 25 hours, 27 hours, and 29 hours. Plasma samples were analyzed for concentrations of Compound 1 and Ml using validated analytical procedures.

[0459] Using a similar procedure, concentrations of Compound 1 and M1 were assessed in minipigs after subcutaneous ...

Claims

1. A method of regulating mean arterial pressure (MAP) in an individual (e.g., in need thereof), comprising subcutaneously injecting into said individual (e.g., in need thereof) a composition comprising an (effective) amount of a compound, wherein said compound is a mixed vasopressin receptor 1A (V1AR) agonist-antagonist.

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

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

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

5. 5. The method of any one of claims 1 to 4, wherein said modulating mean arterial pressure (MAP) in said individual comprises increasing MAP by at least 5% above baseline.

6. 6. The method of any one of claims 1 to 5, wherein the modulation of mean arterial pressure (MAP) in the individual comprises increasing MAP by at least 5 mmHg (e.g., by 5 mmHg or more, or by 10 mmHg or more) above baseline.

7. The compound has the structure of Formula I: D1-L-D2 Formula I or a pharmaceutically acceptable salt thereof (In the formula: D1 is a vasopressin receptor 1A (V1AR) agonist; D2 is a V1AR antagonist; The method of any one of claims 1 to 6, wherein L is a linker.

8. A method of regulating mean arterial pressure (MAP) in an individual (e.g., in need thereof), comprising administering an effective amount of a compound having a structure according to Formula I: D1-L-D2 Formula I or a pharmaceutically acceptable salt thereof (In the formula: D1 is a vasopressin receptor 1A (V1AR) agonist; D2 is a V1AR antagonist; L is a linker. into said individual (e.g., in need thereof).

9. 9. The method of claim 8, wherein D1 is selective for V1AR over V2R.

10. 10. The method of claim 8 or 9, wherein D1 is or comprises a (e.g., cyclic) peptide.

11. The method of any one of claims 8 to 10, wherein D1 is or comprises a cyclic nonapeptide.

12. D1 has the following structure: 【Chemical 1】 12. The method of any one of claims 8 to 11, comprising or comprising:

13. 13. The method of any one of claims 8 to 12, wherein D2 is or comprises a (e.g. linear) peptide.

14. The method of any one of claims 8 to 13, wherein D2 is a linear polypeptide comprising about 7 or more amino acid residues.

15. D2 has the following structure: 【Chemistry 2】 15. The method of any one of claims 8 to 14, comprising or comprising:

16. The method of any one of claims 8 to 15, wherein L is a non-hydrolyzable linker.

17. 17. The method of any one of claims 8 to 16, wherein L comprises one or more linker groups, each linker independently selected from the group consisting of substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl.

18. The method of any one of claims 8 to 17, wherein L is a bond, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.

19. The method of any one of claims 8 to 18, wherein L is or comprises substituted or unsubstituted heteroalkyl.

20. 20. The method of any one of claims 8-19, wherein L is heteroalkyl (e.g., alkylamine) substituted with one or more substituents, each substituent being independently selected from the group consisting of oxo, amino, and substituted heteroalkyl (e.g., alkylamine substituted with oxo).

21. 21. The method of any one of claims 8 to 20, wherein L is or comprises one or more (e.g. modified) amino acid residues.

22. L has the following structure: 【Chemistry 3】 22. The method of any one of claims 8 to 21, comprising or comprising:

23. The method of any one of claims 8 to 22, wherein the compound is Compound 1, or a pharmaceutically acceptable salt thereof.

24. A method for regulating mean arterial pressure (MAP) in an individual (e.g., in need thereof), comprising subcutaneously injecting into said individual (e.g., in need thereof) a composition comprising an (effective) amount of Compound 1, or a pharmaceutically acceptable salt thereof.

25. The method of any one of claims 1 to 24, wherein the composition further comprises a liquid vehicle or solvent (e.g., water or an aqueous vehicle).

26. 26. The method of any one of claims 1 to 25, wherein the method further comprises securing a subcutaneous infusion device to the skin of the individual, the subcutaneous infusion device comprising a chamber body and a hollow tube body, the composition configured to be within the chamber body, the hollow tube body comprising a first opening and a second opening, the first opening being in fluid communication with the chamber body and the second opening being configured to be subcutaneously located within the individual after securing the subcutaneous infusion device to the skin.

27. 27. The method of claim 26, wherein the subcutaneous infusion device further comprises a pump configured to subcutaneously infuse the composition into the individual at a constant or variable rate.

28. A method for regulating mean arterial pressure (MAP) in an individual (e.g., in need thereof), comprising subcutaneously injecting an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, into the individual (e.g., in need thereof).

29. A method of regulating mean arterial pressure (MAP) in an individual (e.g., in need thereof), comprising subcutaneously administering to said individual (e.g., in need thereof) a composition comprising an (effective) amount of a compound, wherein said compound is a mixed vasopressin receptor 1A (V1AR) agonist-antagonist.

30. A method of regulating mean arterial pressure (MAP) in an individual (e.g., in need thereof), comprising administering an effective amount of a compound having a structure according to Formula I: D1-L-D2 Formula I or a pharmaceutically acceptable salt thereof (In the formula: D1 is a vasopressin receptor 1A (V1AR) agonist; D2 is a V1AR antagonist; L is a linker. to said individual (e.g., in need thereof) subcutaneously administering a composition comprising:

31. A method for regulating mean arterial pressure (MAP) in an individual (e.g., in need thereof), comprising subcutaneously administering to the individual (e.g., in need thereof) a composition comprising an (effective) amount of Compound 1, or a pharmaceutically acceptable salt thereof.

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

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

34. 34. The method of any one of claims 1 to 33, wherein when the composition is administered subcutaneously to the individual (e.g., by subcutaneous (bolus) injection or subcutaneous infusion), less than 50% of the compound of formula I degrades (e.g., subcutaneously) to form Ml.

35. 35. The method of any one of claims 1 to 34, wherein when the composition is administered subcutaneously to the individual (e.g., by subcutaneous (bolus) injection or subcutaneous infusion), less than 30% of the compound of formula I degrades (e.g., subcutaneously) to form Ml.

36. 36. The method of any one of claims 1 to 35, wherein when the composition is injected subcutaneously into the individual, less Ml is formed compared to administration of an otherwise identical composition administered by subcutaneous (bolus) injection.

37. 37. The method of any one of claims 1 to 36, wherein when the composition is injected subcutaneously into the individual, less Ml is formed systemically compared to administration of an otherwise identical composition administered by subcutaneous (bolus) injection.

38. 38. The method of any one of claims 1 to 37, wherein when the composition is injected subcutaneously into the individual, less Ml is formed locally (at the injection / infusion site) compared to administration of an otherwise identical composition administered by subcutaneous (bolus) injection.

39. 39. The method of any one of claims 1 to 38, wherein subcutaneous injection of the composition into the individual improves tolerability compared to subcutaneous (bolus) injection (e.g., due to reduced Ml overproduction subcutaneously).

40. 40. The method of any one of claims 1 to 39, wherein subcutaneous injection of the composition into the individual reduces undesired systemic events (e.g., undesired vasoconstriction, e.g., leading to ischemia), reduces undesired administration site events (e.g., local site vasoconstriction, e.g., leading to administration site ischemia), or both.

41. 41. The method of any one of claims 1 to 40, wherein the composition is continuously infused subcutaneously into the individual for at least 1 hour.

42. 42. The method of any one of claims 1-41, wherein the composition is infused subcutaneously into the individual at a rate of about 0.005 milliliters per hour (mL / hr) to about 1 mL / hr for the administration period.

43. The method of any one of claims 1 to 42, wherein the composition comprises a buffer.

44. 44. The method of claim 43, wherein the buffer is selected from the group consisting of acetate buffer, succinate buffer, and citrate buffer.

45. 45. The method of any one of claims 1 to 44, wherein the composition comprises a buffering agent at a concentration of from about 1 millimolar (mM) to about 1 molar (M).

46. 46. ​​The method of any one of claims 1 to 45, wherein the composition comprises a buffering agent at a concentration of about 5 mM to about 250 mM.

47. 47. The method of any one of claims 1 to 46, wherein the composition comprises a buffering agent at a concentration of about 5 mM to about 25 mM.

48. 47. The method of any one of claims 1 to 46, wherein the composition comprises a buffering agent at a concentration of about 50 mM to about 250 mM.

49. 49. The method of any one of claims 1 to 48, wherein the composition has a pH of from about 4 to about 8.

50. 50. The method of any one of claims 1 to 49, wherein the composition has a pH of from about 4 to about 6.

51. 51. The method of any one of claims 1 to 50, wherein the composition has a pH of about 4.5 to about 5.

52. 52. The method of any one of claims 1-51, wherein the compound is administered to the individual (e.g., continuously) in an amount of from about 0.001 milligrams (mg) to about 100 mg, for example, over a period of one or more days.

53. 53. The method of any one of claims 1-52, wherein the composition comprises the compound at a concentration of about 0.001 milligrams per milliliter (mg / mL) to about 100 mg / mL.

54. 54. The method of any one of claims 1 to 53, wherein the composition comprises the compound at a concentration of about 0.1 mg / mL to about 100 mg / mL.

55. 55. The method of any one of claims 1 to 54, wherein the composition comprises the compound at a concentration of about 1 mg / mL to about 10 mg / mL.

56. 56. The method of any one of claims 1 to 55, wherein the composition further comprises a preservative.

57. 57. The method of claim 56, wherein the preservative is present in an amount of about 1 mg / mL to about 20 mg / mL.

58. 58. The method of any one of claims 1 to 57, wherein the composition further comprises a solubilizing agent.

59. 59. The method of claim 58, wherein the solubilizing agent is present in an amount of about 1 mg / mL to about 250 mg / mL (e.g., about 60-80 mg / mL).

60. 60. The method of any one of claims 1 to 59, wherein said compound is administered (continuously) to said individual in need thereof at a dose of about 0.1 mg / day to about 100 mg / day.

61. 1. A method of reducing (the incidence of) local vasoconstriction, e.g., (injection site) ischemia, in an individual in need thereof, comprising administering to a subject a compound having a structure according to Formula I, or a pharmaceutically acceptable salt thereof: D1-L-D2 Formula I or a pharmaceutically acceptable salt thereof (In the formula: D1 is a vasopressin receptor 1A (V1AR) agonist; D2 is a V1AR antagonist; L is a linker. to said individual in need thereof.

62. 1. A method of regulating mean arterial pressure (MAP) in an individual in need thereof, comprising: The method comprises administering to the individual in need thereof a compound having a structure represented by Formula I, or a pharmaceutically acceptable salt thereof: D1-L-D2 Formula I or a pharmaceutically acceptable salt thereof (In the formula: D1 is a vasopressin receptor 1A (V1AR) agonist; D2 is a V1AR antagonist; L is a linker. subcutaneously injecting a composition comprising A method in which less than 50% of the compound of formula I is degraded (eg, subcutaneously).

63. 63. The method of any one of claims 1 to 62, wherein the MAP of the individual is increased following subcutaneous administration of Compound 1 (e.g., compared to a pre-treatment baseline measurement).

64. 64. The method of any one of claims 1 to 63, wherein the MAP of the individual is increased by about 1% to about 10% (e.g., compared to a baseline measurement before treatment) after administering to the individual a compound of any one of claims 1 to 63, or a pharmaceutically acceptable salt thereof.

65. 65. The method of any one of claims 1 to 64, wherein the MAP of the individual increases in a dose-dependent manner after administering to the individual a compound of any one of claims 1 to 64, or a pharmaceutically acceptable salt thereof.

66. 66. The method of any one of claims 1 to 65, wherein the diastolic blood pressure of the individual is increased (e.g., compared to a pre-treatment baseline measurement) after administration of the compound of any one of claims 1 to 65, or a pharmaceutically acceptable salt thereof, to the individual.

67. 67. The method of any one of claims 1 to 66, wherein the systolic blood pressure of the individual is increased (e.g., compared to a baseline measurement before treatment) after administration of the compound of any one of claims 1 to 66, or a pharmaceutically acceptable salt thereof, to the individual.

68. 68. The method of any one of claims 1 to 67, wherein the diastolic and / or systolic blood pressure of the individual is increased in a dose-dependent manner after administration of a compound of any one of claims 1 to 67, or a pharmaceutically acceptable salt thereof, to the individual.

69. 69. The method of any one of claims 1 to 68, wherein the pulse rate and / or peripheral blood flow of the individual is decreased after administering to the individual a compound of any one of claims 1 to 68, or a pharmaceutically acceptable salt thereof.

70. 70. The method of any one of claims 1 to 69, wherein (subcutaneous) administration to said individual of a compound of any one of claims 1 to 69, or a pharmaceutically acceptable salt thereof, improves systemic hemodynamics in said individual.

71. 71. The method of any one of claims 1 to 70, wherein (subcutaneous) administration to said individual of a compound according to any one of claims 1 to 70, or a pharmaceutically acceptable salt thereof, reduces fluid retention and / or overload in said individual.

72. 72. The method of any one of claims 1 to 71, wherein the method comprises administering a compound of any one of claims 1 to 71, or a pharmaceutically acceptable salt thereof, to the individual on a first and a second day (e.g., the second day is one or more days after the first day).

73. 73. The method of any one of claims 1 to 72, wherein the individual receives an initial (e.g., intravenous infusion) dose of the compound of any one of claims 1 to 72, or a pharmaceutically acceptable salt thereof, on the first day (e.g., to acclimate the individual to vasoconstriction before receiving a first subcutaneous therapeutic dose).

74. 74. The method of any one of claims 1-73, wherein the initial (e.g., intravenous infusion) dose is from about 0.01 milligrams (mg) to about 10 mg.

75. 75. The method of any one of claims 1 to 74, wherein the compound of any one of claims 1 to 74, or a pharmaceutically acceptable salt thereof, is administered to the individual (e.g., by intravenous infusion) on said first day for a period of about 4 hours to about 8 hours (e.g., about 6 hours).

76. 76. The method of any one of claims 1 to 75, wherein the initial (e.g., intravenous infusion) dose of the compound of any one of claims 1 to 75, or a pharmaceutically acceptable salt thereof, is a low dose, for example a dose of about 5 μg / hour to about 15 μg / hour (e.g., about 8 μg / hour).

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

78. 78. The method of any one of claims 1 to 77, wherein the method comprises administering (subcutaneously) to the individual a compound of any one of claims 1 to 77, or a pharmaceutically acceptable salt thereof, once daily for 4 to 10 days (e.g. after the first day).

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

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

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

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

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

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

85. 84. The method of any one of claims 1 to 84, wherein the method comprises administering to the individual (e.g., subcutaneously) a compound of any one of claims 1 to 85, or a pharmaceutically acceptable salt thereof, in an amount of from about 0.01 milligrams (mg) per day to about 100 mg per day (e.g., from about 0.01 milligrams (mg) per day to about 10 mg per day (e.g., from about 0.01 mg / day to about 1 mg / day)).

86. 86. The method of any one of claims 1 to 85, wherein the individual has hepatorenal syndrome with HRS-AKI.

87. 87. The method of any one of claims 1 to 86, wherein the individual has end-stage liver disease (ESLD).

88. The method of any one of claims 1 to 87, wherein the individual has developed HRS-AKI as a complication of ESLD.

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

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

91. The method of any one of claims 1, 8, 24, 28-31, 61, and 62, wherein the method comprises any one of the elements of claims 2-7, 9-23, 25-27, 32-60, and 63-90.

92. 1. 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 wherein the composition is formulated for subcutaneous administration.

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

93. The composition of claim 92, having:

94. 94. The composition of claim 92 or 93, wherein the compound is Compound 1.

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

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

97. 97. The composition of any one of claims 92 to 96, wherein the composition is suitable for systemic delivery of an active agent, such as Compound 1.

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

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

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

101. 101. The subcutaneous formulation of any one of claims 98 to 100, further comprising a preservative.

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

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

104. 104. The subcutaneous formulation of any one of claims 98-103, further comprising a preservative (e.g., m-cresol) at a concentration of about 1 mg / mL to about 100 mg / mL.

105. 105. The subcutaneous formulation of any one of claims 98-104, further comprising a solubilizing agent (e.g., cyclodextrin) in an amount of about 1 mg / mL to about 250 mg / mL (e.g., about 60-80 mg / mL).

106. 106. A subcutaneous formulation according to any one of claims 98 to 105, wherein the compound of formula I is relatively resistant to degradation, for example in the subcutaneous layer of an individual to whom the formulation is administered subcutaneously.

107. 107. A subcutaneous formulation according to any one of claims 98 to 106, wherein less than 50% of the compound of formula I is degraded (e.g. in the vial and / or subcutaneously) over a period of, for example, about 1 or 2 days.

108. 108. The subcutaneous formulation of any one of claims 98-107, 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.

109. 109. The subcutaneous formulation of any one of claims 98-108, wherein the compound of formula I is present in the formulation at a concentration of from about 1 mg / mL to about 50 mg / mL.

110. 109. The subcutaneous formulation of any one of claims 98-108, further comprising a buffering agent at a concentration of about 1 millimolar (mM) to about 1 M.

111. 111. The subcutaneous formulation of any one of claims 98 to 110, further comprising a buffering agent having a pKa of about 3.0 to about 6.0, for example at 25°C.

112. 112. The subcutaneous formulation of claim 110 or 111, wherein the buffering agent is selected from the group consisting of acetate, citrate, succinate, and phosphate.

113. 113. The subcutaneous formulation of any one of claims 98 to 112, having a pH sufficient to inhibit (e.g., deactivate or inactivate) proteases (e.g., trypsin), e.g., in the subcutaneous layer of an individual to whom the formulation is administered subcutaneously.

114. 114. The subcutaneous formulation of any one of claims 98 to 113, having a pH of about 4 to about 5 (e.g., about 4.5).

115. 115. The subcutaneous formulation of any one of claims 98 to 114, having an ionic strength of about 5 mM to about 200 mM (e.g., about 10 mM to about 100 mM).

116. 116. The subcutaneous formulation of any one of claims 98 to 115, wherein the pH of the subcutaneous formulation does not (substantially) change when administered subcutaneously to an individual (e.g. by subcutaneous (bolus) injection or subcutaneous infusion).

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

118. The system of claim 117, wherein the system includes an adhesive for (e.g., reversibly) securing the (subcutaneously injected) device to the surface of the skin of the individual.

119. 119. The system of claim 117 or 118, wherein the system includes a chamber body and a hollow tube body, and the composition is configured to be within the chamber body.

120. 120. The system of any one of claims 117 to 119, wherein the hollow tube body includes a first opening and a second opening.

121. The system of any one of claims 117 to 120, wherein the first opening is in fluid communication with the chamber body.

122. A system according to any one of claims 117 to 121, wherein the second opening is configured to be subcutaneously located within the individual after the subcutaneous infusion device is secured to the skin of the individual.

123. 123. The system of any one of claims 117 to 122, wherein the (subcutaneous infusion) device further comprises a pump configured to subcutaneously infuse the composition into the individual at a constant or variable rate.

124. 124. The system of any one of claims 117 to 123, wherein the system is configured to provide the composition to the individual (continuously) for a period of about 24 hours or more.

125. 125. The system of any one of claims 117 to 124, wherein the device is configured to receive a vial and / or cartridge of the composition.

126. The system of any one of claims 117 to 125, wherein the device is a subcutaneous infusion device (e.g., a pump).

127. A system according to any one of claims 117 to 126, wherein the composition is a composition or formulation according to any one of claims 1 to 126.

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