Mixed vasopressin receptor agonist-antagonist for treating end-stage liver disease and complications associated thereof

Abstract

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

Description

MIXED VASOPRESSIN RECEPTOR AGONIST- ANTAGONIST FOR TREATING END-STAGE LIVER DISEASE AND COMPLICATIONS ASSOCIATED THEREOFCROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 378,014, filed September 30, 2022, U.S. Provisional Application No. 63 / 432,976, filed December 15, 2022, and U.S. Provisional Application No. 63 / 471,713, filed June 7, 2023, which are each hereby incorporated by reference in their entirety herein.BACKGROUND OF THE INVENTION

[0002] End-stage liver disease complications account for approximately 1 million deaths per year. Patients suffering from end-stage liver disease often develop portal hypertension. Ascites represents the most common decompensating event and is associated with a high risk of developing further complications which include bacterial infection and acute kidney injury (AKI).SUMMARY OF THE INVENTION

[0003] Management of decompensated cirrhosis often involves using vasoconstrictors that are full vasopressin la receptor (VI AR) agonists. Full (vasopressin V2 receptor (V2R), VI AR) agonists reduce portal pressure by increasing splanchnic arteriolar vasoconstriction, thereby redistributing blood volume to the systemic circulation which in turn can lead to increased glomerular filtration rate and improved renal perfusion. However, (non-selective) full (V2R, VI AR) agonists (e.g., having only agonist portion and no antagonist portion) can cause undesired events, such as undesired systemic events like vasoconstriction that results 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 that results in administration site ischemia, or both (e.g., when administered subcutaneously). Such events can preclude such compounds from being used for out-patient settings (e.g., at-home use), such as limiting their use to intravenous administration and short term applications in in-patient settings under close monitoring by specialists (e.g., thereby being unsuitable for chronic and outpatient setting). Moreover, given the risk profile of full (V2R, VI AR) agonists, careful titration and monitoring is often required to prevent the development of serious adverse events (AEs), such as those related to tissue hypoxia and ischemia resulting from excessive vasoconstriction.

[0004] Moreover, using (non-selective) full (VI AR, V2R) agonists, like vasopressin, to increase mean arterial pressure (MAP) by 10-15 mmHg, which strongly correlates with the reversal of HRS-AKI, is difficult. In some instances, achieving and / or maintaining an increase of MAP of 10-15 mmHg is a therapeutic goal of current therapies. Due to the pharmacokinetics of the vasopressin system and very steep concentration-response curve, it can be easier to either underdose (and lose clinical efficacy) or to produce too much vasoconstriction, which can lead to severe, potentially life-threatening adverse events (AEs). Secondarily, individuals with decompensated cirrhosis can already have high endogenous vasopressin levels, which facilitates water retention through the V2-mediated antidiuretic effect. Clinical vasopressin agonists are first V2 agonists, acting secondarily as Via agonists at pharmacologic concentrations. The inherent V2 activity might contribute to the adverse event profile related to fluid overload and respiratory complications for clinical vasopressin agonists.

[0005] Provided in some embodiments herein is a compound (e.g., a mixed agonist-antagonist) having selectivity for the Via receptor. In some embodiments, the compound reaches and maintains a (target) level of vasoconstriction and avoids fluid retention, such as through a uniform dosing profile. In some instances, the compound has a reduced incidence of (serious) adverse events and improved clinical efficacy (e.g., compared to clinical vasopressin agonists). In some instances, it is not necessary to titrate the compound, such as to achieve a reduced incidence of (serious) adverse events and improved clinical efficacy (e.g., compared to clinical vasopressin agonists). In some instances, a compound described herein (e.g., a mixed Via agonist-antagonist) is administered at a higher dose (than necessary) and effectively reaches maximum efficacy. Contrarily, administering a comparatively high dose of a non-selective full (V2, Via) agonist, like terlipressin, can become toxic and lead to (serious) adverse events.

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

[0007] In some instances, compounds described herein (e.g., mixed Via agonist-antagonists, such as Compound 1) are metabolized to a full vasopressin agonist, such as when administered subcutaneously. In some instances, formation of the full vasopressin agonist is associated with a higher risk of an individual developing adverse events, such as after subcutaneous (bolus) injection of the mixed Via agonist-antagonist. In some instances, the adverse events are systemic events, local administration site events, or both. In some embodiments, the adverse events are associated with excessive vasoconstriction. In some instances, the full vasopressin agonist is partially active (compared to the mixed Via agonist-antagonist). In some instances, administering a mixed Via agonist-antagonist described herein subcutaneously (e.g., by subcutaneous (bolus) injection) provides an overproduction of the full vasopressin agonist (e.g., in the subcutaneous space of the individual). An overproduction of the full vasopressin agonist (e.g., in the subcutaneous space of the individual) is undesirable, for example, since less of the parent compound (e.g., a mixed Via agonist-antagonist described herein, such as Compound 1) is delivered systemically, thereby increasing the risk of undesirable (systemic) events (e.g., toxicities associated with excessive (local and / or systemic) vasoconstriction), such as through full agonism of the Via receptor by the full vasopressin agonist. Additional challenges arising from overproduction of the full vasopressin agonist (e.g., in the subcutaneous space of the individual) after administration of a composition described herein include reduced effectiveness, increased side-effects, and / or difficulty controlling (e.g.. titrating) for efficacy. As shown in FIG. 32, full agonism of the vasopressin receptor(s) can induce serious side-effects and / or be lethal.

[0008] Described in some embodiments herein are methods and formulations for reducing formation of a full vasopressin agonist (e.g., Ml), such as after subcutaneous (bolus) injection of a mixed Via agonist-antagonist described herein (e.g., Compound 1). In some embodiments, reducing formation of a full vasopressin agonist (e.g., Ml), such as after subcutaneous administration of a mixed Via agonist-antagonist described herein, reduces the risk of an individual developing undesirable (systemic) events (e.g., toxicities associated with excessive (local and / or systemic) vasoconstriction), such as through full agonism of the Via receptor by the full vasopressin agonist. In some embodiments, reducing formation of a full vasopressin agonist (e.g., Ml), such as after subcutaneous administration of a mixed Via agonist-antagonist described herein, increases effectiveness of a (e.g., mixed Via agonist-antagonist) treatment described herein, decreases side-effects (e.g., associate with overproduction of the full agonist), and / or improves control (e.g.. titration) of efficacy of a (e.g., mixed Via agonist-antagonist) treatment described herein. In some embodiments, subcutaneously infusing the mixed Viaagonist-antagonist reduces metabolite (Ml) formation (e.g., as measured systemically, such as by serum / plasma concentration). In some embodiments, increasing buffer concentration of a composition comprising the mixed Via agonist-antagonist reduces metabolite (Ml) formation (e.g., as measured systemically, such as by serum / plasma concentration), such as in vitro and in vivo (e.g., after subcutaneous administration). In some embodiments, increasing the concentration of the mixed Via agonist-antagonist in the composition reduces metabolite (Ml) formation (e.g., as measured systemically, such as by serum / plasma concentration), such as in vitro and in vivo (e.g., after subcutaneous administration). In some embodiments, such as when a composition described herein is administered at a relatively slow rate of administration, subcutaneously infusing and increasing the concentration of the mixed Via agonist-antagonist in the composition reduces metabolite (Ml) formation (e.g., as measured systemically, such as by serum / plasma concentration), such as in vitro and in vivo (e.g., after subcutaneous administration). In some embodiments, any combination of subcutaneous infusion, increased buffer concentration of the composition, and increased drug concentration in the composition reduces metabolite (Ml) formation after subcutaneous administration. In some embodiments, subcutaneously infusing a compound described herein, increasing buffer concentration of a composition described herein, and / or increasing drug concentration in a composition describes herein improves systemic delivery of a mixed agonist-antagonist described herein.

[0009] Provided in some embodiments herein is a compound (e.g., a mixed VI AR receptor agonist-antagonist, such as Compound 1) that decreases portal pressure (PP) in an individual (e.g., in need thereof), such as after subcutaneous administration, without excessive vasoconstriction over a broad dose range, such as 10 pg / kg to 500 pg / kg.

[0010] Provided in some embodiments herein is a compound (e.g., a mixed Via receptor agonist-antagonist, such as Compound 1) that increases mean arterial pressure (MAP) in an individual (e.g., in need thereof), such as after subcutaneous administration. In some embodiments, the increase in MAP reaches a peak plateau, such as of about +10 to + 15 mmHg (e.g., even at doses as high as 100 to 500 pg / kg). In contrast, administration of a full, nonselective (V2, Via) receptor agonist described herein, such as terlipressin, at similarly high doses provides markedly higher increases in MAP, such as well beyond a treatment 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).

[0011] In some embodiments, a compound described herein (e.g., a mixed VI AR receptor agonist-antagonist, such as Compound 1) achieves a therapeutic ceiling (e.g., when administered subcutaneously), such that even after increasing the dose of the compound (e.g.,to doses as high as 100 to 500 pg / kg), an effect (e.g., increasing MAP) does not (significantly) change (e.g., increase or decrease).

[0012] In some instances, increasing the dose of a compound described herein (e.g., a full, nonselective (V2R, VI AR) receptor agonist, such as terlipressin) does provide a (significant) change (e.g., an increase) in an effect (e.g., MAP). In some instances, increasing doses of a compound described herein (e.g., a full, non-selective (V2, VI AR) receptor agonist, such as terlipressin) continues pushing an effect (e.g., MAP) into levels that can be detrimental and / or can lead to (severe) side effects in the individual receiving the compound.

[0013] In some instances, increasing a dose of a mixed Via agonist-antagonist described herein, such as Compound 1, does not continue increasing MAP in an individual (e.g., even at doses as high as 100 to 500 pg / kg), whereas increasing a dose of a full, nonselective (V2, Via) agonist, such as terlipressin, does continue increasing MAP in an individual. In some instances, mixed agonist-antagonists described herein, such as Compound 1, are safely used subcutaneously to treat ESLD or symptoms and / or complications thereof, such as without the risk of an individual developing (serious) side effects and / or having an effect, such as MAP, develop to dangerous or harmful levels. In some instances, the therapeutic window (and safety profde) of mixed VI AR agonist-antagonists described herein, such as Compound 1, is significantly improved compared to V 1 AR agonists (e.g., that do not comprise a discrete V 1 AR antagonist portion), such as terlipressin.

[0014] In some embodiments, a compound described herein has an agonist portion (e.g., DI). In some embodiments, a compound described herein has an antagonist portion (e.g., D2). In some embodiments, a compound described herein has an agonist portion (e.g., DI) and an antagonist portion (e.g., D2). In some embodiments, the antagonist portion (e.g., D2) has no (agonist) activity or substantially less (agonist) activity than the agonist portion (e.g., DI), such as having at least about 1.5x less agonist activity than the agonist portion (e.g., DI), at least about 2x less agonist activity than the agonist portion (e.g., DI), at least about 3x less agonist activity than the agonist portion (e.g., DI), 5x less agonist activity than the agonist portion (e.g., DI), at least about lOx less agonist activity than the agonist portion (e.g., DI), or at least about lOOx less agonist activity than the agonist portion (e.g., DI). In some embodiments, the agonism and / or antagonism is of VI AR.

[0015] In some embodiments, compounds described herein (e.g., mixed Via agonistantagonists, such as Compound 1) are not full or nonselective (V2, Via) receptor agonists. In some embodiments, (subcutaneous) administration of compounds described herein (e.g., mixedVla agonist-antagonists, such as Compound 1) is not toxic (at therapeutic levels), e.g., even at doses as high as 100 to 500 pg / kg. In some embodiments, compounds described herein (e.g., mixed Via agonist-antagonists, such as Compound 1) have a wide therapeutic index and are selective for the Via receptor, such as at therapeutic doses. In some embodiments, compounds described herein (e.g., mixed Via agonist-antagonists, such as Compound 1) are useful for subcutaneous administration. In some embodiments, compounds described herein (e.g., mixed Via agonist-antagonists, such as Compound 1) increase mean arterial pressure (MAP) in an individual receiving one or more (subcutaneously administered) dose of the compound. In some embodiments, compounds described herein (e.g., mixed Via agonist-antagonists, such as Compound 1) decrease portal pressure (PP) in an individual receiving one or more (subcutaneously administered) dose of the compound. In some embodiments, compounds described herein (e.g., mixed Via agonist-antagonists, such as Compound 1) increase MAP and decrease PP in an individual receiving one or more (subcutaneously administered) dose of the compound. In some embodiments, such as after subcutaneous administration of a compound described herein (e.g., mixed Via agonist-antagonists, such as Compound 1), a change in MAP plateaus, or reaches a therapeutic maximum, after a period of time (e.g., after about 10 minutes). In some instances, such as after subcutaneous administration of a compound described herein (e.g., a full, nonselective (V2, Via) agonist, such as terlipressin), MAP rapidly increases and peaks after a period of time (e.g., after about 20 minutes). In some embodiments, such as after subcutaneous administration of a compound described herein (e.g., mixed Via agonist-antagonists, such as Compound 1), a change in PP plateaus. In some embodiments, such as after subcutaneous administration of a compound described herein (e.g., mixed Via agonist-antagonists, such as Compound 1), a change in MAP and PP plateaus or reaches a therapeutic maximum after a period of time (e.g., after about 10 minutes).

[0016] Provided in some embodiments herein is a mixed VI AR receptor agonist-antagonist suitable for subcutaneous administration that reduces ascites (and / or the production thereof), such as by lowering the portal pressure and improving renal excretion of excess sodium and water (e.g., thereby reducing the need for paracentesis and improve patient’s quality of life).

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

[0018] In some instances, treatment paradigms focus on re-establishing blood, portal, and splanchnic pressure to a level that will restore renal function. In some instances, treatment success is measured by raising mean arterial pressure (MAP) 10 to 20 mmHg from baseline at presentation (e.g., since this correlates with improved renal function and / or hemodynamic parameters). Unfortunately, available vasoactive agents either have limited efficacy or pose a serious risk of excessive vasoconstriction, fluid overload, or serious respiratory adverse events.

[0019] In some instances, a compound described herein (e.g., Compound 1) is a vasoconstrictor that selectively targets the vasopressin Via molecule as a mixed agonistantagonist. In some instances, the agonist domain of a compound described herein (e.g., Compound 1) causes desired vasoconstriction of the splanchnic vasculature (e.g., thereby reducing portal blood flow and pressure and / or improving an individual’s systemic hemodynamics). In some instances, the antagonist domain of a compound described herein (e.g., Compound 1) prevents the full activation of V la-mediated vasoconstrictive effects that drive safety concerns with other agents. In some instances, such as at therapeutic concentrations, a compound described herein (e.g., Compound 1) does not activate the vasopressin V2 receptor (e.g., which causes undesired water retention).

[0020] In some embodiments, a compound described herein (e.g., a mixed VIA agonistantagonist, such as Compound 1) is useful for treating ESLD (or a manifestation thereof), decompensated cirrhosis, and / or complications (or symptoms) thereof, such as resistant ascites, refractory ascites, or post-paracentesis induced circulatory dysfunction.

[0021] In some instances, a mixed VIA agonist-antagonist provided herein is used to treat ESLD or complications thereof (e.g., refractory ascites) in an individual (e.g., in need thereof). In some instances, a mixed VIA agonist-antagonist provided herein is used to treat ESLD or complications thereof (e.g., refractory ascites) in an individual (e.g., in need thereof) without (significant) injection site reactions (e.g., local vasoconstriction), such as at a subcutaneous injection site. In some instances, the mixed VIA agonist-antagonist is suitable for systemic delivery, such as provided that the mixed agonist-antagonist nature of the mixed VIA agonistantagonist precludes (significant) injection site reactions (e.g., local vasoconstriction), such as at a subcutaneous injection site. In some instances, a mixed VIA agonist-antagonist provided herein has no (functional) vasopressin 2 (V2) receptor activity, such as at therapeutic concentrations. In some embodiments, the mixed VIA receptor agonist-antagonist is Compound 1.

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

[0023] In some instances, a mixed VIA agonist-antagonist provided herein increases mean arterial pressure (MAP). In some instances, a mixed VIA agonist-antagonist provided herein increases MAP without (significant) injection site reactions (e.g., local vasoconstriction), such as at a subcutaneous injection site.

[0024] In some instances, a mixed VIA agonist-antagonist provided herein reduces portal pressure, such as, by increasing splanchnic arteriolar vasoconstriction.

[0025] In some embodiments, a mixed VIA agonist-antagonist provided herein is used for treating complications of ESLD (e.g., cirrhotic portal hypertension), such as, ascites (e.g., ascites that is refractory to treatment). In some embodiments, a mixed VIA agonist-antagonist provided herein is used for treating complications of ESLD (e.g., cirrhotic portal hypertension), such as, refractory ascites.

[0026] In some embodiments, Compound 1 is used for the treatment of complications of ESLD (e.g., cirrhotic portal hypertension), such as, ascites. In some embodiments, Compound 1 is used for the treatment of complications of ESLD (e.g., cirrhotic portal hypertension), such as, refractory ascites.

[0027] In some instances, a mixed VIA agonist-antagonist provided herein (e.g., Compound 1) provides a substantially improved therapeutic index (e.g., arising from a lower maximal vasoconstrictive effect and lower risk for tissue hypoxia), such as, when compared to full, non- selective (V2, VIA) receptor agonists. In some instances, a mixed VIA agonist-antagonist provided herein (e.g., Compound 1) provides about half of the maximal vasoconstriction produced by full agonists, such as, without any concomitant signs of ischemia. In some instances, a mixed VIA agonist-antagonist provided herein (e.g., Compound 1), such as when administered subcutaneously, is a (clinically) efficacious vasoconstrictor, such as having low to no local toxicity. In some instances, a mixed VIA agonist-antagonist provided herein (e.g., Compound 1) is a (clinically) efficacious vasoconstrictor (e.g., having a favorable benefit / risk profde (e.g., when administered subcutaneously), such as, having low to no local toxicity). In some instances, a mixed VIA agonist-antagonist provided herein (e.g., Compound 1) provides sufficient splanchnic vasoconstriction to lower elevated portal pressure, while minimizing riskfor excessive vasoconstriction in other vascular beds with associated adverse events, such as mesenteric ischemia.

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

[0029] Provided in some embodiments herein is a method of treating end-stage liver disease (ESLD) or a symptom (e.g., complication) thereof in an individual (e.g., in need thereof), the method comprising subcutaneously infusing into the individual (e.g., in need thereof) a composition comprising an (effective) amount of a compound, the compound being a mixed vasopressin receptor 1A (VI AR) agonist-antagonist.

[0030] Provided in some embodiments herein is a method of treating end-stage liver disease (ESLD) or a symptom (e.g., complication) thereof 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, the compound being a mixed vasopressin receptor 1A (VI AR) agonist-antagonist.

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

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

[0033] In some embodiments, the modulation of mean arterial pressure (MAP) in the individual comprises raising MAP by at least 5% over baseline. In some embodiments, the modulation of mean arterial pressure (MAP) in the individual comprises raising MAP by at least 5 mmHg (e.g., 5 mmHg or more, or 10 mmHg or more) over baseline .

[0034] In some embodiments, the compound has a structure represented by Formula I:D1-L-D2Formula I or a pharmaceutically acceptable salt thereof, wherein:DI is a vasopressin receptor 1A (VI AR) agonist;D2 is a VI AR antagonist; andL is a linker.

[0035] Provided in some embodiments herein is a method of treating end-stage liver disease (ESLD) or a sign or symptom (e.g., complication) thereof in an individual (e.g., in need thereof), the method comprising subcutaneously administering to the individual (e.g., in need thereof) an (effective) amount of a compound having a structure represented by Formula I:D1-L-D2Formula I or a pharmaceutically acceptable salt thereof, wherein:DI is a vasopressin receptor 1A (VI AR) agonist;D2 is a VI AR antagonist; andL is a linker.

[0036] Provided in some embodiments herein is a method of treating end-stage liver disease (ESLD) or a sign or symptom (e.g., complication) thereof in an individual (e.g., in need thereof), the method comprising subcutaneously infusing into the individual (e.g., in need thereof) a composition comprising an (effective) amount of a compound having a structure represented by Formula I:D1-L-D2Formula I or a pharmaceutically acceptable salt thereof, wherein:DI is a vasopressin receptor 1A (VI AR) agonist;D2 is a VI AR antagonist; andL is a linker.

[0037] In some embodiments, DI is selective for VI AR over V2R.

[0038] In some embodiments, DI is or comprises a (e.g., cyclic) peptide. In some embodiments, DI is or comprises a cyclic nonapeptide. In some embodiments, DI has or comprises the following structure:

[0039] In some embodiments, DI has or comprises the following structure:

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

[0041] In some embodiments, D2 has or comprises the following structure:

[0042] In some embodiments, L is a non-hydrolyzable linker. In some embodiments, L comprises one or more linker group, each linker group being independently selected from the group consisting of a substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl. In some embodiments, L is a bond, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. In some embodiments, L is or comprises substitutedor unsubstituted heteroalkyl. In some embodiments, L is heteroalkyl (e.g., alkylamine) substituted with one or more substituent, each substituent being independently selected form 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 residue. In some embodiments, L has or comprises the following structure:

[0043] In some embodiments, L has or comprises the following structure:

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

[0045] Provided in some embodiments herein is a method of treating end-stage liver disease (ESLD) or a sign or symptom (e.g., complication) thereof in an individual (e.g., in need thereof), 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.

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

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

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

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

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

[0051] In some embodiments, subcutaneously infusing the composition into the individual improves tolerability, relative to subcutaneous (bolus) injection (e.g., based on a reduction of Ml overproduction, such as subcutaneously). In some embodiments, subcutaneously infusing the composition into the individual reduces undesired systemic events (e.g., undesired vasoconstriction, such as resulting in ischemia), reduces undesired administration site events (e.g., local site vasoconstriction, such as resulting in administration site ischemia), or both.

[0052] Provided in some embodiments herein is a method of treating end-stage liver disease (ESLD) in an individual in need thereof, the method comprising subcutaneously infusing into the individual in need thereof a composition comprising a compound having a structure represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein less than 50% of the compound of Formula I degrades (e.g., subcutaneously).

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

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

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

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

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

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

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

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

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

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

[0063] In some embodiments, (e.g., within the first 24-hours, such as within the first 4 hours) urine volume of the individual (significantly) increases (e.g., compared to a vehicle control) following subcutaneous administration of the compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine volume of the individual increases by about 25% or more, 50% or more, 100% or more, 200% or more, 300% or more, 400% or more, or 500% or more (e.g., compared to a vehicle control) following subcutaneous administration of the compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine volume of the individual is about 50% or more or 100% or more higher at least one day (e.g., 3 days or more) after subcutaneous administration of the compound, or the pharmaceutically acceptable salt thereof, described herein to the individual.

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

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

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

[0067] In some embodiments, body weight of the individual (significantly) decreases (e.g., compared to a vehicle control) following subcutaneous administration of the compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, body weight of the individual decreases by about 1% or more, 2.5% or more, 5% or more, or about 10% or more (e.g., compared to a vehicle control) following subcutaneous administration of the compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, body weight of the individual is at least about 1%, at least about 2.5%, at least about 5%, or at least about 10% less at least one day (e.g., 3 days or more (e.g., 5 days)) after subcutaneous administration of the compound, or the pharmaceutically acceptable salt thereof, described herein to the individual.

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

[0069] In some embodiments, diastolic blood pressure of the individual increases (e.g., compared to a baseline measurement before treatment) after administering a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual.

[0070] In some embodiments, systolic blood pressure of the individual increases (e.g., compared to a baseline measurement before treatment) after administering a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual.

[0071] In some embodiments, the diastolic and / or systolic blood pressure of the individual dose-dependently increases after administering a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual.

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

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

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

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

[0076] In some embodiments, the individual is subcutaneously administered the compound, or the pharmaceutically acceptable salt thereof, described herein multiple times, such as over the course of numerous days. In some embodiments, the compound is continuously administered to the individual, such as over a period of numerous days.

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

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

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

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

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

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

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

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

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

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

[0087] Provided in some embodiments herein is a pharmaceutical composition comprising an effective amount of a compound, or a pharmaceutically acceptable salt thereof, wherein thecompound is a mixed vasopressin receptor 1A (VI AR) agonist-antagonist, the composition being formulated for subcutaneous administration.

[0088] In some embodiments, the compound has a structure represented by Formula I:D1-L-D2Formula I or a pharmaceutically acceptable salt thereof, wherein:DI is a vasopressin receptor 1A (VI AR) agonist;D2 is a VI AR antagonist; andL is a linker.

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

[0090] Provided in some embodiments herein is a pharmaceutical composition comprising an effective amount of a compound having a structure represented by Formula I:D1-L-D2Formula I or a pharmaceutically acceptable salt thereof, wherein:DI is a vasopressin receptor 1A (VI AR) agonist;D2 is a VI AR antagonist; andL is a linker,

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

[0092] In some embodiments, the composition is suitable for routes of administration beyond intravenous administration, such as subcutaneous administration.

[0093] In some embodiments, the composition is suitable for systemic delivery of an active agent, such as Compound 1.

[0094] Provided in some embodiments pharmaceutical composition comprising an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, the composition being formulated for subcutaneous administration.

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

[0096] In some embodiments, the composition is suitable for systemic delivery of an active agent, such as Compound 1.

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

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

[0099] Provided in some embodiments herein is 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.

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

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

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

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

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

[0105] Provided in some embodiments herein is a subcutaneous formulation comprising a compound having a structure represented by Formula I, or a pharmaceutically acceptable salt thereof, and a preservative.

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

[0107] Provided in some embodiments herein is a subcutaneous formulation comprising a compound having a structure represented by Formula I, or a pharmaceutically acceptable salt thereof, and a solubilizing agent.

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

[0109] In some embodiments, the compound of Formula I is less susceptible to degradation, such as in the subcutaneous layer of an individual subcutaneously administered the formulation.

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

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

[0112] In some instances, a mixed VIA agonist-antagonist provided herein (e.g., Compound 1) is administered in the form of an acetate salt.

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

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

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

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

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

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

[0119] In some embodiments, the device is a subcutaneous infusion device (e.g., pump).BRIEF DESCRIPTION OF THE DRAWINGS

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

[0121] FIG. 1 illustrates the study design described in Example 1 for each subject in Period 1 (intravenous infusion) and Period 2 (subcutaneous injection).

[0122] FIG. 2 shows a time course of Compound 1 concentration after intravenous administration, Period 1.

[0123] FIG. 3 A shows a time course of Compound 1 concentration after the 1st subcutaneous administration, Period 2.

[0124] FIG. 3B shows a time course of Compound 1 concentration after the 5th subcutaneous administration, Period 2.

[0125] FIG. 4A shows diastolic blood pressure, intravenous infusion (mean values).

[0126] FIG. 4B shows diastolic blood pressure, intravenous infusion (mean percent change).

[0127] FIG. 5 A shows diastolic blood pressure, repeated subcutaneous injections (mean values).

[0128] FIG. 5B shows diastolic blood pressure, repeated subcutaneous injections (mean percent change).

[0129] FIG. 6 A shows systolic blood pressure, intravenous infusion (mean values).

[0130] FIG. 6B shows systolic blood pressure, intravenous infusion (mean percent change).

[0131] FIG. 7A shows systolic blood pressure, subcutaneous injections (mean values).

[0132] FIG. 7B shows systolic blood pressure, subcutaneous injections (mean percent change).

[0133] FIG. 8A shows change in mean arterial pressure over time (mean percentage change from baseline in mean arterial pressure after intravenous infusion).

[0134] FIG. 8B shows change in mean arterial pressure over time (mean percentage change from baseline in mean arterial pressure after repeated subcutaneous injections).

[0135] FIG. 9 A shows pulse rate after intravenous infusion (mean values).

[0136] FIG. 9B shows pulse rate after intravenous infusion (mean percent change).

[0137] FIG. 10A shows pulse rate after subcutaneous injections (mean values).

[0138] FIG. 10B shows pulse rate after subcutaneous injections (mean percent change).

[0139] FIG. 11 shows amount of Compound 1 excreted intact in urine after intravenous infusion.

[0140] FIG. 12A shows amount Compound 1 excreted after 1st subcutaneous injection.

[0141] FIG. 12B shows amount Compound 1 excreted after 5th subcutaneous injection.

[0142] FIG. 13A shows mean plasma concentration of metabolite Ml after 1st s.c. injection of Compound 1.

[0143] FIG. 13B shows mean plasma concentration of metabolite Ml after 5th s.c. injection of Compound 1.

[0144] FIG. 14 shows the structure of Ml (encircled) in relation to Compound 1.

[0145] FIG. 15 shows urine volume time course after subcutaneous administration of Compound 1.

[0146] FIG. 16 shows urine sodium excretion time course after subcutaneous administration of Compound 1.

[0147] FIG. 17 shows body weight time course after subcutaneous administration of Compound 1.

[0148] FIG. 18 shows urine volume time course after intravenous administration of Compound 1.

[0149] FIG. 19 shows urine sodium excretion time course after intravenous administration of Compound 1.

[0150] FIG. 20 shows glomerular filtration rate time course after intravenous administration of Compound 1.

[0151] FIG. 21 shows portal pressure time course after intravenous administration of Compound 1.

[0152] FIG. 22 shows cardiac output time course after intravenous administration of Compound 1.

[0153] FIG. 23 shows mean arterial pressure time course after intravenous administration of Compound 1.

[0154] FIG. 24 shows systemic vascular resistance time course after intravenous administration of Compound 1.

[0155] FIG. 25 shows effect on body weight after subcutaneous administration of Compound 1.

[0156] FIG. 26A shows effect on urine volume measured 4-hours after subcutaneous administration of Compound 1.

[0157] FIG. 26B shows effect on urine volume measured 5- to 24-hours after subcutaneous administration of Compound 1.

[0158] FIG. 26C shows effect on urine volume measured 24-hours after subcutaneous administration of Compound 1.

[0159] FIG. 27 shows effect on net fluid balance measured 24-hours after subcutaneous administration of Compound 1.

[0160] FIG. 28A shows effect on urine sodium measured 4-hours after subcutaneous administration of Compound 1.

[0161] FIG. 28B shows effect on urine sodium measured 5- to 24-hours after subcutaneous administration of Compound 1.

[0162] FIG. 28C shows effect on urine potassium measured 4-hours after subcutaneous administration of Compound 1.

[0163] FIG. 28D shows effect on urine potassium measured 5- to 24-hours after subcutaneous administration of Compound 1.

[0164] FIG. 28E shows effect on urine creatinine measured 4-hours after subcutaneous administration of Compound 1.

[0165] FIG. 28F shows effect on urine creatinine measured 5- to 24-hours after subcutaneous administration of Compound 1.

[0166] FIG. 29 shows effect on ascites volume after subcutaneous administration of Compound 1.

[0167] FIG. 30 shows effect on spleen weight after subcutaneous administration of Compound 1.

[0168] FIG. 31A shows effect on BUN after subcutaneous administration of Compound 1.

[0169] FIG. 31B shows effect on Cl after subcutaneous administration of Compound 1.

[0170] FIG. 31C shows effect on PHOS after subcutaneous administration of Compound 1.

[0171] FIG. 3 ID shows effect on Na after subcutaneous administration of Compound 1.

[0172] FIG. 31E shows effect on BUN / CREA after subcutaneous administration of Compound 1.

[0173] FIG. 32 illustrates exemplary dose-response curves for full agonists, partial agonists, and weak agonists. FIG. 32 generally illustrates that a broader therapeutic window for vasoconstriction can be achieved with curve 2 than curves 1 or 3. Portion A illustrates levels of full agonists where vasoconstriction can be lethal. Portion A illustrates levels of full agonists where vasoconstriction can induce serious side-effects.

[0174] FIG. 33 illustrates the change in portal pressure (APP) over time in rats with bile duct ligation (BDL) following subcutaneous administration of various doses of a mixed Via agonist-antagonist.

[0175] FIG. 34 illustrates the change in portal mean arterial pressure (AMAP) over time in methionine / choline-deficient (MCD) diet rats following subcutaneous administration of a full, non-selective (V2, Via) agonist and various doses of a mixed Via agonist-antagonist.

[0176] FIG. 35 illustrates the change in portal pressure (APP) over time in methionine / choline- deficient (MCD) diet rats following subcutaneous administration of a full, nonselective (V2, Via) agonist and various doses of a mixed Via agonist-antagonist.

[0177] FIG. 36 illustrates an exemplary dose response curve of maximal possible effect at human Via (hVla) receptors for a full, nonselective (V2, Via) agonist and a mixed Via agonist-antagonist.

[0178] FIG. 37 illustrates an exemplary dose response curve of maximal possible effect at human Via (hVla) receptors and human V2 (hV2) receptors for a mixed Via agonistantagonist.

[0179] FIG. 38 illustrates an exemplary dose response curve for contractility of human mesenteric resistance arteries in response to a mixed Via agonist-antagonist.

[0180] FIG. 39A shows a normalized plasma concentration time profile of Compound 1 after IV administration an individual (e.g., a mammal) (10 mg / kg).

[0181] FIG. 39B shows a normalized plasma concentration time profile of Compound 1 after subcutaneous administration in an individual (e.g., a mammal) (1.0 mg / kg).

[0182] FIG. 40A shows a dose response of Compound 1, vasopressin, and the vehicle on skin blood flow (SBF) (% baseline) in an individual (e.g., a mammal) after IV administration.

[0183] FIG. 40B shows a dose response of Compound 1 , vasopressin, and the vehicle on blood lactate concentration (mM) in an individual (e.g., a mammal) after IV administration.

[0184] FIG. 40C shows a comparison of blood lactate concentration in an individual (e.g., a mammal) after administration of vehicle, Compound 1, or vasopressin (A VP).

[0185] FIG. 41A shows mean arterial pressure (MAP) following subcutaneous administration of Compound 1 in an individual (e.g., a mammal).

[0186] FIG. 41B shows systolic arterial blood pressure following subcutaneous administration of Compound 1 in an individual (e.g., a mammal).

[0187] FIG. 41C shows diastolic arterial blood pressure following subcutaneous administration of Compound 1 in an individual (e.g., a mammal).

[0188] FIG. 41D shows heart rate following subcutaneous administration of Compound 1 in an individual (e.g., a mammal).

[0189] FIG. 42A shows a time profile of normalized plasma concentration (ng / mL) of Compound 1 following IV bolus (0.05 mg / kg) administration in an individual (e.g., a mammal).

[0190] FIG. 42B shows a time profile of normalized plasma concentration of Compound 1 following subcutaneous bolus (0.5 mg / kg) administration in an individual (e.g., a mammal).

[0191] FIG. 43A shows a change from baseline in mean arterial pressure (AMAP) following administration of Compound 1 over 480 minutes in an individual (e.g., a mammal).

[0192] FIG. 43B shows a change from baseline in mean arterial pressure (AMAP) following administration of terlipressin over 480 minutes in an individual (e.g., a mammal).

[0193] FIG. 44 shows that little to no metabolism of Compound 1 occurs in healthy humans after intravenous (IV) infusion (panel A), and the concentration of Compound 1 and Ml are about equimolar in healthy humans after subcutaneous (bolus) injection (panel B).

[0194] FIG. 45 shows that little to no metabolism of Compound 1 occurs in mini-pigs after subcutaneous (SC) infusion of relatively low (panels A and B) and high (panels C and D) doses of Compound 1.

[0195] FIG. 46 depicts the Compound 1 / MI ratio of FIG. 45, panels A and B.

[0196] FIG. 47 shows that little to no metabolism of Compound 1 occurs in mini-pigs after relatively slow subcutaneous (SC) infusion of relatively low (panels A and B) and high (panels C and D) doses of Compound 1.

[0197] FIG. 48 depicts the Compound 1 / MI ratios of FIG. 47, panels A-D.DETAILED DESCRIPTION OF THE INVENTIONCertain Definitions

[0198] As used herein and in the appended claims, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example,reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary between 1% and 15% of the stated number or numerical range. Any recitation of “about” provided herein also includes disclosure of the number itself. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, may "consist of or "consist essentially of the described features.

[0199] The terms “treat,” “treating,” or “treatment” as used herein, include reducing, alleviating, abating, ameliorating, managing, relieving, or lessening the symptoms associated with a disease, disease state, condition, or indication (e.g., provided herein) in either a chronic or acute therapeutic scenario. Also, treatment of a disease or disease state described herein includes the disclosure of use of such compound or composition for the treatment of such disease, disease state, disorder, or indication.

[0200] The terms “modulate” or “modulating” as used herein, refer to a change in a biological, chemical, and / or biochemical response, such as a physiological response, in an individual. In some instances, the change is an increase in the biological, chemical, and / or biochemical response of individual. In some instances, the change is a decrease in the biological, chemical, and / or biochemical response of individual. In some instances, the change is observed (e.g., immediately, 30 mins 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.

[0201] The terms “adverse event” or “AE” as used herein, refer to an untoward medical occurrence in an individual, such as an individual participating in a clinical trial. In some instances, an AE is an unfavorable and / or unintended sign, symptom, or disease, such as being temporally associated with the use of an investigative medicinal product (IMP), whether or not considered to be caused by the IMP. For example, an AE can include accidental injuries, reasons for any change in medication (drug and / or dose), reasons for any medical, nursing or pharmacy consultation, or reasons for admission to hospital or surgical procedures, andoverdoses and medication errors with or without clinical consequences. In some instances, AEs are anticipated based on the pharmacological effect of the IMP. In some instances, an AE is a laboratory abnormality, vital sign or finding from physical or gynecological examination assessed as clinically significant by the investigator. In some instances, a pre-treatment adverse event is any untoward medical occurrence arising or observed between signing of informed consent and the first administration of the IMP. In some instances, a treatment emergent adverse event is an AE occurring after the administration of the IMP and within the time of residual drug effect, or a pre-treatment adverse event or pre-existing medical condition that worsens in intensity after administration of the IMP and within the time of residual drug effect. In some instances, the time of residual drug effect is the estimated period of time after the administration of the IMP, where the effect of the product is still considered to be present based on PK, PD or other substance characteristics. In some instances, the residual drug effect is 5 times the terminal half-life. In some instances, the terminal half-life of Compound 1 is about 1.5-2 hours. In some instances, the residual drug effect is within the time to the last assessment in Period 1 and the follow-up visit in Period 2 (as described in the examples hereinbelow). In some instances, a post-treatment emergent adverse event is an AE occurring after the time of residual drug effect of the IMP (e.g., prior to the first administration in Period 2 after the last assessment in Period 1, and after the follow-up visit in Period 2).

[0202] “Amino” refers to the -NH2 radical.

[0203] “Cyano” refers to the -CN radical.

[0204] “Nitro” refers to the -NO2 radical.

[0205] “Oxo” refers to the =0 radical.

[0206] “Hydroxyl” refers to the -OH radical.

[0207] “Alkyl” generally refers to an acyclic (e.g., straight or branched) or cyclic hydrocarbon (e.g., chain) radical consisting solely of carbon and hydrogen atoms, such as having from one to fifteen carbon atoms (e.g., C1-C15 alkyl). Unless otherwise state, alkyl is saturated or unsaturated (e.g., an alkenyl, which comprises at least one carbon-carbon double bond). Disclosures provided herein of an “alkyl” are intended to include independent recitations of a saturated “alkyl,” unless otherwise stated. Alkyl groups described herein are generally monovalent, but may also be divalent (which may also be described herein as “alkylene” or “alkylenyl” groups). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g., C1-C13 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., Ci-Cs alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (e.g.,C1-C5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (e.g., C1-C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (e.g., C1-C3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (e.g., C1-C2 alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., Ci alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., Cs-Cs alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (e.g., C2-C5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1 -propyl (n-propyl), 1 -methylethyl ( / .so-propyl), 1 -butyl (n-butyl), 1 -methylpropyl (.sec-butyl), 2-methylpropyl ( / .so-butyl), 1,1 -dimethylethyl (tert-butyl), 1 -pentyl (n-pentyl). The alkyl is attached to the rest of the molecule by a single bond. In general, alkyl groups are each independently substituted or unsubstituted. Each recitation of “alkyl” provided herein, unless otherwise stated, includes a specific and explicit recitation of an unsaturated “alkyl” group. Similarly, unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, - OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, - N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Rais 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).

[0208] “Alkoxy” refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above.

[0209] “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 two to twelve carbon atoms. In certain embodiments, an alkenyl comprises twoto eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is optionally substituted as described for “alkyl” groups.

[0210] “Alkylene” or “alkylene chain” generally refers to a straight or branched divalent alkyl group linking the rest of the molecule to a radical group, such as having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, z-propylene, n-butylene, and the like. Unless stated otherwise specifically in the specification, an alkylene chain is optionally substituted as described for alkyl groups herein.

[0211] “Aryl” refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) K-cIcctron system in accordance with the Huckel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. Unless stated otherwise specifically in the specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is meant to include aryl radicals optionally substituted by one or more substituents independently selected from 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, -Rb-ORa, -Rb-OC(O)- Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb- C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb- S(O)tN(Ra)2(where t is 1 or 2), where each Rais 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 withhalogen, hydroxy, methoxy, or trifluoromethyl), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0212] “Aralkyl” or “aryl-alkyl” refers to a radical of the formula -Rc-aryl where Rcis an alkylene chain as defined above, for example, methylene, ethylene, and the like. 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.

[0213] “Carbocyclyl” or “cycloalkyl” refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, having from three to fifteen carbon atoms. In certain embodiments, a carbocyclyl comprises three to ten carbon atoms. In other embodiments, a carbocyclyl comprises five to seven carbon atoms. The carbocyclyl is attached to the rest of the molecule by a single bond. Carbocyclyl or cycloalkyl is saturated (i.e., containing single C-C bonds only) or unsaturated (i.e., containing one or more double bonds or triple bonds). Examples of saturated cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl is also referred to as "cycloalkenyl." Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbomyl (i.e., bicyclo[2.2.1]heptanyl), norbomenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, the term “carbocyclyl” is meant to include carbocyclyl radicals that are optionally substituted by one or more substituents independently selected from 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-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)- N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb- N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2), where each Rais 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), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0214] “Carbocyclylalkyl” refers to a radical of the formula -Rc-carbocyclyl where Rcis an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.

[0215] “Carbocyclylalkenyl” refers to a radical of the formula -Rc-carbocyclyl where Rcis an alkenylene chain as defined above. The alkenylene chain and the carbocyclyl radical is optionally substituted as defined above.

[0216] “Carbocyclylalkoxy” refers to a radical bonded through an oxygen atom of the formula -O-Rc-carbocyclyl where Rcis an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.

[0217] “Halo" or “halogen” refers to fluoro, bromo, chloro, or iodo substituents.

[0218] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halogen radicals, as defined above, for example, trihalomethyl, dihalomethyl, halomethyl, and the like. In some embodiments, the haloalkyl is a fluoroalkyl, such as, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, l-fhioromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.

[0219] The term “heteroalkyl” refers to an alkyl group as defined above in which one or more skeletal carbon atoms of the alkyl are substituted with a heteroatom (with the appropriate number of substituents or valencies - for example, -CH2- may be replaced with -NH- or -O-). For example, each substituted carbon atom is independently substituted with a heteroatom, such as wherein the carbon is substituted with a nitrogen, oxygen, sulfur, or other suitable heteroatom. In some instances, each substituted carbon atom is independently substituted for an oxygen, nitrogen (e.g. -NH-, -N(alkyl)-, or -N(aryl)- or having another substituentcontemplated herein), or sulfur (e.g. -S-, -S(=O)-, or -S(=O)2-). In some embodiments, a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In some embodiments, a heteroalkyl is attached to the rest of the molecule at a heteroatom of the heteroalkyl. In some embodiments, a heteroalkyl is a Ci-Cis heteroalkyl. In some embodiments, a heteroalkyl is a C1-C12 heteroalkyl. In some embodiments, a heteroalkyl is a Ci-Ce heteroalkyl. In some embodiments, a heteroalkyl is a C1-C4 heteroalkyl. In some embodiments, heteroalkyl includes alkylamino, alkylaminoalkyl, aminoalkyl, heterocycloalkyl, heterocycloalkyl, heterocyclyl, and heterocycloalkylalkyl, as defined herein. Unless stated otherwise specifically in the specification, heteroalkyl does not include alkoxy as defined herein. Unless stated otherwise specifically in the specification, a heteroalkyl group is optionally substituted as defined above for an alkyl group.

[0220] “Hetero alkylene” refers to a divalent heteroalkyl group defined above which links one part of the molecule to another part of the molecule. Unless stated specifically otherwise, a heteroalkylene is optionally substituted, as defined above for an alkyl group.

[0221] “Heterocyclyl” refers to a stable 3- to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which optionally includes fused or bridged ring systems. The heteroatoms in the heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical is partially or fully saturated. The heterocyclyl radical is saturated (i.e., containing single C-C bonds only) or unsaturated (e.g., containing one or more double bonds or triple bonds in the ring system). In some instances, the heterocyclyl radical is saturated. In some instances, the heterocyclyl radical is saturated and substituted. In some instances, the heterocyclyl radical is unsaturated. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, the term “heterocyclyl” is meant to include heterocyclyl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionallysubstituted 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-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, - Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc- C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb- S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(0)tN(Ra)2 (where t is 1 or 2), where each Rais 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), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0222] “A-heterocyclyl” or “N-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. An / V-hctcrocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such A-heterocyclyl radicals include, but are not limited to, 1- morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

[0223] ‘ ‘C-heterocyclyl” or “C-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one heteroatom and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a carbon atom in the heterocyclyl radical. A C-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such C-heterocyclyl radicals include, but are not limited to, 2- morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.

[0224] “Heterocyclylalkyl” refers to a radical of the formula -Rc-heterocyclyl where Rcis an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, theheterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the hetero cyclylalkyl radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group.

[0225] “Hetero cyclylalkoxy” refers to a radical bonded through an oxygen atom of the formula -O-Rc-heterocyclyl where Rcis 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 part of the heterocyclylalkoxy radical is optionally substituted as defined above for a heterocyclyl group.

[0226] “Heteroaryl” refers to a radical derived from a 3- to 18-membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, the heteroaryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) K-cIcctron system in accordance with the Hiickel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quatemized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[6][l,4]dioxepinyl, benzo [b][ 1,4] oxazinyl, 1 ,4-benzodioxanyl, benzonaphtho furanyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[l,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl,5.6.7.8.9.10-hexahydrocycloocta[d]pyrimidinyl,5.6.7.8.9.10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, 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, 10,1 Oa-octahydrobenzo[h]quinazolinyl, 1 -phenyl- 1 / / -pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl,5.6.7.8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6.7.8.9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, the term "heteroaryl" is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from 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, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, - Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc- C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb- S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2), where each Rais 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), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0227] ‘ ‘ / V-hctcroaryl” refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the moleculeis through a nitrogen atom in the heteroaryl radical. An A-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0228] “C-heteroaryl” refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical. A C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0229] “Hetero arylalkyl” refers to a radical of the formula -Rc-heteroaryl, where Rcis an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.

[0230] “Hetero arylalkoxy” refers to a radical bonded through an oxygen atom of the formula -O-Rc-heteroaryl, where Rcis 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 hetero arylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.

[0231] The compounds disclosed herein, in some embodiments, contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R}~ or (5)-. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure. When the compounds described herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers (e.g., cis or trans. Likewise, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included. The term “geometric isomer” refers to E or Z geometric isomers (e.g., cis or trans} of an alkene double bond. The term “positional isomer” refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring.

[0232] In general, optionally substituted groups are each independently substituted or unsubstituted. Each recitation of a optionally substituted group provided herein, unless otherwise stated, includes an independent and explicit recitation of both an unsubstituted group and a substituted group (e.g., substituted in certain embodiments, and unsubstituted in certainother embodiments). Unless otherwise stated, a substituted group provided herein (e.g., substituted alkyl) is substituted by one or more substituent, each substituent being independently selected from the group consisting of halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SIU, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, - N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2), where each Rais 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).

[0233] “Pharmaceutically acceptable salt” includes both acid 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.

[0234] “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are 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. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc. and include, 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. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates,trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. 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 forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.

[0235] “Pharmaceutically acceptable base addition salt” refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. 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, for example, 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, A-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, A-ethylpiperidine, polyamine resins and the like. See Berge et al., supra.

[0236] The compounds disclosed herein, in some embodiments, contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R}~ or (5)-. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure. When the compounds described herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers (e.g., cis or trans. Likewise, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included. The term “geometric isomer” refers to E or Z geometric isomers (e.g., cis or trans} of an alkene doublebond. The term “positional isomer” refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring.

[0237] Systemic hemodynamic complications can be indicative of cirrhosis and portal hypertension (PHT). Individuals can often develop elevations of portal pressure (PP) due to an increase in intrahepatic resistance. The combination of increased blood flow and elevated intrahepatic resistance can lead to the development of PHT and the common manifestations of decompensated cirrhosis. Clinical PHT can occur when the hepatic venous pressure gradient (HVPG) is >5 mmHg. PHT can then lead to a hyperdynamic state characterized by a decrease in splanchnic and systemic vascular resistance, which can further increase portal blood flow. As advanced cirrhosis progresses, splanchnic arteriolar vasodilation can worsen PHT, which can then lead to further increases in the HVPG, further leading to hypoperfusion of the kidneys at 10 mmHg or above. The kidney can sense low perfusion pressure and reduced glomerular filtration rate as hypovolemia, which can then activate the renin-angiotensin-aldosterone (RAAS) and vasopressin systems, leading to severe vasoconstriction within the kidney and retention of sodium and water. If hypoperfusion of the kidneys is severe enough, it can result in the development of ascites and renal injury in the form of hepatorenal syndrome-acute kidney injury (HRS-AKI).

[0238] Ascites is a common complication of cirrhosis, and ascites requiring paracentesis is a frequent hepatic-related reason for hospitalization. HRS-AKI is a severe complication of cirrhosis; only 50% of patients with HRS-AKI are expected to respond to currently available treatments, and more than half of patients die within 90 days. However with early intervention, HRS-AKI is reversible.

[0239] Ascites is a serious and rapidly progressive consequence of end-stage liver disease (ESLD) that can lead to acute renal failure and often death. For example, refractory ascites, which is an end-stage form of ascites, impacts up to an estimated 60,000 - 100,000 individuals (e.g., globally) per year and is associated with a mortality rate of approximately 50 percent at 3 years following diagnosis, with a 1-year survival rate of less than 50%. As the incidence of (chronic) liver disease increases, the prevalence of ascites is anticipated to also increase. There has been no therapeutic drug innovation for ascites in over two decades and there are no FDA- approved treatments for the disease. Therapeutic interventions often produce only modest effects and / or fall short in achieving the goals of reversing renal failure and prolonging survival in critically-ill patients. Patients are often managed symptomatically to remove ascites either mechanically via paracentesis or with the surgical placement of a shunt (Transjugular Intrahepatic Portosystemic Shunt [TIPS]). While such treatments can offer symptomatic reliefof ascites, they do not improve the underlying circulatory derangements and have no impact on survival. The cirrhotic manifestations may also result in other complications such as bleeding esophageal varices, spontaneous bacterial peritonitis, and renal failure.

[0240] Patients suffering from refractory ascites often have an abnormally high splanchnic blood flow, such as due to excess hepatic vascular resistance and systemic vasodilation. Vasoconstrictor agents that constrict splanchnic vessels can reduce ascites formation by reducing venous blood flow. While studies with terlipressin, a non-selective vasopressin receptor full agonist, have demonstrated reduced ascites formation, such compounds are limited to continuous (e.g., 24-hour) intravenous infusion, such as due to local vasoconstriction at an injection site that precludes alternative routes of administration, like subcutaneous administration.

[0241] Management of HRS-AKI often focuses on restoring systemic arterial blood pressure and reducing PHT through splanchnic vasoconstriction, with the vasopressin system being a target, and a long-term goal being liver transplantation. While challenging to monitor and titrate, increases in vasoconstriction (i.e., mean arterial pressure (MAP)) have been correlated with improved hemodynamic parameters. Vasoconstrictive agents, including terlipressin, norepinephrine, and midodrine / octreotide, have been used as therapy 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, as 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 with rapid reduction in kidney function.

[0242] There are three vasopressin receptors: Via, Vlb, and V2. Via receptors are found throughout the circulatory system and modulate vasoconstriction. The V2 receptors modulate aquaresis through an antidiuretic effect at the level of the kidney by mediating water reabsorption in collecting tubules. Vlb receptors are found in the anterior pituitary and peripheral tissues, and one potential role is to mediate the release of adrenocorticotropin hormone, which can stimulate water retention. Vasopressin, also known as arginine vasopressin (A VP) or antidiuretic hormone, is a peptide involved in water balance and vascular tone. At normal physiologic concentrations, there is little to no activity on the Via system; only at supraphysiologic concentrations is there meaningful vasoconstriction. With pharmacologic application, intense vasoconstriction can be achieved in a concentration-dependent manner.

[0243] Arginine vasopressin (A VP) is the endogenous ligand of the vasopressin VIA, V1B, and V2 G-protein-coupled receptors (VI AR, V1BR, V2R). Homeostatic functions of the vasopressin system, such as regulation of blood osmolality and pressor effects, are mediated by the V2 and VIA receptor subtypes. Activation of V2 receptors located in kidney collecting ducts plays a role in the regulation of fluid balance through antidiuretic action. Activation of VIA receptors located on vascular smooth muscle cells provides vasoconstriction and increased arterial pressure.

[0244] Lysine vasopressin (LVP), the active metabolite of terlipressin, has activity at Via, Vlb, and V2 receptors and is a full agonist. Despite significantly improving renal function, terlipressin use is associated with serious adverse events, including gastrointestinal disorders, sepsis, and respiratory failure. These adverse effects, which can be attributed to the strength of LVP binding to Via and off-target effects on V2, may lead to further water retention. As a result of the potential for serious side effects, terlipressin carries a black box warning from the US FDA for serious or fatal respiratory failure.

[0245] 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 VIA receptor full agonists is the potential to induce severe vasoconstriction and tissue hypoperfusion when used at therapeutic doses. The pharmacological activity of VI AR partial agonists (e.g., compounds that have a reduced maximal efficacy at the VIA receptor) can be used in a variety of conditions where a modest increase in blood flow and / or blood pressure without hypoperfusion is desirable. For example, such indications include hepatorenal syndrome, refractory ascites, bleeding esophageal varices, anesthesia-induced hypotension, vasodilatory shock, paracentesis-induced circulatory dysfunction, and spontaneous bacterial peritonitis.

[0246] Individuals with liver cirrhosis often develop numerous clinical complications, among which ascites accumulation is paramount and indicates poor prognosis. In some instances, ascites formation results from the homeostatic activation of endogenous sodium and water retaining systems in attempt to counteract the circulatory dysfunction, such as developed in patients with advanced liver disease. In some instances, a feature of the circulatory dysfunction is the existence of splanchnic vasodilation and portal hypertension. In some embodiments, a compound described herein (e.g., Compound 1) has an effect on ascites volume, sodium and water excretion, portal hypertension, and systemic hemodynamics following administration of the compound or vehicle to cirrhotic rats with ascites.

[0247] In some embodiments, a compound described herein (e.g., a mixed Via agonist / antagonist, such as Compound 1) is systemically delivered in an individual after intravenous (IV) and / or subcutaneous (SC) administration of a composition comprising the compound (see Example 1). In some embodiments, the individual has systemic effects, 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 were comparable, more adverse events were measured in individuals receiving SC (bolus) injection of the composition (see Example 1). Generally, the compound was well-tolerated by individuals receiving the composition by IV infusion.

[0248] In some instances, a metabolite (e.g., a substantial amount of the metabolite Ml) forms (e.g., an overproduction of Ml) after SC (bolus) injection of a composition comprising a compound described herein (e.g., a mixed Via agonist / antagonist, such as Compound 1) (see FIG. 44, panel B). In some instances, minimal amounts of the metabolite (e.g., less than 15% of the metabolite Ml) forms after IV infusion of a composition comprising a compound described herein (e.g., a mixed Via agonist / antagonist, such as Compound 1) (see FIG. 44, panel A). As discussed herein, full vasopressin receptor agonists described herein (e.g., terlipressin) are known to cause (serious) adverse events when administered subcutaneously. As such, the overproduction of a full agonist (Ml) after SC (bolus) injection provides an explanation for the differences between the tolerability profile of the composition in healthy individuals after IV infusion and (SC) bolus injection.

[0249] As described herein, in some instances, metabolite (Ml) formation is reduced by subcutaneously infusing a composition comprising a compound described herein into an individual (see Example 3). Additionally, in some instances, metabolite (Ml) formation is reduced by increasing buffer concentration of a composition comprising a compound described herein (see Example 4). Moreover, in some instances, metabolite (Ml) formation is reduced by increasing parent drug (e.g., Compound 1) concentration of a composition comprising a compound described herein (see Example 4). In some instances, metabolite (Ml) formation is reduced through a combination of any one or more of subcutaneous infusion, increased buffer concentration, and increased drug concentration.

[0250] Provided in some embodiments herein is a method of treating end-stage liver disease (ESLD) in an individual in need thereof, the method comprising subcutaneously infusing intothe individual in need thereof a composition comprising a compound described herein, such as a compound having a structure represented by Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, less than 50% of the compound, such as the compound of Formula I, degrades. In some embodiments, less than 50% of the compound, such as the compound of Formula I, degrades subcutaneously.

[0251] In some embodiments, a composition described herein is subcutaneously administered to the individual and less than 50% of the compound of Formula I degrades (e.g., subcutaneously). In some embodiments, a composition described herein is subcutaneously administered to the 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 subcutaneously administered to the 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.

[0252] In some embodiments, such as after subcutaneous (bolus) injection, more than 50% of the parent compound (e.g., Compound 1) degrades (e.g., to form Ml). In some embodiments, such as after subcutaneous (bolus) injection, more than 60% of the parent compound (e.g., Compound 1) degrades (e.g., to form Ml). In some embodiments, such as after subcutaneous (bolus) injection, more than 70% of the parent compound (e.g., Compound 1) degrades (e.g., to form Ml). In some embodiments, such as after subcutaneous (bolus) injection, more than 80% of the parent compound (e.g., Compound 1) degrades (e.g., to form Ml).

[0253] In some embodiments, a composition described herein is subcutaneously administered to the individual and less than 30% of the compound of Formula I degrades (e.g., subcutaneously). In some embodiments, a composition described herein is subcutaneously administered to the 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 subcutaneously administered to the 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.

[0254] In some embodiments, the composition is subcutaneously infused into the individual and less Ml is formed relative to administration of an otherwise identical composition administered by subcutaneous (bolus) injection.

[0255] In some embodiments, the composition is subcutaneously infused into the individual and less Ml is formed systemically relative to administration of an otherwise identical composition administered by subcutaneous (bolus) injection.

[0256] In some embodiments, the composition is subcutaneously infused into the individual and less Ml is formed locally (injection / infusion site) relative to administration of an otherwise identical composition administered by subcutaneous (bolus) injection.

[0257] In some embodiments, subcutaneously infusing the composition into the individual improves tolerability. In some embodiments, subcutaneously infusing the composition into the individual improves tolerability relative to subcutaneous (bolus) injection, such as based on a reduction of Ml overproduction, such as subcutaneously.

[0258] In some embodiments, subcutaneously infusing the composition into the individual reduces undesired systemic events, such as undesired vasoconstriction that results in ischemia. In some embodiments, subcutaneously infusing the composition into the individual reduces undesired administration site events, such as local site vasoconstriction that result in administration site ischemia. In some embodiments, subcutaneously infusing the composition into the individual reduces undesired systemic events and undesired administration site events.

[0259] Provided in some embodiments herein is a method of reducing (incidence of) local vasoconstriction in an individual in need thereof. In some embodiments, the method is a method for reducing the incidence of local vasoconstriction in an individual in need thereof. In some embodiments, the method is a method of reducing (incidence of) ischemia in an individual in need thereof. In some embodiments, the method is a method of reducing (incidence of) injection site ischemia in an individual in need thereof. In some embodiments, the method comprises subcutaneously infusing into the individual in need thereof a composition comprising a compound described herein, such as a compound having a structure represented by Formula I, or a pharmaceutically acceptable salt thereof.

[0260] In some instances, a compound described herein (e.g., Compound 1) is used to treat complications of ESLD, such as refractory ascites.

[0261] Provided in some embodiments herein is a method of treating ESLD in an individual (e.g., described herein), the method comprising subcutaneously administering to the individual (e.g., described herein) an amount of a compound, the compound being a mixed vasopressin receptor 1A (VI AR) agonist-antagonist. In some embodiments, the amount of the compound is an effective amount of the compound.

[0262] Provided in some embodiments herein is a method of treating a symptom of ELSD in an individual (e.g., described herein), the method comprising subcutaneously administering to the individual (e.g., described herein) an amount of a compound, the compound being a mixed vasopressin receptor 1A (VI AR) agonist-antagonist. In some embodiments, the amount of the compound is an effective amount of the compound.

[0263] Provided in some embodiments herein is a method of treating a complication of ELSD in an individual (e.g., described herein), the method comprising subcutaneously administering to the individual (e.g., described herein) an amount of a compound, the compound being a mixed vasopressin receptor 1A (VI AR) agonist-antagonist. In some embodiments, the complication is ascites. In some embodiments, the complication is refractory ascites. In some embodiments, the amount of the compound is an effective amount of the compound.

[0264] Provided in some embodiments herein is a method of treating end-stage liver disease (ESLD) or a symptom (e.g., complication) thereof in an individual (e.g., in need thereof), the method comprising subcutaneously infusing into the individual (e.g., in need thereof) a composition comprising an (effective) amount of a compound described herein, such as a mixed vasopressin receptor 1A (VI AR) agonist-antagonist described herein. In some embodiments, the compound has a structure represented by Formula I. In some embodiments, the compound is Compound 1.

[0265] In some embodiments, the method further comprises affixing a subcutaneous infusion device to the skin (e.g., skin surface) of the individual. In some embodiments, the subcutaneous infusion device comprises a chamber body and a hollow tube body. In some embodiments, the composition is configured within the chamber body. In some embodiments, the hollow tube body comprises a first opening and a second opening. In some embodiments, the first opening is in fluid contact with the chamber body. In some embodiments, the second opening is configured subcutaneously within the individual after affixing the subcutaneous infusion device to the skin. In some embodiments, the hollow tube is a needle, such as having any gauge suitable for subcutaneous administration (e.g., subcutaneous infusion).

[0266] 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 varying rate. In some embodiments, the rate is a flow rate. In some embodiments, the continuous infusion is at a flow that is insufficient to provide a stream of the composition. In some embodiments, thecontinuous infusion is at a flow that provides a continuous drip to 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 more. 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 an 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 an 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 an administration period. In some embodiments, the administration period is for at least about one hour. In some embodiments, the administration period is for at least about one day. In some embodiments, the administration period is for at least about one week. In some embodiments, the administration period is for at least about one month. In some embodiments, the administration period is about one month or more. In some embodiments, the administration period is about two months or more. In some embodiments, the administration period is about three months or more. In some embodiments, the administration period is about four months or more. In some embodiments, the administration period is about five months or more. In some embodiments, the administration period is about six months or more. In some embodiments, the administration period is about nine months or more. In some embodiments, the administration period is about twelve months or more.

[0267] In some embodiments, a composition described herein is subcutaneously infused into the individual for at least one hour. In some embodiments, the composition is subcutaneously infused into the individual for at least one day. In some embodiments, the composition is subcutaneously infused into the individual for at least one week. In some embodiments, the composition is subcutaneously infused into the individual for at least one month.

[0268] In some embodiments, a composition described herein is subcutaneously infused into the individual continuously for at least one hour. In some embodiments, the composition is subcutaneously infused into the individual continuously for at least one day. In some embodiments, the composition is subcutaneously infused into the individual continuously for at least one week. In some embodiments, the composition is subcutaneously infused into the individual continuously for at least one month.

[0269] In some embodiments, a compound described herein is administered to the individual (e.g., continuously) in an amount of about 0.001 milligram (mg) to about 100 mg. In some embodiments, the compound is administered to the individual (e.g., continuously) in an amountof about 0.01 mg to about 50 mg. In some embodiments, the compound is administered to the individual (e.g., continuously) in an amount of about 0.01 mg to about 20 mg. In some embodiments, the compound is administered to the individual (e.g., continuously) in an amount of about 0.01 mg to about 10 mg. In some embodiments, the compound is administered to the individual (e.g., continuously) in an amount of about 0.1 mg to about 1 mg. In some embodiments, the compound is administered to the individual (e.g., continuously) in an amount of about 0.2 mg. In some embodiments, the composition is administered to the individual over a period of one or more days.

[0270] In some embodiments, a composition described herein comprises the compound in a concentration of about 0.001 milligrams per milliliters (mg / mL) or more. In some embodiments, the composition comprises the compound in a concentration of about 100 mg / mL or less. In some embodiments, the composition comprises the compound in a concentration of about 0.001 mg / mL to about 100 mg / mL. In some embodiments, the composition comprises the compound in a concentration of about 0.01 mg / mL to about 100 mg / mL. In some embodiments, the composition comprises the compound in a concentration of about 0.1 mg / mL to about 100 mg / mL. In some embodiments, the composition comprises the compound in a concentration of about 1 mg / mL to about 100 mg / mL. In some embodiments, the composition comprises the compound in a concentration of about 0.1 mg / mL to about 50 mg / mL. In some embodiments, the composition comprises the compound in a concentration of about 1 mg / mL to about 50 mg / mL. In some embodiments, the composition comprises the compound in a concentration of about 0.1 mg / mL to about 10 mg / mL. In some embodiments, the composition comprises the compound in a concentration of about 1 mg / mL to about 10 mg / mL.

[0271] In some embodiments, a compound described herein is administered to an individual described in need thereof at a dose of about 0.1 milligram (mg) / day. In some embodiments, a compound described herein is administered to an individual described in need thereof at a dose of about 100 mg / day. In some embodiments, a compound described herein is administered to an individual described in need thereof at a dose of about 0.1 mg / day to about 100 mg / day. In some embodiments, a compound described herein is administered to an individual described in need thereof at a dose of about 0.1 mg / day to about 50 mg / day. In some embodiments, a compound described herein is administered to an individual described in need thereof at a dose of about 1 mg / day to about 50 mg / day. In some embodiments, a compound described herein is administered to an individual described in need thereof at a dose of about 1 mg / day to about10 mg / day. In some embodiments, the compound is administered to the individual continuously.

[0272] Provided in some embodiments herein is a method of modulating mean arterial pressure (MAP) in an individual, the method comprising subcutaneously administering to the individual an effective amount of a compound, the compound being a mixed vasopressin receptor 1A (VI AR) agonist-antagonist. In some embodiments, the individual is in need of an increase in MAP. In some embodiments, the individual has end-stage liver disease (ESLD) or a complication thereof. In some embodiments, the individual has ascites. In some embodiments, the individual has developed ascites as a complication of ESLD. In some embodiments, the individual has refractory ascites. In some embodiments, the individual has developed refractory ascites as a complication of ESLD.

[0273] In some embodiments, the MAP of the individual increases (e.g., compared to a baseline measurement before treatment) following subcutaneous administration of a compound described herein (e.g., Compound 1). In some embodiments, the MAP of the individual increases (e.g., compared to a baseline measurement before treatment) following subcutaneous administration of Compound 1.

[0274] In some embodiments, the MAP of the individual increases by about 1% or more (e.g., compared to a baseline measurement before treatment) after administering the compound, or the pharmaceutically acceptable salt thereof, described herein (e.g., Compound 1). In some embodiments, the MAP of the individual increases by about 5% or more (e.g., compared to a baseline measurement before treatment) after administering the compound, or the pharmaceutically acceptable salt thereof, described herein (e.g., Compound 1). In some embodiments, the MAP of the individual increases by about 10% or more (e.g., compared to a baseline measurement before treatment) after administering the compound, or the pharmaceutically acceptable salt thereof, described herein (e.g., Compound 1). In some embodiments, the MAP of the individual increases by about 15% or more (e.g., compared to a baseline measurement before treatment) after administering the compound, or the pharmaceutically acceptable salt thereof, described herein (e.g., Compound 1). In some embodiments, the MAP of the individual increases by about 20% or more (e.g., compared to a baseline measurement before treatment) after administering the compound, or the pharmaceutically acceptable salt thereof, described herein (e.g., Compound 1). In some embodiments, the MAP of the individual increases by about 1% to about 20% (e.g., compared to a baseline measurement before treatment) after administering the compound, or the pharmaceutically acceptable salt thereof, described herein (e.g., Compound 1). In someembodiments, the MAP of the individual increases by about 5% to about 20% (e.g., compared to a baseline measurement before treatment) after administering the compound, or the pharmaceutically acceptable salt thereof, described herein (e.g., Compound 1). In some embodiments, the MAP of the individual increases by about 10% to about 20% (e.g., compared to a baseline measurement before treatment) after administering the compound, or the pharmaceutically acceptable salt thereof, described herein (e.g., Compound 1). In some embodiments, the MAP of the individual increases by about 1% to about 10% (e.g., compared to a baseline measurement before treatment) after administering the compound, or the pharmaceutically acceptable salt thereof, described herein (e.g., Compound 1). In some embodiments, the increase in MAP occurs about one or more hours after the compound, or the pharmaceutically acceptable salt thereof, is administered to the individual. In some embodiments, the increase in MAP occurs about two or more hours after the compound, or the pharmaceutically acceptable salt thereof, is administered to the individual. In some embodiments, the increase in MAP occurs about three or more hours after the compound, or the pharmaceutically acceptable salt thereof, is administered to the individual. In some embodiments, the increase in MAP occurs about four or more hours after the compound, or the pharmaceutically acceptable salt thereof, is administered to the individual. In some embodiments, the increase in MAP occurs about five or more hours after the compound, or the pharmaceutically acceptable salt thereof, is administered to the individual. In some embodiments, the increase in MAP occurs about six or more hours after the compound, or the pharmaceutically acceptable salt thereof, is administered to the individual. In some embodiments, the increase in MAP occurs about twelve or more hours after the compound, or the pharmaceutically acceptable salt thereof, is administered to the individual. In some embodiments, the increase in MAP occurs about one to twelve hours after the compound, or the pharmaceutically acceptable salt thereof, is administered to the individual. In some embodiments, the increase in MAP occurs about one to six hours after the compound, or the pharmaceutically acceptable salt thereof, is administered to the individual. In some embodiments, the increase in MAP occurs about four to six hours after the compound, or the pharmaceutically acceptable salt thereof, is administered to the individual.

[0275] In some embodiments, the MAP of the individual dose-dependently increases after administering the compound, or the pharmaceutically acceptable salt thereof.

[0276] In some embodiments, a compound provided herein has a maximal therapeutic concentration. In some embodiments, the maximal therapeutic concentration comprises an increase in concentration that does not provide dose-dependent increases in MAP. In someembodiments, a compound provided herein has a non-linear dose dependency, such as above the maximal therapeutic concentration. In some embodiments, a dose dependent increase in MAP includes the maximal therapeutic concentration. In some embodiments, dose dependently includes situations where the effect increases with dose for at least a certain dose range. For example, higher doses may provide no or lower dose-dependent increases.

[0277] In some embodiments, a compound described herein (e.g., Compound 1) is a selective vasopressin Via 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 a selective for VI AR. In some embodiments, a compound described herein (e.g., Compound 1) is a selective for VI AR over vasopressin 2 (V2) receptor (V2R). In some instances, a compound described herein (e.g., Compound 1) has no functional V2R activity. In some instances, a compound described herein (e.g., Compound 1) has no functional V2R activity at therapeutic concentrations. In some embodiments, the therapeutic concentration is a concentration sufficient to modulate VI AR.

[0278] In some instances, the activity and selectivity of a compound described herein (e.g., a mixed agonist-antagonist, such as Compound 1) is demonstrated by Tables 35 and 36. In some instances, the activity and selectivity of a compound described herein (e.g., a mixed agonistantagonist, such as Compound 1) is demonstrated by FIGs. 36-38.

[0279] In some embodiments, a compound described herein (e.g., Compound 1) is selective for V 1 AR over V2R by more than 10-fold. In some embodiments, a compound described herein (e.g., Compound 1) is selective for VI AR over V2R by more than 100-fold. In some embodiments, a compound described herein (e.g., Compound 1) is selective for VI AR over V2R by more than 1,000-fold. In some embodiments, a compound described herein (e.g., Compound 1) is selective for VI AR over V2R by more than 10,000-fold. In some embodiments, a compound described herein (e.g., Compound 1) is inactive at V2R.

[0280] In some embodiments, a compound described herein (e.g., Compound 1) comprises a first portion having agonist activity. In some embodiments, a compound described herein (e.g., Compound 1) comprises a second portion having antagonist activity. In some embodiments, a compound described herein (e.g., Compound 1) comprises a first portion having agonist activity and a second portion having antagonist activity.

[0281] In some embodiments, a compound provided herein has a ratio of agonist to antagonist activity of about 90: 10 to about 10:90. In some embodiments, a compound provided herein has a ratio of agonist to antagonist activity of about 50:50.

[0282] In some embodiments, an agonist-antagonists refers to a compound having an agonist portion and an antagonist portion. In specific embodiments, the agonist portion and the antagonist portion are discrete.

[0283] In some embodiments, a V 1 AR agonist-antagonist has a wider therapeutic window than a VI AR agonist. In some embodiments, a VI AR agonist-antagonist described herein has a selective Via agonist portion and a selective Via antagonist portion. In some instances, either the selective Via agonist portion or the selective Via antagonist portion binds to VI AR, such that both the selective Via agonist portion and the selective Via antagonist portion do not bind to the VI AR simultaneously. In some instances, the Via antagonist portion competes with the selective Via agonist portion for binding to V 1 AR. In some instances, V 1 AR agonism provides a (desired) vasoconstrictive effect. In some instances, VI AR antagonism prevents maximal activation of the Via pathway.

[0284] In some instances, FIG. 32, curve 1 illustrates a concentration-response curve for a compound (e.g., a full, nonselective (V2, Via) agonist, such as terlipressin) that provides a lethal level of vasoconstriction (e.g., at relatively high doses, depicted as portion A in FIG. 32) and / or serious adverse events (e.g., at doses above therapeutic levels and at doses below lethal levels of vasoconstriction, depicted as portion B in FIG. 32). In some embodiments, a compound described herein (e.g., a full, nonselective (V2, Via) agonist, such as terlipressin) has a concentration-response curve illustrated in FIG. 32, line 1. In some instances, FIG. 32, line 1 illustrates that a compound described herein (e.g., a full, nonselective (V2, Via) agonist, such as terlipressin) has a relatively narrow therapeutic window. In some instances, FIG. 32, line 1 illustrates that at relatively high doses, a compound described herein (e.g., a full, nonselective (V2, Via) agonist, such as terlipressin) provides a level of vasoconstriction that is lethal (depicted as portion A in FIG. 32) and / or associated with serious adverse events (depicted as portion B in FIG. 32), such as elevated lactate and / or vasoconstriction with ischemia.

[0285] In some embodiments, FIG. 32, curve 2 illustrates a concentration-response curve for a compound (e.g., a mixed Via agonist-antagonist, such as Compound 1) that has a safe and efficacious profile. In some embodiments, a compound described herein (e.g., a mixed Via agonist-antagonist, such as Compound 1) has a concentration-response curve illustrated in FIG. 32, line 2. In some instances, FIG. 32, line 2 illustrates that even at high doses, a compound described herein (e.g., a mixed Via agonist-antagonist, such as Compound 1) has a relatively large therapeutic window. In some instances, FIG. 32, line 2 illustrates that even at high doses,a compound described herein (e.g., a mixed Via agonist-antagonist, such as Compound 1) is safe and efficacious.

[0286] In some instances, FIG. 32, curve 3 illustrates a concentration-response curve for a compound that does not reach therapeutic levels. In some instances, FIG. 32, curve 3 illustrates a concentration-response curve for a full agonist or a partial agonist, such as a compound that has relatively low activity for VI AR.

[0287] In some instances, FIGs. 32-38 demonstrate that a compound described herein (e.g., a mixed Via agonist-antagonist, such as Compound 1) can be safely used (over a large dose range) to treat ESLD or symptoms and / or complications thereof. In some instances, FIG. 32 demonstrates that even at excessively high concentrations, a compound described herein (e.g., a mixed Via agonist-antagonist, such as Compound 1) provides a maximal effect (e.g., a change (increase) in MAP) in an individual (e.g., after subcutaneous administration). In some instances, FIG. 32-38 demonstrate that a compound described herein (e.g., a mixed Via agonist-antagonist, such as Compound 1) provides a robust effect (e.g., change (increase) in MAP) in an individual (e.g., after subcutaneous administration). In some instances, FIGs. 32- 38 demonstrate that a compound described herein (e.g., a mixed Via agonist-antagonist, such as Compound 1) reaches, maintains, and does not go above a safe and efficacious therapeutic effect (e.g., change (increase) in MAP), such as after subcutaneous administration. In some instances, FIGs. 32-38 demonstrate that a compound described herein (e.g., a mixed Via agonist-antagonist, such as Compound 1) maintains (a safe level of) therapeutic efficacy (e.g., after subcutaneous administration) over a prolonged period of time, such as for at least 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 70 minutes, 80 minutes, 90 minutes, or 100 minutes or more. In some instances, FIGs. 32-38 demonstrate that a compound described herein (e.g., a full, nonselective (V2, Via) agonist, such as terlipressin) quickly reaches toxic and potentially harmful concentrations, such as at relatively high doses. In some instances, FIGs. 32-38 demonstrate that a compound described herein (e.g., a full, nonselective (V2, Via) agonist, such as terlipressin) the effect of full, nonselective (V2, Via) agonists diminishes rapidly, such as quickly falling below therapeutic levels after a relatively short period of time (e.g., after about 80 mins or more).

[0288] 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 sitereactions (e.g., local vasoconstriction), such as at a 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 complication(s) of ESLD, such as refractory ascites.

[0289] In some embodiments, the modulation of mean arterial pressure (MAP) in the individual comprises raising MAP by at least 5% over baseline (e.g., such as a level prior to administration of a compound described herein (e.g., Compound 1)). In some embodiments, the modulation of MAP in the individual comprises raising MAP by at least 10% over baseline (e.g., such as a level prior to administration of a compound described herein (e.g., Compound 1)). In some embodiments, the modulation of MAP in the individual comprises raising MAP by at least 15% over baseline (e.g., such as a level prior to administration of a compound described herein (e.g., Compound 1)). In some embodiments, baseline is a level prior to administration of a compound described herein (e.g., Compound 1). In some instances, baseline is a level compared to a control, such as a placebo.

[0290] In some embodiments, the modulation of mean arterial pressure (MAP) in the individual comprises raising MAP by at most 5% over baseline (e.g., such as a level prior to administration of a compound described herein (e.g., Compound 1)). In some embodiments, the modulation of MAP in the individual comprises raising MAP by at most 10% over baseline (e.g., such as a level prior to administration of a compound described herein (e.g., Compound 1)). In some embodiments, the modulation of MAP in the individual comprises raising MAP by at most 15% over baseline (e.g., such as a level prior to administration of a compound described herein (e.g., Compound 1)). In some embodiments, baseline is a level prior to administration of a compound described herein (e.g., Compound 1). In some instances, baseline is a level compared to a control, such as a placebo.

[0291] In some embodiments, the modulation of MAP in the individual comprises raising MAP by at least 5 mmHg over baseline (e.g., such as a level prior to administration of a compound described herein (e.g., Compound 1)). In some embodiments, the modulation of MAP in the individual comprises raising MAP by 1 mmHg or more over baseline (e.g., such as a level prior to administration of a compound described herein (e.g., Compound 1)). In some embodiments, the modulation of MAP in the individual comprises raising MAP by 5 mmHg or more over baseline (e.g., such as a level prior to administration of a compound described herein (e.g., Compound 1)). In some embodiments, the modulation of MAP in the individual comprises raising MAP by 10 mmHg or more over baseline (e.g., such as a level prior to administration of a compound described herein (e.g., Compound 1)). In some embodiments, the modulationof MAP in the individual comprises raising MAP by about 20 mmHg or more over baseline (e.g., such as a level prior to administration of a compound described herein (e.g., Compound 1)). In some embodiments, baseline is a level prior to administration of a compound described herein (e.g., Compound 1).

[0292] Provided in some embodiments herein is a method of modulating mean arterial pressure (MAP) in an individual (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, DI is a vasopressin receptor 1A (VI AR) agonist. In some embodiments, D2 is a VI AR antagonist. In some embodiments, L is a linker. In some embodiments, the compound is administered to the individual as a pharmaceutically acceptable salt.

[0293] In some embodiments, a compound described herein (e.g., Compound 1) has a structure represented by Formula I: D1-L-D2. In some embodiments, DI is a vasopressin receptor 1A (VI AR) agonist. In some embodiments, D2 is a VI AR antagonist. In some embodiments, L is a linker. In some embodiments, the compound is administered to the individual as a pharmaceutically acceptable salt.

[0294] In some embodiments, DI is selective for VI AR. In some embodiments, DI is selective for V 1 AR over V2R. In some embodiments, DI is selective for VI AR over V2R by more than 10-fold. In some embodiments, DI is selective for VI AR over V2R by more than 100-fold. In some embodiments, DI is selective for VI AR over V2R by more than 1,000-fold. In some embodiments, DI is selective for VI AR over V2R by more than 10,000-fold. In some embodiments, DI is inactive at V2R.

[0295] In some embodiments, DI comprises a peptide. In some embodiments, DI is a peptide. In some embodiments, DI comprises a cyclic peptide. In some embodiments, DI is a cyclic peptide. In some embodiments, DI comprises a cyclic nonapeptide. In some embodiments, DI is a cyclic nonapeptide.

[0296] In some embodiments, DI has or comprises the following structure:

[0297] In some embodiments, DI has or comprises the following structure:

[0298] In some instances, D2 is selective for VI AR. In some embodiments, D2 is selective for V 1 AR over V2R. In some instances, D2 is selective for V 1 AR over V2R by more than 10-fold. In some instances, D2 is selective for VI AR over V2R by more than 100-fold. In some instances, D2 is selective for V 1 AR over V2R by more than 1 ,000-fold. In some instances, D2 is selective for VI AR over V2R by more than 10,000-fold. In some instances, D2 is inactive at V2R.

[0299] In some embodiments, at least one of DI and D2 is selective for VI AR. In some embodiments, at least one of DI and D2 is selective for VI AR over V2R.

[0300] 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, is a linear polypeptide comprising about seven or more amino acid residues. In some embodiments, D2 comprises seven to twelve amino acid residues.

[0301] In some embodiments, D2 has or comprises the following structure:

[0302] In some embodiments, D2 has or comprises the following structure:

[0303] In some embodiments, L is a non-hydrolyzable linker.

[0304] In some embodiments, L comprises a peptide bond. In some embodiments, L comprises one or more amino acid residue. In some embodiments, L is one or more amino acid residue.In some embodiments, L comprises one or more modified amino acid residue. In some embodiments, L is one or more modified amino acid residue.

[0305] In some embodiments, L comprises one or more linker group, each linker group being independently selected from the group consisting of a substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl. In some embodiments, L is a bond, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. In some embodiments, L is or comprises substituted or unsubstituted heteroalkyl. In some embodiments, L is heteroalkyl substituted with one or more substituent, each substituent being independently selected form the group consisting of oxo, amino, and substituted heteroalkyl. In some embodiments, L is alkylamine substituted with one or more substituent, each substituent being independently selected form the group consisting of oxo, amino, and substituted heteroalkyl. In some embodiments, L is alkylamine substituted with oxo.

[0306] In some embodiments, L has or comprises the following structure:

[0307] In some embodiments, L has or comprises the following structure:

[0308] In some embodiments, the compound described herein is Compound 1, or a pharmaceutically acceptable salt thereof.

[0309] In some instances, 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-£-lysy l)-L-2,4-diaminobutyryl-, cyclic (1 — >6)-disulfide.

[0310] In some instances, Compound 1 has an empirical molecular formula of C110H161N31O27S2.

[0311] In some instances, Compound 1 has an average molecular mass of 2413.78 u.

[0312] In some instances, a mixed VIA agonist-antagonist provided herein (e.g., Compound 1) is a white to off-white powder.

[0313] In some instances, a mixed VIA agonist-antagonist provided herein (e.g., Compound 1) has a solubility in water of at least 10 mg / mL.

[0314] In some embodiments, Compound 1 has a structure represented by Formula (I- A):Formula (I -A) or a pharmaceutically acceptable salt thereof.

[0315] In some instances, a mixed VIA agonist-antagonist provided herein (e.g., Compound 1) is a 20-mer monocyclic, branched peptide, such as, containing natural and unnatural amino acids, such as, from non-animal origin. In some instances, a mixed VIA agonist-antagonist provided herein (e.g., Compound 1) has an S-S bridge between the Cys1and Cys6residues. In some instances, the branch is linked through the position 8 side chain amino function.

[0316] In some instances, provided herein is a compound having a structure represented by Formula (I-B):Formula (I-B)or a pharmaceutically acceptable salt thereof, wherein:Dab is 2,4-diamino butyric acid, D-Tyr(Me) is O-methyl-D-tyrosine andPhAc is phenylacetic acid (e.g., wherein L-2,4-diamino butyric acid, N-c-acetyl-L- lysine, L-isoglutamine and O- methyl-D-tyrosine are unnatural, and the N-terminal moiety is substituted with phenylacetic acid).

[0317] In some instances, a mixed VIA agonist-antagonist provided herein (e.g., Compound 1) is provided as a pharmaceutically acceptable salt. In some instances, a mixed VIA agonistantagonist provided herein (e.g., Compound 1) is provided as an acetate salt. In some instances, a mixed VIA agonist-antagonist provided herein (e.g., Compound 1) is administered in the form described in Example 1.

[0318] In some embodiments, a compound described herein is any compound described in any of U.S. Patent Number 9,644,000 or U.S. Patent Number 9,388,214, each of which is incorporated herein by reference, in their entirety, in particular for the compounds provided therein.

[0319] In some instances, Compound 1 has an empirical molecular formula of C110H161N31O27S2 (AcOH)z, where z is any integer (e.g., from 1-100).

[0320] Provided in some embodiments herein is a method of modulating mean arterial pressure (MAP) in an individual (e.g., as described herein), the method comprising subcutaneously administering to the individual an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof.

[0321] Provided in some embodiments herein is a pharmaceutical composition comprising an amount of a compound, or a pharmaceutically acceptable salt thereof, described herein (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 (VI AR) 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.

[0322] Provided in some embodiments herein is a subcutaneous formulation comprising a compound described herein, such as a compound having a structure represented by Formula I, or a pharmaceutically acceptable salt thereof.

[0323] In some embodiments, less than 50% of the compound, such as the compound of Formula I, degrades. In some embodiments, less than 50% of the compound, such as thecompound of Formula I, degrades to form Ml. In some embodiments, less than 50% of the compound, such as the compound of Formula I, degrades subcutaneously. In some embodiments, less than 50% of the compound, such as the compound of Formula I, degrades to form Ml subcutaneously.

[0324] In some embodiments, less than 30% of the compound, such as the compound of Formula I, degrades. In some embodiments, less than 30% of the compound, such as the compound of Formula I, degrades to form Ml. In some embodiments, less than 30% of the compound, such as the compound of Formula I, degrades subcutaneously. In some embodiments, less than 30% of the compound, such as the compound of Formula I, degrades to form Ml subcutaneously.

[0325] In some embodiments, a composition described herein further comprises a liquid vehicle or solvent (e.g., water or an aqueous vehicle).

[0326] Provided in some embodiments herein is a subcutaneous formulation having a concentration of a compound described herein, such a compound having a structure represented by Formula I, of about 0.001 milligrams (mg) / milliliters (mL) or more. In some embodiments, the subcutaneous formulation has a concentration of a compound described herein, such a compound having a structure represented by Formula I, of about 100 mg / mL or less. In some embodiments, the subcutaneous formulation has a concentration of a compound described herein, such a compound having a structure represented by Formula I, of about 0.001 mg / mL 100 mg / mL. In some embodiments, the subcutaneous formulation comprises the compound in a concentration of about 0.01 mg / mL to about 100 mg / mL. In some embodiments, the subcutaneous formulation comprises the compound in a concentration of about 0.1 mg / mL to about 100 mg / mL. In some embodiments, the subcutaneous formulation comprises the compound in a concentration of about 1 mg / mL to about 100 mg / mL. In some embodiments, the subcutaneous formulation comprises the compound in a concentration of about 0.1 mg / mL to about 50 mg / mL. In some embodiments, the subcutaneous formulation comprises the compound in a concentration of about 1 mg / mL to about 50 mg / mL. In some embodiments, the subcutaneous formulation comprises the compound in a concentration of about 0.1 mg / mL to about 10 mg / mL. In some embodiments, the subcutaneous formulation comprises the compound in a concentration of about 1 mg / mL to about 10 mg / mL.

[0327] In some embodiments, the compound is formulated as described in the Examples herein. In some embodiments, the compound is formulated as an aqueous solution. In some embodiments, the compound is formulated as an aqueous solution having a concentration ofthe compound of at least about 0.01 mg / mL. In some embodiments, the compound is formulated as an aqueous solution having a concentration of the compound of at least about 0.1 mg / mL. In some embodiments, the compound is formulated as an aqueous solution having a concentration of the compound of at least about 1 mg / mL. In some embodiments, the compound is formulated as an aqueous solution having a concentration of the compound of at least about 10 mg / mL. In some embodiments, the compound is formulated as an aqueous solution having a concentration of the compound of at most about 50 mg / mL. In some embodiments, the compound is formulated as an aqueous solution having a concentration of the compound of at most about 10 mg / mL. In some embodiments, the compound is formulated as an aqueous solution having a concentration of the compound of at most about 1 mg / mL. In some embodiments, the compound is formulated as an aqueous solution having a concentration of the compound of at most about 0.1 mg / mL. In some embodiments, the compound is formulated as an aqueous solution having a concentration of the compound of at most about 0.01 mg / mL. In some embodiments, the compound is formulated as an aqueous solution having a concentration of the compound of about 0.01 mg / mL to about 50 mg / mL. In some embodiments, the compound is formulated as an aqueous solution having a concentration of the compound of about 0.01 mg / mL to about 10 mg / mL. In some embodiments, the compound is formulated as an aqueous solution having a concentration of the compound of about 1 mg / mL to about 10 mg / mL. In some embodiments, the composition is formulated with acetate buffer. In some embodiments, the composition is formulated at a pH of 4.5. In some embodiments, the composition is formulated with mannitol.

[0328] In some embodiments, additives (e.g., preservatives) were added to a (e.g., subcutaneous) composition having a pH of about 3-6 (e.g., 4.5) and comprising at least about 1 millimolar (mM) acetate buffer (e.g., about 5 mM sodium acetate to about 150 mM sodium acetate) and about 10 milligram per milliliters (mg / mL) to about 100 mg / mL mannitol (e.g., about 43.6 mg / mL mannitol). In some instances, the additive is a preservative. In some instances, 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.

[0329] In some embodiments, provided herein is a composition comprising Compound 1. In some embodiments, the composition is suitable for subcutaneous administration. In some embodiments, the formulation is suitable for subcutaneous (bolus) injection. In some embodiments, the subcutaneous (bolus) injection is provided to the individual as a single dose (e.g., all at once). In some embodiments, the formulation is suitable for subcutaneous infusion.

[0330] In some embodiments, a composition described herein comprises an additive. In some embodiments, a composition described herein is a subcutaneous composition and comprises an additive. In some embodiments, the additive is selected from the group consisting of a preservative, a solubilizing agent (e.g., a cyclodextrin), a buffering agent, and a chelating agent (e.g., zinc acetate or ethylenediaminetetraacetic acid (EDTA)). In some embodiments, the additive is a preservative.

[0331] Provided in some embodiments herein is a subcutaneous formulation comprising a compound having a structure represented by Formula I and a preservative.

[0332] In some embodiments, a composition described herein further comprises a preservative. In some embodiments, the preservative is any suitable preservative, such as meta (m)-cresol, phenol, chlorobutanol, or benzyl alcohol. In some embodiments, the preservative is present in the composition in an amount of about 0.1 mg / mL or more. In some embodiments, the preservative is present in the composition in an amount of about 50 mg / mL or less. In some embodiments, the preservative is present in the composition in an amount of about 0.1 mg / mL to about 50 mg / mL. In some embodiments, the preservative is present in the composition in an amount of about 1 mg / mL to about 20 mg / mL.

[0333] In some instances, a composition comprising a preservative described herein showed no physical interaction (e.g., aggregation) with any screened preservatives (e.g., between the preservative and Compound 1), even at relatively high concentrations of the preservative.

[0334] Provided in some embodiments herein is a subcutaneous formulation comprising a compound having a structure represented by Formula I and a solubilizing agent.

[0335] In some embodiments, a composition described herein further comprises a solubilizing agent. In some embodiments, the preservative is any suitable solubilizing agent, such as a cyclodextrin (e.g., sulfobutylether-P-cyclodextrin (SBECD)). In some embodiments, the solubilizing agent is present in the composition in an amount of about 0.1 mg / mL or more. 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 someembodiments, the solubilizing agent is present in the composition in an amount of about 1 mg / mL to about 100 mg / mL. In some embodiments, the solubilizing agent is present in the composition in an amount of about 60 mg / mL to about 80 mg / mL.

[0336] In some embodiments, the composition further comprises a buffering agent. In some embodiments, the buffering agent has a pKa of about 3.0 to about 6.0, such as at 25 °C. In some embodiments, the buffering agent is selected from the group consisting of acetate buffer, succinate buffer, phosphate buffer, and citrate buffer. In some embodiments, the composition further comprises acetate buffer. In some embodiments, the acetate buffer is a combination of acetate and acetic acid. In some embodiments, the composition further comprises succinate buffer. In some embodiments, the succinate buffer is a combination of succinate and succinic acid. In some embodiments, the composition further comprises citrate buffer. In some embodiments, the citrate buffer is a combination of citrate and citric acid.

[0337] Provided in some embodiments herein is a subcutaneous formulation comprising a compound having a structure represented by Formula I and a buffering agent at a concentration of about 1 millimolar (mM) to about 1 M.

[0338] In some embodiments, a composition described herein comprises a buffering agent in a concentration of about 1 millimolar (mM) or more. In some embodiments, a composition described herein comprises a buffering agent in a concentration of about 1 molar (M) or less. In some embodiments, a composition described herein comprises a buffering agent in a concentration of about 1 mM to about 1 M. In some embodiments, a composition described herein comprises a buffering agent in a concentration of about 1 mM to about 500 mM. In some embodiments, a composition described herein comprises a buffering agent in a concentration of about 1 mM to about 250 mM. In some embodiments, a composition described herein comprises a buffering agent in a concentration of about 50 mM to about 250 mM. In some embodiments, a composition described herein comprises a buffering agent in a concentration of about 50 mM to about 150 mM. In some embodiments, a composition described herein comprises a buffering agent in a concentration of about 100 mM. In some embodiments, a composition described herein comprises a buffering agent in a concentration of about 1 mM to about 50 mM. In some embodiments, a composition described herein comprises a buffering agent in a concentration of about 5 mM to about 25 mM. In some embodiments, a composition described herein comprises a buffering agent in a concentration of about 10 mM.

[0339] In some embodiments, a composition described herein has a pH sufficient to inhibit (e.g., deactivate or inactivate) a protease (e.g., trypsin), such as in subcutaneous layer of an individual subcutaneously administered the formulation.

[0340] In some embodiments, the pH of a composition described herein does not (substantially) change when administered subcutaneously to an individual. In some embodiments, the pH of a composition described herein does not (substantially) change when administered subcutaneously to an individual by subcutaneous (bolus) injection. In some embodiments, the pH of a composition described herein does not (substantially) change when administered subcutaneously to an individual subcutaneous infusion).

[0341] In some embodiments, a composition described herein has a pH of at least about 3. In some embodiments, a composition described herein has 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, a composition described herein has a pH of about 4 to about 8. In some embodiments, a composition described herein has a pH of about 4 to about 6. In some embodiments, a composition described herein has a pH of about 4.5 to about 5. In some embodiments, a composition described herein has a pH of about 4. In some embodiments, a composition described herein has a pH of about 4.5.

[0342] In some embodiments, a composition described herein has an ionic strength of about 1 mM or more. In some embodiments, a composition described herein has an ionic strength of about 1 M or less. In some embodiments, a composition described herein has an ionic strength of about 1 mM to about 500 mM. In some embodiments, a composition described herein has an ionic strength of about 5 mM to about 200 mM. In some embodiments, a composition described herein has an ionic strength of about 5 mM to about 10 mM to about 100 mM.

[0343] In some embodiments, a compound described herein, such as a compound having a structure represented by Formula I, is (e.g., substantially) less susceptible to (e.g., protease) degradation. In some embodiments, a compound described herein, such as a compound having a structure represented by Formula I, is (e.g., substantially) less susceptible to (e.g., protease) degradation in the subcutaneous layer of an individual subcutaneously administered a composition comprising the compound.

[0344] In some embodiments, a compound described herein, such as a compound having a structure represented by Formula I, is stable in a composition described herein. In some embodiments, less than 50% of a compound described herein, such as a compound having a structure represented by Formula I, degrades in a vial. In some embodiments, less than 50% of a compound described herein, such as a compound having a structure represented by FormulaI, degrades in a vial over a period of at least about one week (e.g., about one week or more, two week or more, three weeks or more, or four weeks or more). In some embodiments, less than 50% of a compound described herein, such as a compound having a structure represented by Formula I, degrades subcutaneously. In some embodiments, less than 50% of a compound described herein, such as a compound having a structure represented by Formula I, degrades subcutaneously over a period of at least about one hour (e.g., about one hour or more, six hours or more, twelve hours or more, or twenty-four hours or more).

[0345] In some embodiments, a composition described herein, such as 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) is well-tolerated after subcutaneous (e.g., injection or infusion) administration (see Examples 3 and 4).

[0346] In some embodiments, a composition described herein comprises a pH and / or buffer (e.g., acetate buffer) concentration that is sufficient to inhibit, reduce, or eliminate formation of undesirable metabolites of a compound described herein (e.g., Compound 1), such as full (Via) agonists like Ml. In some instances, compositions comprising relatively high buffer concentrations (e.g., 50 mM or more of the buffer) prolong the amount of time a local environment (e.g., at or near the injection site) maintains a certain pH (e.g., a pH of about 3 or more) that is sufficient to inhibit, reduce or eliminate formation of undesirable metabolites of a compound described herein (e.g., Compound 1), such as full (Via) agonists like Ml . In some instances, compositions having an acidic pH (e.g., pH of 1 to 6) produce undesirable effects when (subcutaneously) injected, such effects including injection site burning, stinging, pain, or the like. Injecting a composition (subcutaneously) that has a relatively acidic pH or a buffer concentration that prolongs the amount of time a local environment (e.g., at or near the injection site) maintains a certain (e.g., acidic) pH would be expected to prolong such undesirable effects. In contrast, compositions described herein that have a relatively acidic pH (e.g., a pH of 4 or 4.5) and / or a buffer concentration that prolongs the amount of time a local environment (e.g., at or near the injection site) maintains a certain (e.g., acidic) pH do not produce (noticeable) undesirable effects when administered subcutaneously (e.g., by injection or infusion). In some instances, higher buffer concentrations inhibit, reduce, or eliminate formation of Ml to provide sufficient amount of time for absorption of a compound described herein, such as due to an extended time that the pH of the local environment is acidic (e.g., 4.5) after administration. In some embodiments, the buffer concentration of a composition provided herein that prolongs the amount of time a local environment (e.g., at or near the injection site) maintains a certain (e.g., acidic) is about 50 mM or more. In some embodiments, the pH of a composition providedherein that sufficiently inhibits, reduces, or eliminates formation of undesirable metabolites of a compound described herein (e.g., Compound 1), such as full (Via) agonists like Ml, when administered subcutaneously (e.g., by injection or infusion) is acidic. In some embodiments, the pH of a composition provided herein that sufficiently inhibits, reduces, or eliminates formation of undesirable metabolites of a compound described herein (e.g., Compound 1), such as full (Via) agonists like Ml, when administered subcutaneously (e.g., by injection or infusion) is about 3 or more. In some embodiments, the pH of a composition provided herein that sufficiently inhibits, reduces, or eliminates formation of undesirable metabolites of a compound described herein (e.g., Compound 1), such as full (Via) agonists like Ml, when administered subcutaneously (e.g., by injection or infusion) is about 4 or 4.5.

[0347] In some embodiments, a composition described herein (e.g., a composition suitable for intravenous or subcutaneous administration) comprises acetate buffer in a concentration of about 10 mM or more. In some embodiments, a composition described herein comprises acetate buffer in a concentration of about 50 mM or more.

[0348] In some embodiments, a composition described herein (e.g., a composition suitable for intravenous or subcutaneous administration) has a pH of about 3 or more.

[0349] In some embodiments, a composition described herein (e.g., a composition suitable for intravenous or subcutaneous administration) comprises acetate buffer in 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 does not comprise a preservative. In some embodiments, the composition is suitable for subcutaneous administration. In some embodiments, the composition is suitable for subcutaneous infusion.

[0350] In some embodiments, a composition described herein (e.g., a composition suitable for subcutaneous administration) comprises acetate buffer in a concentration of 100 mM (or more) and has a pH of about 4 or 4.5. In some embodiments, the composition is suitable for subcutaneous administration. In some embodiments, the composition is suitable for subcutaneous (bolus) injection. In some embodiments, the composition is suitable for subcutaneous infusion.

[0351] In some embodiments, a composition described herein (e.g., a composition suitable for intravenous or subcutaneous administration) comprises acetate buffer in a concentration of about 10 mM or more. In some embodiments, a composition described herein comprises acetate buffer in a concentration of about 50 mM or more.

[0352] In some embodiments, a composition described herein comprises a concentration of a compound described herein (e.g., Compound 1) that is sufficient to inhibit, reduce, or eliminate formation of undesirable metabolites of the compound, such as full (Via) agonists like Ml. In some instances, compositions comprising relatively high drug concentrations (e.g., 0.1 milligrams / milliliter (mg / mL) or more) saturate a local environment (e.g., at or near the injection site) with drug such that more of the drug absorbs before substantial formation of undesirable metabolites of the drug, such as full (Via) agonists. In some embodiments, compositions described herein that have a relatively high concentration of a compound provided herein sufficiently inhibits, reduces, or eliminates formation of undesirable metabolites of a compound described herein (e.g., Compound 1), such as full (Via) agonists like Ml, when administered subcutaneously (e.g., by injection or infusion). In some embodiments, the drug concentration (e.g., the concentration of a compound described herein) in the composition is about 0.1 mg / mL or more.

[0353] In some embodiments, a composition provided herein has a concentration of a compound described herein that is about 0.1 mg / mL or more. In some embodiments, a composition provided herein has a concentration of a compound described herein that is about 1 mg / mL or more. In some embodiments, a composition provided herein has a concentration of a compound described herein that is about 100 mg / mL or less. In some embodiments, a composition provided herein has a concentration of a compound described herein that is about 0.1 mg / mL to about 100 mg / mL. In some embodiments, a composition provided herein has a concentration of a compound described herein that is about 0.1 mg / mL to about 10 mg / mL. In some embodiments, the composition is suitable for subcutaneous administration. In some embodiments, the composition is suitable for subcutaneous (bolus) injection. In some embodiments, the composition is suitable for subcutaneous infusion. In some embodiments, a composition provided herein has a concentration of a compound described herein that is about 0.1 mg / mL or less. In some embodiments, the composition is suitable for intravenous administration.

[0354] In some embodiments, a composition described herein is suitable for subcutaneous infusion. In some embodiments, a composition suitable for subcutaneous infusion is administered to an individual in a way that reduces (injection site) injury or trauma. In some embodiments, a composition suitable for subcutaneous infusion is administered to an individual over a certain (prolonged) period of time. In some embodiments, a composition suitable for subcutaneous infusion is administered to an individual at a certain (relatively slow) rate, such as a drip. In some embodiments, the composition is administered at a rate that issufficient to provide a drip (e.g., not a stream) of the composition. In some embodiments, the composition is administered at a rate that is about 0.1 milliliters per hour (mL / hr) or less, such as over a prolonged period of time (e.g., a period of about 24 hours or more).

[0355] Provided in some embodiments herein is a pharmaceutical composition comprising an amount of a compound having a structure represented by Formula I. In some embodiments, the composition is formulated for subcutaneous administration. In some embodiments, the amount of the compound is an effective amount of the compound.

[0356] Provided in some embodiments herein is a pharmaceutical composition comprising an amount of Compound 1, or a pharmaceutically acceptable salt thereof, the composition being formulated for subcutaneous administration. In some embodiments, the amount of the compound is an effective amount of the compound.

[0357] In some embodiments, a composition described herein is suitable for systemic delivery of an active agent described herein, such as a compound having a structure represented by Formula I. In some embodiments, a composition described herein is suitable for administration of an active agent described herein, such as a compound having a structure represented by Formula I, in an out-patient setting, such as at-home. In some embodiments, a composition described herein is suitable for systemic delivery of Compound 1. In some embodiments, a composition described herein is suitable for administration of Compound 1 in an out-patient setting, such as at-home.

[0358] Provided in some embodiments herein is a system for treating end-stage liver disease (ESLD), the system comprising a composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof and a device configured to provide subcutaneous infusion of the composition to an individual when the device is positioned on the skin of the individual.

[0359] In some embodiments, the system comprises an adhesive body for affixing the (subcutaneous infusion) device to the surface of the skin of the individual. In some embodiments, the system comprises an adhesive body for reversibly affixing the (subcutaneous infusion) device to the surface of the skin of the individual.

[0360] In some embodiments, the system comprises a chamber body and a hollow tube body. In some embodiments,, the composition is configured within the chamber body. In some embodiments, wherein the hollow tube body comprises a first opening and a second opening. In some embodiments, the first opening is in fluid contact with the chamber body. In some embodiments, the second opening is configured subcutaneously within the individual afteraffixing the subcutaneous infusion device to the skin of the individual. In some embodiments, the hollow tube is a needle, such as having any gauge suitable for subcutaneous administration (e.g., subcutaneous infusion).

[0361] In some embodiments, the system does not comprise an adhesive body. In some embodiments, the device is not attached to the surface of the skin of the individual. In some embodiments, the chamber body is attached to an injection port. In some embodiments, the system does not comprise an adhesive body and the chamber body is attached to an injection port.

[0362] In some embodiments, the (subcutaneous infusion) device further comprises a pump configured to subcutaneously infuse the composition into the individual at a constant or varying 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.

[0363] In some embodiments, the device is configured to receive a vial and / or a cartridge of the composition.

[0364] In some embodiments, the device is a subcutaneous infusion device. In some embodiments, the device is a pump.

[0365] In some instances, provided herein is a pharmaceutical composition comprising an effective amount of a first compound, or a pharmaceutically acceptable salt thereof, and an effective amount of a second compound, or a pharmaceutically acceptable salt thereof, wherein the first compound is a vasoconstrictor, and wherein the second compound sufficiently blocks a (e.g., local) vasoconstrictive effect of the first compound, such as providing sufficient uptake of the first compound to the circulatory system and / or an internal organ (e.g., a kidney) of an individual (e.g., in need thereof). In some embodiments, the pharmaceutical composition is injectable. In some instances, the pharmaceutical composition is suitable for intravitreal administration. In some instances, the pharmaceutical composition is suitable for subcutaneous administration. In some instances, the first compound is a vasopressin receptor 1A (VI AR) agonist. In some instances, the first compound is a selective VI AR agonist. In some instances, the second compound is a VI AR antagonist. In some instances, the second compound is a selective VI AR antagonist. In some instances, the second compound is a vasodilator.

[0366] In some instances, such as in the carbon tetrachloride model described in Example 6, a compound described herein (e.g., Compound 1) administered (e.g., subcutaneously) to anindividual (e.g., in need thereof) improves renal perfusion, renal excretory function, and systemic hemodynamics in an individual (e.g., in need thereof) (e.g., relative to vehicle-treated animals).

[0367] In some instances, a compound described herein (e.g., Compound 1) administered subcutaneously improves excretory renal function (see Example 6). In some instances, a compound described herein (e.g., Compound 1) administered twice daily by subcutaneous injection improves excretory renal function (see Example 6). In some instances, a compound described herein (e.g., Compound 1) administered twice daily by subcutaneous bolus injection improves excretory renal function (see Example 6). In some instances, a compound described herein (e.g., Compound 1) administered twice daily by subcutaneous injection over three days improves excretory renal function (see Example 6).

[0368] In some instances, such as in the bile duct ligation (BDL) and ascites model described in Example 6, a compound described herein (e.g., Compound 1) administered (e.g., subcutaneously) to an individual (e.g., in need thereof) decreases ascites volume, splenic vasodilation, fluid retention, body weight, and / or net fluid balance in an individual (e.g., in need thereof) (e.g., relative to vehicle-treated animals). In some instances, such as in the bile duct ligation (BDL) and ascites model described in Example 6, a compound described herein (e.g., Compound 1) administered (e.g., subcutaneously) to an individual (e.g., in need thereof) provides improved urine potassium and urine sodium excretion in an individual (e.g., in need thereof) (e.g., relative to vehicle control).

[0369] In some instances, such as in the bile duct ligation (BDL) and ascites model described in Example 6, repeat subcutaneous administration of a compound described herein (e.g., Compound 1) provides a decrease in ascites volume, a decrease in splanchnic vasodilation, a reduction in fluid retention, and / or significant urine potassium and urine sodium excretion without hyponatremia immediately after the compound is administered. In some embodiments, repeat subcutaneous administration of a compound described herein (e.g., Compound 1) provides a significant reduction in urine potassium excretion (e.g., compared to vehicle control), such as 5-24 hours after the compound is administered.

[0370] In some instances, a compound described herein (e.g., Compound 1) administered subcutaneously decreases ascites volume, spleen weight, and body weight (e.g., relative to vehicle control). In some instances, a compound described herein (e.g., Compound 1) administered via subcutaneous bolus administration decreases ascites volume, spleen weight, and body weight (e.g., relative to vehicle control). In some instances, a compound describedherein (e.g., Compound 1) administered daily via subcutaneous administration decreases ascites volume, spleen weight, and body weight (e.g., relative to vehicle control). In some instances, a compound described herein (e.g., Compound 1) administered twice-daily via subcutaneous administration decreases ascites volume, spleen weight, and body weight (e.g., relative to vehicle control). In some instances, a compound described herein (e.g., Compound 1) administered twice-daily via subcutaneous bolus administration decreases ascites volume, spleen weight, and body weight (e.g., relative to vehicle control). In some instances, a compound described herein (e.g., Compound 1) administered twice-daily via subcutaneous administration for consecutive days decreases ascites volume, spleen weight, and body weight (e.g., relative to vehicle control). In some instances, a compound described herein (e.g., Compound 1) administered twice-daily via subcutaneous administration for two or more days decreases ascites volume, spleen weight, and body weight (e.g., relative to vehicle control). In some instances, a compound described herein (e.g., Compound 1) administered twice-daily via subcutaneous administration for five or more days decreases ascites volume, spleen weight, and body weight (e.g., relative to vehicle control).

[0371] In some instances, a compound described herein (e.g., Compound 1) administered subcutaneously increases urine volume, urine sodium excretion, and urine potassium excretion (e.g., relative to vehicle control). In some instances, a compound described herein (e.g., Compound 1) administered via subcutaneous bolus administration de increases urine volume, urine sodium excretion, and urine potassium excretion (e.g., relative to vehicle control). In some instances, a compound described herein (e.g., Compound 1) administered daily via subcutaneous administration increases urine volume, urine sodium excretion, and urine potassium excretion (e.g., relative to vehicle control). In some instances, a compound described herein (e.g., Compound 1) administered twice-daily via subcutaneous administration increases urine volume, urine sodium excretion, and urine potassium excretion (e.g., relative to vehicle control). In some instances, a compound described herein (e.g., Compound 1) administered twice-daily via subcutaneous bolus administration increases urine volume, urine sodium excretion, and urine potassium excretion (e.g., relative to vehicle control). In some instances, a compound described herein (e.g., Compound 1) administered twice-daily via subcutaneous administration for consecutive days increases urine volume, urine sodium excretion, and urine potassium excretion (e.g., relative to vehicle control). In some instances, a compound described herein (e.g., Compound 1) administered twice-daily via subcutaneous administration for two or more days increases urine volume, urine sodium excretion, and urine potassium excretion (e.g., relative to vehicle control). In some instances, a compound described herein (e.g.,Compound 1) administered twice-daily via subcutaneous administration for five or more days increases urine volume, urine sodium excretion, and urine potassium excretion (e.g., relative to vehicle control).

[0372] In some instances, a compound described herein (e.g., Compound 1) administered subcutaneously decreases urine potassium excretion (e.g., relative to vehicle control). In some instances, a compound described herein (e.g., Compound 1) administered via subcutaneous bolus administration decreases urine potassium excretion (e.g., relative to vehicle control). In some instances, a compound described herein (e.g., Compound 1) administered daily via subcutaneous administration decreases urine potassium excretion (e.g., relative to vehicle control). In some instances, a compound described herein (e.g., Compound 1) administered twice-daily via subcutaneous administration decreases urine potassium excretion (e.g., relative to vehicle control). In some instances, a compound described herein (e.g., Compound 1) administered twice-daily via subcutaneous bolus administration decreases urine potassium excretion (e.g., relative to vehicle control). In some instances, a compound described herein (e.g., Compound 1) administered twice-daily via subcutaneous administration for consecutive days decreases urine potassium excretion (e.g., relative to vehicle control). In some instances, a compound described herein (e.g., Compound 1) administered twice-daily via subcutaneous administration for two or more days decreases urine potassium excretion (e.g., relative to vehicle control). In some instances, a compound described herein (e.g., Compound 1) administered twice-daily via subcutaneous administration for five or more days decreases urine potassium excretion (e.g., relative to vehicle control).

[0373] In some embodiments, urine volume of the individual increases (e.g., compared to a vehicle control) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, such as within the first 24-hours, urine volume of the individual significantly increases (e.g., compared to a vehicle control) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, such as within the first 4 hours, urine volume of the individual significantly increases (e.g., compared to a vehicle control) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual.

[0374] In some embodiments, urine volume of the individual increases by about 25% or more (e.g., compared to a vehicle control) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In someembodiments, urine volume of the individual increases by about 50% or more (e.g., compared to a vehicle control) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine volume of the individual increases by about 100% or more (e.g., compared to a vehicle control) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine volume of the individual increases by about 200% or more (e.g., compared to a vehicle control) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine volume of the individual increases by about 300% or more (e.g., compared to a vehicle control) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine volume of the individual increases by about 400% or more (e.g., compared to a vehicle control) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine volume of the individual increases by about 500% or more (e.g., compared to a vehicle control) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual.

[0375] In some embodiments, urine volume of the individual increases by about 25% or less (e.g., compared to a vehicle control) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine volume of the individual increases by about 50% or less (e.g., compared to a vehicle control) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine volume of the individual increases by about 100% or less (e.g., compared to a vehicle control) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine volume of the individual increases by about 200% or less (e.g., compared to a vehicle control) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine volume of the individual increases by about 300% or less (e.g., compared to a vehicle control) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine volume of the individual increases by about 400% or less (e.g., comparedto a vehicle control) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine volume of the individual increases by about 500% or less (e.g., compared to a vehicle control) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual.

[0376] In some embodiments, urine volume of the individual increases by about 10% to about 1000% (e.g., compared to a vehicle control) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine volume of the individual increases by about 50% to about 500% (e.g., compared to a vehicle control) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine volume of the individual increases by about 100% to about 500% (e.g., compared to a vehicle control) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual.

[0377] In some embodiments, urine volume of the individual is about 10% or more higher at least one day after subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine volume of the individual is about 50% or more at least one day after subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine volume of the individual is about 100% or more higher at least one day after subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine volume of the individual is higher for two or more days after subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine volume of the individual is higher for three or more days after subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual.

[0378] In some embodiments, urine sodium of the individual increases (e.g., compared to a vehicle control) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine sodium of the individual significantly increases (e.g., compared to a vehicle control) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine sodium excretion of the individual increases (e.g., compared to a vehiclecontrol) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine sodium excretion of the individual significantly increases (e.g., compared to a vehicle control) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual.

[0379] In some embodiments, urine potassium of the individual increases (e.g., compared to a vehicle control) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine potassium of the individual significantly increases (e.g., compared to a vehicle control) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine potassium excretion of the individual increases (e.g., compared to a vehicle control) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine potassium excretion of the individual significantly increases (e.g., compared to a vehicle control) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual.

[0380] In some embodiments, urine potassium excretion of the individual decreases (e.g., compared to a vehicle control) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine potassium excretion of the individual substantially decreases (e.g., compared to a vehicle control) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual.

[0381] In some embodiments, urine sodium excretion of the individual increases by about 10% or more (e.g., compared to a vehicle control, such as within the first 4 hours of treatment) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine sodium excretion of the individual increases by about 100% or more (e.g., compared to a vehicle control, such as within the first 4 hours of treatment) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine sodium excretion of the individual increases by about 250% or more (e.g., compared to a vehicle control, such as within the first 4 hours of treatment) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine sodium excretion of theindividual increases by about 500% or more (e.g., compared to a vehicle control, such as within the first 4 hours of treatment) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine sodium excretion of the individual increases by about 750% or more (e.g., compared to a vehicle control, such as within the first 4 hours of treatment) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine sodium excretion of the individual increases by about 1000% or more (e.g., compared to a vehicle control, such as within the first 4 hours of treatment) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine sodium excretion of the individual increases by about 1500% or more (e.g., compared to a vehicle control, such as within the first 4 hours of treatment) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine sodium excretion of the individual increases by about 2000% or more (e.g., compared to a vehicle control, such as within the first 4 hours of treatment) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual.

[0382] In some embodiments, urine sodium excretion of the individual increases by about 10% to about 5000% (e.g., compared to a vehicle control, such as within the first 4 hours of treatment) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine sodium excretion of the individual increases by about 10% to about 2500% (e.g., compared to a vehicle control, such as within the first 4 hours of treatment) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine sodium excretion of the individual increases by about 10% to about 2000% (e.g., compared to a vehicle control, such as within the first 4 hours of treatment) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine sodium excretion of the individual increases by about 100% to about 2000% (e.g., compared to a vehicle control, such as within the first 4 hours of treatment) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine sodium excretion of the individual increases by about 100% to about 1000% (e.g., compared to a vehicle control, such as within the first 4 hours of treatment)following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual.

[0383] In some embodiments, urine sodium excretion of the individual increases by about 10% or more (e.g., compared to a vehicle control, such as within the first 4 hours of treatment) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine sodium excretion of the individual increases by about 100% or more (e.g., compared to a vehicle control, such as within the first 4 hours of treatment) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine sodium excretion of the individual increases by about 250% or more (e.g., compared to a vehicle control, such as within the first 4 hours of treatment) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine sodium excretion of the individual increases by about 500% or more (e.g., compared to a vehicle control, such as within the first 4 hours of treatment) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine sodium excretion of the individual increases by about 750% or more (e.g., compared to a vehicle control, such as within the first 4 hours of treatment) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine sodium excretion of the individual increases by about 1000% or more (e.g., compared to a vehicle control, such as within the first 4 hours of treatment) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine sodium excretion of the individual increases by about 1500% or more (e.g., compared to a vehicle control, such as within the first 4 hours of treatment) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine sodium excretion of the individual increases by about 2000% or more (e.g., compared to a vehicle control, such as within the first 4 hours of treatment) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual.

[0384] In some embodiments, urine sodium excretion of the individual increases by about 10% to about 5000% (e.g., compared to a vehicle control, such as within the first 4 hours of treatment) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine sodiumexcretion of the individual increases by about 10% to about 2500% (e.g., compared to a vehicle control, such as within the first 4 hours of treatment) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine sodium excretion of the individual increases by about 10% to about 2000% (e.g., compared to a vehicle control, such as within the first 4 hours of treatment) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine sodium excretion of the individual increases by about 100% to about 2000% (e.g., compared to a vehicle control, such as within the first 4 hours of treatment) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine sodium excretion of the individual increases by about 100% to about 1000% (e.g., compared to a vehicle control, such as within the first 4 hours of treatment) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual.

[0385] In some embodiments, urine potassium excretion of the individual increases by about 10% or more (e.g., compared to a vehicle control, such as within the first 4 hours of treatment) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine potassium excretion of the individual increases by about 100% or more (e.g., compared to a vehicle control, such as within the first 4 hours of treatment) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine potassium excretion of the individual increases by about 250% or more (e.g., compared to a vehicle control, such as within the first 4 hours of treatment) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine potassium excretion of the individual increases by about 500% or more (e.g., compared to a vehicle control, such as within the first 4 hours of treatment) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine potassium excretion of the individual increases by about 750% or more (e.g., compared to a vehicle control, such as within the first 4 hours of treatment) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine potassium excretion of the individual increases by about 1000% or more (e.g., compared to a vehicle control, such as within the first 4 hours of treatment) following subcutaneous administration of a compound, orthe pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine potassium excretion of the individual increases by about 1500% or more (e.g., compared to a vehicle control, such as within the first 4 hours of treatment) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine potassium excretion of the individual increases by about 2000% or more (e.g., compared to a vehicle control, such as within the first 4 hours of treatment) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual.

[0386] In some embodiments, urine potassium excretion of the individual increases by about 10% to about 5000% (e.g., compared to a vehicle control, such as within the first 4 hours of treatment) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine potassium excretion of the individual increases by about 10% to about 2500% (e.g., compared to a vehicle control, such as within the first 4 hours of treatment) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine potassium excretion of the individual increases by about 10% to about 2000% (e.g., compared to a vehicle control, such as within the first 4 hours of treatment) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine potassium excretion of the individual increases by about 100% to about 2000% (e.g., compared to a vehicle control, such as within the first 4 hours of treatment) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine potassium excretion of the individual increases by about 100% to about 1000% (e.g., compared to a vehicle control, such as within the first 4 hours of treatment) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual.

[0387] In some embodiments, urine potassium excretion of the individual decreases by about 10% or more (e.g., compared to a vehicle control, such as about 5 hours after treatment) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine potassium excretion of the individual decreases by about 100% or more (e.g., compared to a vehicle control, such as about 5 hours after treatment) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine potassium excretion of the individual decreases by about 250% or more(e.g., compared to a vehicle control, such as about 5 hours after treatment) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine potassium excretion of the individual decreases by about 500% or more (e.g., compared to a vehicle control, such as about 5 hours after treatment) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual.

[0388] In some embodiments, urine potassium excretion of the individual decreases by about 10% to about 5000% (e.g., compared to a vehicle control, such as about 5 hours after treatment) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine potassium excretion of the individual decreases by about 10% to about 2500% (e.g., compared to a vehicle control, such as about 5 hours after treatment) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine potassium excretion of the individual decreases by about 10% to about 2000% (e.g., compared to a vehicle control, such as about 5 hours after treatment) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine potassium excretion of the individual decreases by about 10% to about 500% (e.g., compared to a vehicle control, such as about 5 hours after treatment) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, urine potassium excretion of the individual decreases by about 10% to about 100% (e.g., compared to a vehicle control, such as about 5 hours after treatment) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual.

[0389] In some embodiments, ascites volume of the individual decreases (e.g., compared to a vehicle control) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, ascites volume of the individual significantly decreases (e.g., compared to a vehicle control) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual.

[0390] In some embodiments, ascites volume of the individual decreases by about 10% or more (e.g., compared to a vehicle control, such as when measured after 3 days of treatment) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, ascites volume of theindividual decreases by about 50% or more (e.g., compared to a vehicle control, such as when measured after 3 days of treatment) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, ascites volume of the individual decreases by about 100% or more (e.g., compared to a vehicle control, such as when measured after 3 days of treatment) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, ascites volume of the individual decreases by about 200% or more (e.g., compared to a vehicle control, such as when measured after 3 days of treatment) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, ascites volume of the individual decreases by about 300% or more (e.g., compared to a vehicle control, such as when measured after 3 days of treatment) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual.

[0391] In some embodiments, ascites volume of the individual decreases by about 10% to about 1000% (e.g., compared to a vehicle control, such as when measured after 3 days of treatment) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, ascites volume of the individual decreases by about 10% to about 500% (e.g., compared to a vehicle control, such as when measured after 3 days of treatment) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, ascites volume of the individual decreases by about 50% to about 300% (e.g., compared to a vehicle control, such as when measured after 3 days of treatment) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual.

[0392] In some embodiments, body weight of the individual decreases (e.g., compared to a vehicle control) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, body weight of the individual significantly decreases (e.g., compared to a vehicle control) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual.

[0393] In some embodiments, body weight of the individual decreases by about 1% or more (e.g., compared to a vehicle control) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In someembodiments, body weight of the individual decreases by about 2.5% or more (e.g., compared to a vehicle control) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, body weight of the individual decreases by about 5% or more (e.g., compared to a vehicle control) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, body weight of the individual decreases by about 10% or more (e.g., compared to a vehicle control) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, the change in body weight is measured at least one day after administration of the compound. In some embodiments, the change in body weight is measured two or more days after administration of the compound. In some embodiments, the change in body weight is measured three or more days after administration of the compound. In some embodiments, the change in body weight is measured four or more days after administration of the compound. In some embodiments, the change in body weight is measured five or more days after administration of the compound.

[0394] In some embodiments, plasma chemistry markers are statistically different following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, plasma chemistry markers BUN, Cl, PHOS, Na, and / or the BUN / CREA ratio are statistically different following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, plasma chemistry markers ALB, ALP, ALT, AST, BCARB, Ca, CHOL, CPK, CREA, DBIL, GGT, GLOB, GLU, IBIL, K, LDH, TBIL, and TPRO are not statistically different following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual.

[0395] In some embodiments, body weight of the individual decreases by about 1% to about 10% (e.g., compared to a vehicle control) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual. In some embodiments, body weight of the individual decreases by about 1% to about 5% (e.g., compared to a vehicle control) following subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein to the individual.

[0396] In some embodiments, a compound described herein (e.g., Compound 1) is safe (e.g., in humans) (e.g., see Example 1). In some embodiments, a compound described herein (e.g., Compound 1) is well tolerated (e.g., in humans) (e.g., see Example 1). In some embodiments,a compound described herein (e.g., Compound 1) is safe and well tolerated (e.g., in humans) (e.g., see Example 1). In some embodiments, a compound described herein (e.g., Compound 1) has a pharmacodynamic profile that has a submaximal partial agonism consistent with a mixed agonist-antagonist of the Via receptor.

[0397] In some instances, a compound described herein (e.g., Compound 1) is tested in a phase 1, double-blinded, placebo-controlled, within dose-group randomized trial to investigate the safety, tolerability, and pharmacokinetic and pharmacodynamic (PD) profiles of the compound administered to healthy adults aged 18 to 45 years (see Example 1). In some instances, the trial comprised 2 treatment periods: Period 1 (6-h intravenous [IV] infusion of the compound over a dose range of 0.1 to 0.9 mg or placebo) and Period 2 (once-daily subcutaneous [SC] injection of the compound 0.1, 0.3 mg, or placebo for 5 consecutive days). In some instances, Period 1 included 32 men and women. In some instances, 8 men and 5 women continued into Period 2. In some instances, such as after IV administration, exposure, as measured by AUC and Cmaxwas roughly dose proportional over the dose range studied. In some instances, such as after SC administration, Tmaxwas 0.3 h, exposure was more than proportional, and bioavailability was 18% without any apparent accumulation after repeated administration. In some instances, the terminal half-life (ti / 2) of a compound described herein (e.g., Compound 1) was about 1.5 h and 1.0 h after IV and SC administration, respectively, such as indicating that absorption is not ratelimiting for elimination after SC administration. In some instances, diastolic and, to a lesser extent, systolic blood pressure (BP) increased for subjects treated with a compound described herein (e.g., Compound 1) in all dose groups, while pulse rate decreased. In some instances, overall changes in mean arterial pressure (MAP) after IV and SC administration were similar to changes in diastolic BP. In some instances, absolute changes in cardiac output, by echocardiography, appeared to be dose dependent, with mean reductions of 3%-12% after 0.9 mg IV dose, and individual reductions <20-25% across any dose. In some instances, adverse events (AEs) included abdominal pain and diarrhea, with laboratory tests negative for and no reported cases of mesenteric ischemia. In some instances, AEs were related to treatment, generally mild or moderate in severity and attributable to the expected pharmacologic effect.

[0398] In some embodiments, diastolic blood pressure of an individual increases (e.g., compared to a baseline measurement before treatment) after administration of a compound, or the pharmaceutically acceptable salt thereof, described herein (e.g., Compound 1). In some embodiments, diastolic blood pressure of the individual increases (e.g., compared to a baseline measurement before treatment) after subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein (e.g., Compound 1).

[0399] In some embodiments, systolic blood pressure of an individual increases (e.g., compared to a baseline measurement before treatment) after administration of a compound, or the pharmaceutically acceptable salt thereof, described herein (e.g., Compound 1). In some embodiments, systolic blood pressure of the individual increases (e.g., compared to a baseline measurement before treatment) after subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein (e.g., Compound 1).

[0400] In some embodiments, diastolic and / or systolic blood pressure of an individual dose- dependently increases (e.g., compared to a baseline measurement before treatment) after administration of a compound, or the pharmaceutically acceptable salt thereof, described herein (e.g., Compound 1). In some embodiments, diastolic and / or systolic blood pressure of the individual dose dependently increases (e.g., compared to a baseline measurement before treatment) after subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein (e.g., Compound 1).

[0401] In some embodiments, a compound provided herein has a maximal therapeutic concentration. In some embodiments, the maximal therapeutic concentration comprises an increase in concentration that does not provide dose-dependent increases in blood pressure, such as diastolic blood pressure, systolic blood procedure, and / or MAP. In some embodiments, a compound provided herein has a non-linear dose dependency, such as above the maximal therapeutic concentration. In some embodiments, a dose dependent increase in blood pressure, such as diastolic blood pressure, systolic blood procedure, and / or MAP, includes the maximal therapeutic concentration. In some embodiments, dose dependently includes situations where the effect increases with dose for at least a certain dose range. For example, higher doses may provide no or lower dose-dependent increases.

[0402] In some embodiments, MAP is calculated from measurements of systolic blood pressure and diastolic blood pressure. In some embodiments, MAP is calculated when taking into account the pressure during a single cardiac cycle. In some embodiments, MAP is 1 / 3 (systolic blood pressure - diastolic blood pressure) + diastolic blood pressure.

[0403] In some embodiments, the pulse rate of the individual decreases (e.g., compared to a baseline measurement before treatment) after administration of a compound, or the pharmaceutically acceptable salt thereof, described herein (e.g., Compound 1). In some embodiments, the peripheral blood flow of the individual decreases (e.g., compared to a baseline measurement before treatment) after administration of a compound, or the pharmaceutically acceptable salt thereof, described herein (e.g., Compound 1). In someembodiments, the pulse rate and peripheral blood flow of the individual decreases (e.g., compared to a baseline measurement before treatment) after administration of a compound, or the pharmaceutically acceptable salt thereof, described herein (e.g., Compound 1).

[0404] In some embodiments, administration of a compound, or the pharmaceutically acceptable salt thereof, described herein (e.g., Compound 1) to an individual (e.g., described herein) improves systemic hemodynamics in the individual. In some embodiments, subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein (e.g., Compound 1) to an individual (e.g., described herein) improves systemic hemodynamics in the individual.

[0405] In some embodiments, administration of a compound, or the pharmaceutically acceptable salt thereof, described herein (e.g., Compound 1) to an individual (e.g., described herein) reduces fluid retention in the individual. In some embodiments, administration of a compound, or the pharmaceutically acceptable salt thereof, described herein (e.g., Compound 1) to an individual (e.g., described herein) reduces fluid overload in the individual. In some embodiments, administration of a compound, or the pharmaceutically acceptable salt thereof, described herein (e.g., Compound 1) to an individual (e.g., described herein) reduces fluid retention and overload in the individual. In some embodiments, subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein (e.g., Compound 1) to an individual (e.g., described herein) reduces fluid retention in the individual. In some embodiments, subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein (e.g., Compound 1) to an individual (e.g., described herein) reduces fluid overload in the individual. In some embodiments, subcutaneous administration of a compound, or the pharmaceutically acceptable salt thereof, described herein (e.g., Compound 1) to an individual (e.g., described herein) reduces fluid retention and overload in the individual.

[0406] In some embodiments, (e.g., subcutaneous) administration of a compound, or the pharmaceutically acceptable salt thereof, described herein (e.g., Compound 1) to an individual (e.g., described herein) reduces serum creatinine (sCr) (value) in the individual (e.g., compared to a baseline measurement before treatment). In some embodiments, a compound, or the pharmaceutically acceptable salt thereof, described herein (e.g., Compound 1) is (e.g., subcutaneously) administered to an individual (e.g., described herein) at least until the individual has a sCr value of 1.5 milligrams (mg) / deciliters (dL) or less. In some embodiments, a compound, or the pharmaceutically acceptable salt thereof, described herein (e.g., Compound1) is (e.g., subcutaneously) administered to an individual (e.g., described herein) at least until the sCr value of the individual returns to normal (e.g., baseline).

[0407] In some instance, intravenous (i.v.) administration of a compound described herein (e.g., Compound 1) provides a terminal half-life of about 1.5 hours with clearance and distribution volumes of about 13 L / h and about 15-20 L, respectively. In some instances, the tmax after subcutaneous (s.c.) administration of a compound described herein (e.g., Compound 1) is about 0.3 hours with a terminal half-life of about 1 hour (e.g., without any accumulation after repeated administrations). In some instances, the bioavailability after subcutaneous (s.c.) administration of a compound described herein (e.g., Compound 1) is about 18%.

[0408] In some instances, a compound described herein (e.g., Compound 1) has a proportional increase in exposure, by means of AUC and Cmax, following i.v. administration. In some instances, a compound described herein (e.g., Compound 1) has more than approximate proportionality following s.c. administration. In some instances, a compound described herein (e.g., Compound 1) has a higher exposure in women than in men, such as after both i.v. infusion and subcutaneous injection.

[0409] In some instances, a compound described herein (e.g., Compound 1) metabolizes to metabolite Ml (see FIG. 14). Ml has a structure that is the free form of the structure circled in FIG. 14. In some embodiments, Ml is a full (VIA) agonist. In some embodiments, Ml has a molecular weight of 1405.68 g / mol. In some embodiments, Ml has a chemical formula of C60H98N19O16S2C Ml is (substantially) less active (for Via) than Compound 1. Specifically, Ml has about one-tenth of the activity for Via as Compound 1.

[0410] In some instances, such as in single subjects after i.v. administration, Ml is found in the plasma of an individual administered Compound 1. In some instances, such as in all investigated subjects at comparable concentrations to Compound 1 after s.c. administration, Ml is found. In some instances, a compound described herein (e.g., Compound 1) is metabolized (e.g., to Ml) during the transport to the circulation after s.c. injection. As discussed hereinabove, full agonists described herein are known to be toxic and lead to (serious) adverse events when administered subcutaneously. As such, formation of a full agonist (e.g., Ml), such as when a compound described herein is administered by subcutaneous (bolus) injection, is undesirable, such as when being used for the purposes described herein.

[0411] In some instances, a dose-independent increase in diastolic, and to a lesser extent, systolic blood pressure is more pronounced after s.c. injection compared with i.v. infusion of a compound described herein (e.g., Compound 1) (e.g., accompanied by a reflex decrease inpulse rate). In some instances, the peripheral blood flow decreases after intravenous and subcutaneous administration of a compound described herein (e.g., Compound 1).

[0412] In some instances, an individual receiving a dose of a compound described herein (e.g., Compound 1) had an adverse event (AE) (e.g., related to a treatment). In some instances, an AE occurs at the beginning of a s.c. treatment period. In some instances, there are more AEs after s.c. administration compared with i.v. administration. In some instances, there are more AEs in women compared with men. In some instances, the AEs are of mild or moderate intensity. In some instances, the AEs are of severe intensity. In some instances, an AE of severe intensity is elevated troponin I of mild intensity.

[0413] In some instances, a compound described herein (e.g., Compound 1) induces a reversible increase in diastolic. In some instances, a compound described herein (e.g., Compound 1) induces a reversible increase in systolic. In some instances, a compound described herein (e.g., Compound 1) induces a reversible increase in MAP. In some instances, a compound described herein (e.g., Compound 1) induces a reversible increase in diastolic and MAP. In some instances, a compound described herein (e.g., Compound 1) induced a decrease in heart rate and cardiac output. In some instance, evaluation of ECG, clinical chemistry, hematology, hemostasis, and urinalysis parameters did not provide any safety concerns of a compound described herein (e.g., Compound 1).

[0414] In some instance, such as when administered as a single i.v. infusion, a compound described herein (e.g., Compound 1) is safe and well tolerated (e.g., in both men and women), such as at a dose of about 0.9 mg or less. In some instances, the maximum tolerated s.c. dose (MTD) is about 0.1 mg of a compound described herein (e.g., Compound 1).

[0415] In some instances, the pharmacokinetic parameters for a compound described herein (e.g., Compound 1) (e.g., in plasma for the 0.1 to 0.9 mg i.v. dose groups) provides dose proportionality. In some instances, the pharmacokinetic parameters for a compound described herein (e.g., Compound 1) (e.g., in plasma for the 0.1 to 0.9 mg i.v. dose groups) provides that the dose independent PK parameters are comparable between dose groups (see Example 1). In some instances, men clear a compound described herein (e.g., Compound 1) at a higher rate than women. In some instances, men administered a compound described herein (e.g., Compound 1) have a lower Cmaxof the compound than women. In some instances, men administered a compound described herein (e.g., Compound 1) have a lower AUC of the compound than women. In some instances, men administered a compound described herein (e.g., Compound 1) have a lower Cmax and AUC of the compound than women.

[0416] In some instances, such as after s.c. administration of a compound described herein (e.g., Compound 1), the tmaxis consistent between the first and the fifth dose. In some instances, such as after s.c. administration of a compound described herein (e.g., Compound 1), the ti / 2 is consistent between the first and the fifth dose. In some instances, such as after s.c. administration of a compound described herein (e.g., Compound 1), the tmaxand ti / 2 are consistent between the first and the fifth dose. In some instances, such as after s.c. administration of a compound described herein (e.g., Compound 1), the AUC is variable between the first and the fifth dose. In some instances, such as after s.c. administration of a compound described herein (e.g., Compound 1), the Cmaxis variable between the first and the fifth dose. In some instances, such as after s.c. administration of a compound described herein (e.g., Compound 1), the AUC and Cmaxare variable between the first and the fifth dose. In some instance, the dose proportionality for AUC and Cmaxis proportional (e.g., for Cmaxat the fifth administration only).

[0417] In some instances, the terminal half-life of a compound described herein (e.g., Compound 1) is about 1.5 hours after intravenous administration. In some instances, the terminal half-life of a compound described herein (e.g., Compound 1) is about 1 hour after subcutaneous administration. In some instances, the terminal half-life of a compound described herein (e.g., Compound 1) is comparable in men and women (e.g., suggesting that absorption is not rate limiting for the elimination after s.c. administration, such as also being supported by the short time to Cmaxafter subcutaneous administration, about 0.3 hours, similar in both men and women). In some instances, the bioavailability of a compound described herein (e.g., Compound 1) is about 18%. In some instances, the formation of metabolites after s.c. administration, such as resulting in comparable concentrations of metabolites and the compound, provides a bioavailability of about 18%. In some instances, the fraction of the unchanged, excreted dose in the urine is about <10% after i.v. administration. In some instances, the fraction of the unchanged, excreted dose of a compound described herein (e.g., Compound 1) in the urine is about <5% after s.c. administration. In some instances, the fraction of the unchanged, excreted dose of a compound described herein (e.g., Compound 1) in the urine is constant throughout the dose range (e.g., of the study provided in Example 1).

[0418] The presence of the metabolite Ml (a full agonist) in plasma after subcutaneous administration (but only at very low concentrations (<1% of Compound 1) after intravenous administration) demonstrates that Compound 1 is metabolized somewhere on the path between the subcutaneous tissue and the systemic circulation. In some instances, the half-life of Ml is longer than for Compound 1 after i.v. and s.c. administration. In some instances, the half-lifeof Compound 1 is shorter after s.c. compared with i.v. administration (e.g., about 2 hours and 4 hours, respectively). In some instances, a compound described herein (e.g., Compound 1) metabolizes in the kidneys.

[0419] In some instances, the pharmacodynamic effects of a compound described herein (e.g., Compound 1) on blood pressure and heart rate is as expected of a vasopressin Via specific agonist. In some instances, administration of a compound described herein (e.g., Compound 1) to an individual provides an increase in the diastolic blood pressure of the individual. In some instances, administration of a compound described herein (e.g., Compound 1) to an individual provides an increase in the systolic blood pressure of the individual. In some instances, administration of a compound described herein (e.g., Compound 1) to an individual provides an increase in the MAP of the individual. In some instances, administration of a compound described herein (e.g., Compound 1) to an individual provides a decrease in the pulse of the individual. In some instances, administration of a compound described herein (e.g., Compound 1) to an individual provides a decrease in the peripheral blood flow of the individual. In some instances, the effects on blood pressure and heart rate are dose independent (e.g., the changes that are seen in the lowest dose group were about the same as seen in the higher dose groups). In some instances, s.c. injections provided more pronounced PD effects compared with the same doses given i.v., (e.g., despite an about 50% lower Cmax following s.c. administration). In some instances, the active metabolite Ml (e.g., a full (Via) agonist) in plasma after s.c. administration contributes (significantly) to the total (e.g., local and / or systemic) Via vasopressor activity, such as in individuals that have a (serious) adverse event after a compound described herein is administered by subcutaneous (bolus) injection. In some instances, increased Ml formation, such as after subcutaneous (bolus) injection, provides substantially decreases (systemic) delivery of Compound 1, such as resulting in undesirable effects (e.g., due to less delivery of active agent (e.g., Ml or a mixed Via agonist-antagonist described herein) and / or increased amounts of vasoconstriction, which can increase risk of developing ischemia, cyanosis, pain, inflammation, and / or necrosis).

[0420] In some instances, the safety evaluation of a compound described herein (e.g., Compound 1) provided a profde that is improved compared to other (e.g., nonselective) a vasopressin receptor agonists described herein. In some instances, the absolute changes in mean cardiac output are dose dependent. In some instances, the relative changes in mean cardiac output are comparable between doses (e.g., and well separated from the placebo). In some instances, individual decreases in cardiac output are about 20-25% (e.g., as observed in all active treatment groups, including the placebo group, after both i.v. and s.c.administrations). In some instances, the decrease in cardiac output is secondary to a decreased heart rate. In some instances, an ECG evaluation did not indicate any influence of a compound described herein (e.g., Compound 1). In some instances, clinical laboratory parameters did not show any signs of heart or mesenteric ischemia (e.g., or negative effects on the liver or kidney).

[0421] In some instances, adverse events in individuals (e.g., intravenously or subcutaneously) receiving a partial agonist described herein (e.g., Compound 1) were comparable to the pharmacological vasopressor activity of compounds 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). Moreover, the frequency of AEs after subcutaneous administration of a compound described herein (e.g., Compound 1) decreases over 5 days of treatment. For example, in some instances, s.c. administration provided about 0.5-fold more AEs per administration on Day 1 than the i.v. administration (e.g., although only 3 subjects received 0.3 mg s.c. compared to 35 subjects receiving 0.45 mg or higher doses i.v.). Additionally, s.c. administration of a partial agonist described herein (e.g., Compound 1) provided about 3-fold more AEs per administration (see Example 1) than i.v. administration of the same compound. Given that (1) Ml (a full (Via) agonist) forms after subcutaneous administration of Compound 1 , (2) full vasopressin agonists are known to be toxic and lead to adverse events, (3) Compound 1 and Ml are present at about equimolar concentrations after subcutaneous administration of Ml, and (4) the exposure to Compound 1 (by means of Cmax and AUC) after s.c. administration was lower than after i.v. infusion, the presence of Ml (not Compound 1) in plasma after s.c. administration contributes to the total Via vasopressor activity and the (e.g., exaggerated) pharmacological effects and / or AE profile after subcutaneous administration of Compound 1.

[0422] Moreover, given that the presence of a vasopressin receptor full agonist, Ml, contributed to an increased number of vasoconstriction related AEs compared with much higher concentrations of Compound 1 , further demonstrates (in combination with the over a wide concentration range similar pharmacodynamic and adverse effects of Compound 1) that Compound 1 is a partial agonist and / or mixed agonist-antagonist. Further, observations from the study in Example 1 also demonstrate that a mixed agonist-antagonist mechanism of action caps the (local vasoconstrictive) effect(s) in the individual (and limit such effects to a level below the maximally possible). As further support of this explanation, studies with terlipressin, a VIA receptor full agonist, have demonstrated blood pressure increases greater than those provided in Example 1 (e.g., further supporting that the maximal pharmacodynamic effects ofCompound 1 are ‘capped’ and that Compound 1 is a VI A receptor partial agonist and / or mixed agonist-antagonist) .

[0423] In some instances, the pharmacological effects of a compound described herein (e.g., Compound 1) are attributed to vasopressin Vla-receptor agonism. In some instances, the absence of any effect on diuresis and hemostasis demonstrated a high degree of specificity (e.g., providing the desired pharmacological profile) to the Vla-receptor.

[0424] In some instances, the terminal half-life of a compound described herein (e.g., Compound 1) is about 1.5 hours (after i.v. administration).

[0425] In some instances, the total clearance of a compound described herein (e.g., Compound 1) is about 13 L / h (after i.v. administration).

[0426] In some instances, the terminal half-life of a compound described herein (e.g., Compound 1) is about 1 hour (after s.c. administration). In some instances, the tmaxof a compound described herein (e.g., Compound 1) is about 0.3 hours (after s.c. administration). In some instances, the bioavailability of a compound described herein (e.g., Compound 1) is about 18% (without any apparent accumulation of a compound described herein (e.g., Compound 1), such as after repeated subcutaneous administration).

[0427] In some instances, the increase in exposure of a compound described herein (e.g., Compound 1) (e.g., by means of AUC and Cmax) is approximately proportional for AUC and Cmaxafter intravenous administration of the compound described herein (e.g., Compound 1).

[0428] In some instance, the exposure of a compound described herein (e.g., Compound 1) (by means of AUC and Cmax) is higher in women than in men after intravenous infusion of the compound described herein (e.g., Compound 1).

[0429] In some instances, administration of a compound described herein (e.g., Compound 1) provided an increase in the diastolic blood pressure of the individual receiving the compound. In some instances, administration of a compound described herein (e.g., Compound 1) provided an increase in the systolic blood pressure of the individual receiving the compound. In some instances, administration of a compound described herein (e.g., Compound 1) provided an increase in the MAP of the individual receiving the compound. In some instances, administration of a compound described herein (e.g., Compound 1) provided a reflex decrease in the pulse rate (e.g., in an apparent dose independent manner) of the individual receiving the compound.

[0430] In some instances, the peripheral blood flow decreased after intravenous and subcutaneous administration of a compound described herein (e.g., Compound 1).

[0431] In some instances, such as during subcutaneous administration of a compound described herein (e.g., Compound 1), the active metabolite Ml (a full (Via) agonist) is generated, such as at comparable concentrations to Compound 1.

[0432] In some embodiments, such as described in the studies provided in Example 6, a compound described herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1) decreases portal pressure (PP) (after subcutaneous administration) without excessive vasoconstriction, such as over a wide dose range (e.g., 10 pg / kg to 500 pg / kg of Compound 1), see FIGs. 33 and 35. In some embodiments, such as described in the studies provided in Example 6, a compound described herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1) decreases PP (after subcutaneous administration), such as over a wide dose range (e.g., 10 pg / kg to 500 pg / kg of Compound 1) , see FIGs. 33 and 35.

[0433] In some embodiments, a method provided herein further comprises evaluating a biological sample (e.g., of an individual). In some embodiments, the method further comprises evaluating a biological sample of an individual for a biomarker, such as 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 a standard (e.g., amount or level of the biomarker).

[0434] In some embodiments, a biomarker described herein, such as a biomarker described in Example 6, is evaluated at a first time point and a second time point. In some embodiments, the second time point is used to determine responsiveness or efficacy, such as of a compound described herein (e.g., a mixed V1AR agonist-antagonist, such as Compound 1). In some embodiments, the second time point is an endpoint. In some instances, the endpoint is used to determine an amount or level of a biomarker sufficient to achieve the desired responsiveness or efficacy of a compound described herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1). In some embodiments, a method provided herein further comprises administering a compound described herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1) to an individual at least until the level or amount of a biomarker (of the individual) reaches the endpoint. In some embodiments, the method comprises continuing to administer the compound after the level or amount of a biomarker (of the individual) reaches the endpoint.

[0435] In some embodiments, a level or amount of a biomarker described herein, such as a biomarker described in Example 6, is higher (e.g., at least 5% higher, at least 15% higher, at least 25% higher, at least 35% higher, at least 45% higher, at least 55% higher, at least 65%higher, at least 75% higher, at least 85% higher, at least 95% higher, or more) at the second timepoint compared to the first timepoint.

[0436] In some embodiments, a level or amount of a biomarker described herein, such as a biomarker described in Example 6, is lower (e.g., at most 95% lower, at most 85% lower, at most 75% lower, at most 65% lower, at most 55% lower, at most 45% lower, at most 35% lower, at most 25% lower, at most 15% lower, at most 5% lower, or less) at the second timepoint compared to the first timepoint.

[0437] In some instances, a compound described herein (e.g., a mixed VI AR agonistantagonist, such as Compound 1) has an effect (e.g., increase or decrease) on the level of a biomarker described herein, such as a biomarker described in Example 5 or Example 6. In some embodiments, a 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, urine sodium, urine 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, a biomarker described herein is MAP. In some embodiments, a biomarker described herein is aldosterone. In some embodiments, a biomarker described herein is renin. In some embodiments, a biomarker described herein is ascites volume. In some embodiments, a biomarker described herein is body weight. In some embodiments, a biomarker described herein is urine volume. In some embodiments, a biomarker described herein is net fluid balance. In some embodiments, a biomarker described herein is urine sodium. In some embodiments, a biomarker described herein is urine potassium. In some embodiments, a biomarker described herein is spleen weight. In some embodiments, a biomarker described herein is systolic arterial pressure. In some embodiments, a biomarker described herein is diastolic arterial pressure. In some embodiments, a biomarker described herein is heart rate. In some embodiments, a biomarker described herein is portal pressure. In some embodiments, a biomarker described herein is skin blood flow (SBF). In some embodiments, a biomarker described herein is blood lactate concentration. In some embodiments, a biomarker described herein is blood pH. In some embodiments, a biomarker described herein is an increase in glomerular filtration (rate). In some embodiments, a biomarker described herein is an increase in renal blood flow.

[0438] In some embodiments, such as described in Example 6, a compound described herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1) reduces hyperaldosteronism in an individual (e.g., in need thereof). In some embodiments, a compound provided herein (e.g.,a mixed VI AR agonist-antagonist, such as Compound 1) reduces aldosterone (e.g., in serum) in an individual (e.g., in need thereof). In some embodiments, a compound provided herein reduces aldosterone (e.g., in serum) in an individual (e.g., in need thereof) by at least 20% (e.g., at least 30%, at least 40%, at least 50%, at least 60%). In some embodiments, a compound provided herein reduces aldosterone (e.g., in serum) in an individual (e.g., in need thereof) by no more than 90% (e.g., no more than 80%, no more than 70%, no more than 60%). In some embodiments, a compound provided herein reduces aldosterone in serum of an individual (e.g., in need thereof) by more than 50% (e.g., compared to a control (e.g., vehicle) and / or a first timepoint).

[0439] In some instances, a reduction in portal hypertension and / or hyperaldosteronism provides diuretic and natriuretic effects (see Example 6). In some embodiments, the diuretic and natriuretic effects are associated with (e.g., total) mobilization (e.g., improvement) of ascites, such as after three days of s.c. treatment of a compound described herein.

[0440] In some embodiments, a compound provided herein (e.g., a mixed VI AR agonistantagonist, such as Compound 1) reduces ascites volume in an individual (e.g., in need thereof) , such as after 5 days of treatment as described in Example 6. In some embodiments, a compound provided herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1) reduces ascites volume in an individual (e.g., in need thereof) by at least 30% (e.g., at least 40%, at least 50%, at least 60%, at least 70%, at least 80%). In some embodiments, a compound provided herein (e.g., a mixed V 1 AR agonist-antagonist, such as Compound 1) reduces ascites volume in an individual (e.g., in need thereof) by no more than 95% (e.g., no more than 90%, no more than 85%, no more than 80%, no more than 75%). In some embodiments, a compound provided herein (e.g., a mixed V 1 AR agonist-antagonist, such as Compound 1) reduces ascites volume in an individual (e.g., in need thereof) by about 30% to about 95%. In some embodiments, a compound provided herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1) reduces ascites volume in an individual (e.g., in need thereof) by about 67%. In some embodiments, a compound provided herein (e.g., a mixed V 1 AR agonist-antagonist, such as Compound 1) reduces ascites volume in an individual (e.g., in need thereof) by about 80%. In some embodiments, the reduction in ascites volume is compared to a control (e.g., vehicle) and / or a first timepoint.

[0441] In some embodiments, a compound described herein (e.g., a mixed VI AR agonistantagonist, such as Compound 1) increases urine volume (excretion) in an individual (e.g., in need thereof) (see Example 6). In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist, such as Compound 1) increases urine sodium (excretion) inan individual (e.g., in need thereof) (see Example 6). In some embodiments, a compound described herein (e.g., a mixed V 1 AR agonist-antagonist, such as Compound 1) increases urine volume and urine sodium excretion in an individual (e.g., in need thereof), such as during the first 24 hours of treatment (see Example 6). In some instances, the increase in urine volume and urine sodium excretion (fully) evacuates the ascites accumulated in the peritoneal cavity in an individual (e.g., in need thereof). In some embodiments, the increase in urine volume and urine sodium excretion provide a decrease in ascites volume of an individual (e.g., in need thereof). In some embodiments, urine volume and / or urine sodium excretion increase in an individual (e.g., in need thereof) within 24-hours of treatment.

[0442] In some embodiments, a compound described herein (e.g., a mixed VI AR agonistantagonist, such as Compound 1) increases urine volume, as described in Example 6. In some embodiments, urine volume is compared to (and greater than) a basal measurement, such as described in Example 6. In some embodiments, a compound described herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1) increases urine volume by at least 20% (e.g., at least 30%, at least 40%, at least 50%, at least 60%, at least 70%). In some embodiments, a compound described herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1) increases urine volume by about 75%. In some embodiments, a compound described herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1) increases urine volume by at least 100% (at least 150%, at least 200%, at least 250%, at least 300%, at least 350%). In some embodiments, a compound described herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1) increases urine volume by about 430%. In some embodiments, a compound described herein (e.g., a mixed V 1 AR agonist-antagonist, such as Compound 1) increases urine volume by at most 750% (e.g., at most 500%, at most 400%, at most 300%). In some embodiments, urine volume increases in an individual (e.g., in need thereof) within the first 4 hours of treatment. In some embodiments, urine volume increases in an individual (e.g., in need thereof) after 1 day of treatment.

[0443] In some embodiments, a compound described herein (e.g., a mixed VI AR agonistantagonist, such as Compound 1) provides a positive net fluid balance in an individual (e.g., in need thereof), such as described in Example 6. In some embodiments, urine volume of the individual (e.g., in need thereof) is greater than liquid intake.

[0444] In some embodiments, a compound provided herein (e.g., a mixed VI AR agonistantagonist, such as Compound 1) increases urine sodium excretion and / or urine potassium excretion in an individual (e.g., in need thereof), such as described in Example 6. In some embodiments, a compound provided herein (e.g., a mixed VI AR agonist-antagonist, such asCompound 1) increases urine sodium excretion by at least 20% (e.g., at least 100%, at least 250%, at least 500%, at least 750%). In some embodiments, a compound provided herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1) increases urine sodium excretion by at most 1000% (e.g., at most 750%, at most 500%, at most 250%, at most 100%). In some embodiments, a compound provided herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1) increases urine sodium excretion by about 600%. In some embodiments, a compound provided herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1) increases urine potassium by at least 10% (e.g., at least 20%, at least 30%, at least 40%, at least 50%). In some embodiments, a compound provided herein (e.g., a mixed VI AR agonistantagonist, such as Compound 1) increases urine potassium by at most 100% (e.g., at most 75%, at most 50%, at most 40%, at most 30%). In some embodiments, a compound provided herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1) increases urine potassium by about 20%. In some embodiments, urine sodium excretion and / or urine potassium excretion is compared to (and greater than) a basal measurement. In some embodiments, urine sodium excretion and / or urine potassium excretion increases in an individual (e.g., in need thereof) within the first 4 hours of treatment. In some embodiments, urine sodium excretion and / or urine potassium excretion increases in an individual (e.g., in need thereof) after 1 day of treatment.

[0445] In some embodiments, a compound provided herein (e.g., a mixed VI AR agonistantagonist, such as Compound 1) decreases urine potassium excretion in an individual (e.g., in need thereof), such as described in Example 6. In some embodiments, a compound provided herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1) decreases urine potassium excretion by at least 10% (e.g., at least 20%, at least 30%, at least 40%, at least 50%). In some embodiments, a compound provided herein (e.g., a mixed VI AR agonistantagonist, such as Compound 1) decreases urine potassium excretion by at most 100% (e.g., at most 75%, at most 50%, at most 40%, at most 30%). In some embodiments, a compound provided herein (e.g., a mixed V 1 AR agonist-antagonist, such as Compound 1) decreases urine potassium excretion by about 20%. In some embodiments, urine potassium excretion is compared to (and greater than) a basal measurement.

[0446] In some embodiments, urine sodium excretion increases, such as within the first 4 hours of treatment, and urine potassium excretion decreases, such as 5 or more hours after treatment, in an individual (e.g., in need thereof).

[0447] In some embodiments, a compound provided herein (e.g., a mixed VI AR agonistantagonist, such as Compound 1) decreases body weight of an individual (e.g., in need thereof),such as provided in Example 6. In some embodiments, a compound provided herein (e.g., a mixed V 1 AR agonist-antagonist, such as Compound 1) decreases body weight of an individual (e.g., in need thereof) by at least 5% (e.g., at least 7%, at least 9%, at least 11%). In some embodiments, a compound provided herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1) decreases body weight of an individual (e.g., in need thereof) by at most 15%, at most 13%, at most 11%, at most 9%). In some embodiments, a compound provided herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1) decreases body weight of an individual (e.g., in need thereof) by about 14%. In some embodiments, body weight of the individual is compared to (and less than) a basal measurement. In some embodiments, body weight of the individual (e.g., in need thereof) decreases after about 1 day or more, such as 3 days, of treatment.

[0448] In some embodiments, a compound provided herein (e.g., a mixed VI AR agonistantagonist, such as Compound 1) decreases spleen weight, such as described in Example 6. In some embodiments, a compound provided herein (e.g., a mixed V 1 AR agonist-antagonist, such as Compound 1) decreases spleen weight of an individual (e.g., in need thereof) by at least 2% (at least 4%, at least 8%, at least 12%, at least 15%). In some embodiments, a compound provided herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1) decreases spleen weight of an individual (e.g., in need thereof) by at most 20% (e.g., at most 18%, at most 16%, at most 14%). In some embodiments, a compound provided herein (e.g., a mixed V 1 AR agonist-antagonist, such as Compound 1) decreases spleen weight of an individual (e.g., in need thereof) by about 16%. In some embodiments, spleen weight of the individual is compared to (and less than) a basal measurement. In some embodiments, spleen weight of the individual (e.g., in need thereof) decreases after about 1 day or more, such as 5 days after, of treatment.

[0449] In some embodiments, a compound provided herein (e.g., a mixed VI AR agonistantagonist, such as Compound 1) decreases creatinine levels in an individual (e.g., in need thereof), such as described in Example 6. In some embodiments, a compound provided herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1) decreases creatinine levels in an individual (e.g., in need thereof) by at least 30% (e.g., at least 40%, at least 50%, at least 60%, at least 70%). In some embodiments, a compound provided herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1) decreases creatinine levels in an individual (e.g., in need thereof) by at most 80% (e.g., at most 70%, at most 60%, at most 50%, at most 40%). In some embodiments, a compound provided herein (e.g., a mixed V 1 AR agonist-antagonist, such as Compound 1) decreases creatinine levels by about 50%. In some embodiments, creatininelevels in an individual (e.g., in need thereof) decrease by about 80%. In some embodiments, creatine levels of the individual are compared to (and less than) a basal measurement. In some embodiments, creatine levels of the individual (e.g., in need thereof) decrease after about 1 day or hour, such as about 5 to 25 hours after, of treatment.

[0450] In some embodiments, a compound provided herein (e.g., a mixed VI AR agonistantagonist, such as Compound 1) increases urine creatinine levels in an individual (e.g., in need thereof), such as described in Example 6. In some embodiments, a compound provided herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1) increases urine creatinine levels in an individual (e.g., in need thereof) by at least 30% (e.g., at least 40%, at least 50%, at least 60%, at least 70%). In some embodiments, a compound provided herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1) increases urine creatinine levels in an individual (e.g., in need thereof) by at most 80% (e.g., at most 70%, at most 60%, at most 50%, at most 40%). In some embodiments, a compound provided herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1) increases urine creatinine levels by about 50%. In some embodiments, urine creatinine levels in an individual (e.g., in need thereof) increase by about 80%. In some embodiments, urine creatine levels of the individual are compared to (and less than) a basal measurement. In some embodiments, urine creatine levels of the individual (e.g., in need thereof) increase after about 1 day or hour, such as about 5 to 25 hours after, of treatment.

[0451] In some embodiments, a compound provided herein (e.g., a mixed VI AR agonistantagonist, such as Compound 1) decreases urine creatinine levels in an individual (e.g., in need thereof), such as described in Example 6. In some embodiments, a compound provided herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1) decreases urine creatinine levels in an individual (e.g., in need thereof) by at least 30% (e.g., at least 40%, at least 50%, at least 60%, at least 70%). In some embodiments, a compound provided herein (e.g., a mixed V 1 AR agonist-antagonist, such as Compound 1) decreases urine creatinine levels in an individual (e.g., in need thereof) decrease by at most 80% (e.g., at most 70%, at most 60%, at most 50%, at most 40%). In some embodiments, a compound provided herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1) decreases urine creatinine levels decrease by about 50%. In some embodiments, urine creatinine levels in an individual (e.g., in need thereof) decrease by about 80%. In some embodiments, urine creatine levels of the individual are compared to (and less than) a basal measurement. In some embodiments, urine creatine levels of the individual (e.g., in need thereof) decrease after about 1 day or hour, such as about 5 to 25 hours after, of treatment.

[0452] In some instances, diuretic and / or natriuretic effect(s) are identified in an individual within the first 24 hours of treatment, such as after subcutaneous administration of a compound described herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1) as described in the studies provided in Example 6. In some instances, diuretic and / or natriuretic effect(s) are not identified in an individual after the first 24 hours of treatment, such as after subcutaneous administration of a compound described herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1) as described in the studies provided in Example 6. In some embodiments, a return to baseline levels in urine volume and sodium excretion is observed after 24 hours of treatment with a compound described here (e.g., a mixed VI AR agonist-antagonist, such as Compound 1). In some instances, the return to baseline levels in urine volume and sodium excretion are a sign that there is no more excess fluid in the peritoneal cavity (available for removal) of the individual. In some instances, there is minimal to no fluid overload or sodium or water retention after administration of a compound described herein, such as demonstrating the lack of V2 receptor activity of a compound provided herein, such as a mixed V 1 AR agonist antagonist (e.g., Compound 1).

[0453] In some instances, hyponatremia is a potential risk observed during treatment with vasopressin receptor agonists, such as terlipressin or desmopressin. In some embodiments, subcutaneous administration of a compound described here (e.g., a mixed VI AR agonistantagonist, such as Compound 1) does not lead to hyponatremia, such as despite a significant increase in urine sodium excretion following a first dose (e.g., relative to vehicle treated subjects). In some embodiments, repeat administration over 5 days of a compound described herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1) does not lead to hyponatremia. In some instances, hyponatremia is defined in rats as blood sodium levels less than 120 mEq / L.

[0454] In some embodiments, administration of a compound described herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1) provides beneficial effects on factors related to kidney sodium and water retention, such as without side effects or nonspecific toxicities. In some embodiments, administration of a compound described here (e.g., a mixed VI AR agonist-antagonist, such as Compound 1) provides submaximal effects on vasoconstriction, such as demonstrating dual benefits of therapeutic effectiveness and improved safety, such as through less risk of excessive vasoconstriction.

[0455] In some embodiments, a compound described herein (e.g., a mixed VI AR agonistantagonist, such as Compound 1) reduces portal hypertension in an individual (e.g., in needthereof). In some embodiments, a compound described herein (e.g., a mixed VI AR agonistantagonist, such as Compound 1) decreases portal pressure in an individual (e.g., in need thereof) by at least 0.1 mmHg (e.g., at least 0.5 mmHg, at least 1 mmHg, at least 2 mmHg, at least 3 mmHg, at least 4 mmHg). In some embodiments, a compound described herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1) decreases portal pressure in an individual (e.g., in need thereof) by at most 5 mmHg (e.g., at most 4 mmHg, at most 3 mmHg, at most 2 mmHg, at most 1 mmHg).

[0456] In some embodiments, such as described in the studies provided in Example 6, a compound described herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1) increases mean arterial pressure (MAP) (after subcutaneous administration), such as over a wide dose range (e.g., 10 pg / kg to 500 pg / kg of Compound 1), see FIG. 34. In some embodiments, such as described in the studies provided in Example 6, the increase in MAP reaches a peak plateau or a therapeutic ceiling (e.g., an increase in MAP of about 10 to about 15 mmHg), see FIG. 34. In some embodiments, such as described in the studies provided in Example 6, the increase in MAP reaches a peak plateau or a therapeutic ceiling (e.g., an increase in MAP of about 10 to about 15 mmHg) alongside a decrease in PP (of about 2 to about 14 mmHg), see FIG. 34. In some instances, even after a 5-fold increase in dose (e.g., 100 pg / kg or 500 pg / kg of Compound 1), a compound described herein does not produce a meaningful further change in an effect, such as an increase in MAP, see FIG. 34.

[0457] In other instances, administration of a full, nonselective (V2, Via) receptor agonist, such as terlipressin, provide a markedly higher increases in MAP (and beyond a treatment window of 10-15 mmHg), such as despite reductions in PP being similar to those for a compound described herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1), see FIG. 34.

[0458] In some embodiments, a compound described herein (e.g., a mixed VI AR agonistantagonist, such as Compound 1) increases mean arterial blood pressure, systolic arterial blood pressure, and diastolic arterial blood pressure in an individual (e.g., a mammal), such as after subcutaneous administration (e.g., see FIG. 41A-C). In some instances, the occurrence and amplitude of maximum increase in blood pressure is related to dose of a compound described herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1) in an individual (e.g., a mammal), such as after subcutaneous administration. In some embodiments, a compound described herein (e.g., a mixed V 1 AR agonist-antagonist, such as Compound 1) increases mean arterial blood pressure (MAP) by at least about 10 mmHg (e.g., at least 15 mmHg, at least 20 mmHg, at least 30 mmHg, at least 40 mmHg) in an individual (e.g., a mammal), such as aftersubcutaneous administration (e.g., see FIG. 43A). In some embodiments, a compound described herein (e.g., a mixed V 1 AR agonist-antagonist, such as Compound 1) increases mean arterial blood pressure (MAP) by at most about 50 mmHg (e.g., at most 40 mmHg, at most 30 mmHg, at most 20 mmHg, at most 10 mmHg) in an individual (e.g., a mammal), such as after subcutaneous administration. In some embodiments, a compound described herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1) increases mean arterial blood pressure (MAP) by about 10 mmHg to about 50 mmHg in an individual (e.g., a mammal), such as after subcutaneous administration. In some embodiments, a compound described herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1) increases mean arterial blood pressure (MAP) by about 20 mmHg in an individual (e.g., a mammal), such as after subcutaneous administration. In some embodiments, a compound described herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1) increases mean arterial blood pressure (MAP) by about 40 mmHg in an individual (e.g., a mammal), such as after subcutaneous administration. In some embodiments, a compound described herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1) increases mean arterial blood pressure (MAP) by about 25 mmHg in an individual (e.g., a mammal), such as after subcutaneous administration. In some embodiments, a compound described herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1) increases and sustains the increase in mean arterial blood pressure (MAP) for at least 75 minutes (e.g., at least 150 minutes, at least 300 minutes) in an individual (e.g., a mammal), such as after subcutaneous administration. In some instances, a compound described herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1) provides a change in mean arterial blood pressure (MAP) that is statistically different from vehicle in an individual (e.g., a mammal), such as after subcutaneous administration. In some embodiments, a compound described herein (e.g., a mixed V 1 AR agonist-antagonist, such as Compound 1) increases MAP and MAP does not return to baseline values in an individual (e.g., a mammal), such as after subcutaneous administration.

[0459] In some embodiments, a full antagonist, such as terlipressin, increases mean arterial pressure (MAP) in an individual (e.g., a mammal) (e.g., see FIG. 43B). In some embodiments, a full antagonist, such as terlipressin, increases mean arterial pressure (MAP) and the effect is only sustained for a short period of time, such as less than 90 minutes (e.g., no longer than 30, 75, or 90 minutes) after intravenous administration (e.g., see FIG.43B). In some embodiments, a full antagonist, such as terlipressin, provides transient effects on MAP (e.g., see FIG. 43B). In some embodiments, a compound described herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1) provides an increase in MAP spanning a 50-fold dose range in anindividual (e.g., a mammal), which in some instances, may represent the maximal effect on arterial pressure.

[0460] In some embodiments, a compound described herein (e.g., a mixed VI AR agonistantagonist, such as Compound 1) decreases heart rate in an individual (e.g., a mammal), such as following subcutaneous administration, see FIG. 41D. In some embodiments, a compound described herein (e.g., a mixed V 1 AR agonist-antagonist, such as Compound 1) decreases heart rate by at least 2% (e.g., at least 5%, at least 10%, at least 15%) in an individual (e.g., a mammal), such as after subcutaneous administration (e.g., see FIG. 41D). In some embodiments, a compound described herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1) decreases heart rate by at most 20% (e.g., at most 15%, at most 10%, at most 5%) in an individual (e.g., a mammal), such as after subcutaneous administration (e.g., see FIG. 41D). In some embodiments, a compound described herein (e.g., a mixed VI AR agonistantagonist, such as Compound 1) decreases heart rate by about 5% in an individual (e.g., a mammal), such as after subcutaneous administration (e.g., see FIG. 41D). In some instances, a compound described herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1) provides changes in MAP that are correlate with measurable decreases in heart rate in an individual (e.g., a mammal), such as after subcutaneous administration (e.g., see FIG. 4 ID, 43 A). In some instances, a compound described herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1), changes in systolic blood pressure and diastolic blood pressure correlate with changes in MAP in an individual (e.g., a mammal), such as after subcutaneous administration (e.g., see FIG. 41A-C).

[0461] In some embodiments, a compound described herein (e.g., a mixed VI AR agonistantagonist, such as Compound 1) has a terminal half life (ti / 2term) of at least 50 minutes (e.g., at least 70 minutes, at least 90 minutes, at least 110 minutes, at least 130 minutes) in an individual (e.g., a mammal), such as after subcutaneous administration. In some embodiments, a compound described herein (e.g., a mixed V 1 AR agonist-antagonist, such as Compound 1) has a terminal half life (ti / 2term) of at most 150 minutes (e.g., at most 130 minutes, at most 110 minutes, at most 90 minutes, at most 70 minutes) in an individual (e.g., a mammal), such as after subcutaneous injection. In some embodiments, a compound described herein (e.g., a mixed V 1 AR agonist-antagonist, such as Compound 1) has a terminal half life (ti / 2term) of about 50 to about 150 minutes in an individual (e.g., a mammal), such as after subcutaneous injection. In some embodiments, a compound described herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1) has a terminal half life (ti / 2term) of about 110 minutes in an individual (e.g., a mammal), such as after subcutaneous injection. In some embodiments, a compounddescribed herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1) has an elimination half life (ti / 2eiim) of at least 1 minute (e.g., at least 5 minutes, at least 10 minutes, at least 15 minutes, at least 20 minutes) in an individual (e.g., a mammal), such as after intravenous administration. In some embodiments, a compound described herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1) has an elimination half life (ti / 2eiim) 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). In some embodiments, a compound described herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1) has an elimination half life (ti / 2eiim) of about 1 minute to about 40 minutes in an individual (e.g., a mammal). In some embodiments, ca compound described herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1) has an elimination half life (ti / 2eiim) of about 20 minutes in an individual (e.g., a mammal). In some embodiments, the terminal half life (ti / 2term) of the compound after subcutaneous administration is greater than the elimination half life (ti / 2eiim).

[0462] In some embodiments, a compound described herein (e.g., a mixed VI AR agonistantagonist, such as Compound 1) has a bioavailability of at least 40% (e.g., at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%) in an individual (e.g., a mammal), such as after subcutaneous administration. In some embodiments, a compound described herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1) has a bioavailability of at most 75% (e.g., at most 70%, at most 60%, at most 50%, at most 40%) in an individual (e.g., a mammal). In some embodiments, a compound described herein (e.g., a mixed V1AR agonist-antagonist, such as Compound 1) has a bioavailability of about 40% to about 70% in an individual (e.g., a mammal). In some embodiments, a compound described herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1) has a bioavailability of about 60% in an individual (e.g., a mammal).

[0463] In some embodiments, a compound described herein (e.g., a mixed VI AR agonistantagonist, such as Compound 1) has a clearance rate in an individual (e.g., a mammal) similar to the glomerular filtration rate (e.g., 5-15 mL / min / kg), such as after subcutaneous administration. In some embodiments, a compound described herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1) has as 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 V 1 AR agonist-antagonist, such as 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 VI AR 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 VI AR agonist-antagonist, such as Compound 1) has a filtration rate of about 10 mL / min / kg.

[0464] In some embodiments, a compound described herein (e.g., a mixed VI AR agonistantagonist, such as Compound 1) decreases skin blood flow in an individual (e.g., a mammal), such as after intravenous administration (e.g., see FIG. 40A). In some embodiments, a compound described herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1) decreases skin blood flow in an individual (e.g., a mammal) by at most 60% (e.g., at most 55%, at most 50%, at most 45%, at most 40%). In some embodiments, a compound described herein (e.g., a mixed V 1 AR agonist-antagonist, such as Compound 1) decreases skin blood flow by at least 10% (e.g., at least 20%, at least 30%, at least 40%, at least 50%) in an individual (e.g., a mammal). In some embodiments, a compound described herein (e.g., a mixed VI AR agonistantagonist, such as Compound 1) decreases skin blood flow by about 20% to about 60% in an individual (e.g., a mammal). In some embodiments, a compound described herein (e.g., a mixed V 1 AR agonist-antagonist, such as Compound 1) decreases skin blood flow by about 40% in an individual (e.g., a mammal). In some embodiments, a compound described herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1) decreases skin blood flow in an individual (e.g., a mammal) less than vasopressin decreases skin blood flow in an individual (e.g., a mammal), such as after intravenous administration, e.g., see FIG. 40A. In some instances, a compound described herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1) decreases skin blood flow by about 40% in an individual (e.g., a mammal) after intravenous administration and vasopressin decreases skin blood flow by about 90% in an individual (e.g., a mammal) after intravenous administration, demonstrating that a mixed VI AR agonistantagonist described herein, such as Compound 1, is more suitable for intravenous administration than a full, nonselective (V2, Via) agonist (e.g., vasopressin or terlipressin), such as by reducing (significant) injection site reactions (e.g., local vasoconstriction) that prevent a drug from being suitable for systemic delivery. In some instances, the lesser decrease in skin blood flow by a compound provided herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1) in comparison to vasopressin demonstrates a less local vasoconstriction in comparison to vasopressin.

[0465] In some instances, increased serum lactate levels are a clinical marker for anaerobic metabolism and tissue hypoxia and are used as a surrogate marker for the development of vasoconstriction and tissue ischemia. In some embodiments, a compound described herein (e.g., a mixed V 1 AR agonist-antagonist, such as Compound 1) does not (significantly) increase blood lactate concentration in an individual, such as after intravenous administration (e.g., seeFIG. 40B). In some embodiments, a compound described herein (e.g., a mixed VI AR agonistantagonist, such as Compound 1) does not (significantly) increase blood lactate levels while similar doses of vasopressin markedly increase blood lactate levels in an individual, such as after intravenous administration (e.g., see FIG. 40B-C). In some instances, vasopressin increases blood lactate levels by at least a 2-fold (e.g., a 3-fold, 4-fold) in an individual, such as after intravenous administration (e.g., see FIG. 40B).

[0466] In some embodiments, a compound described herein (e.g., a mixed VI AR agonistantagonist, such as Compound 1) decreases plasma concentration (e.g., linearly) (see e.g., FIG. 39A-B, 42A-B).

[0467] In some embodiments, a compound described herein (e.g., a mixed VI AR agonistantagonist, such as Compound 1) increases blood pH in an individual, such as after intravenous administration. In some embodiments, a compound described herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1) decreases blood pH in an individual, such as after intravenous administration.

[0468] In some instances, a compound described herein (e.g., a mixed VI AR agonistantagonist, such as Compound 1) provides an initial apparent volume of the central compartment (Vc) in an individual (e.g., a mammal) of at least 20 mL / kg (e.g., at least 40 mg / kg, at least 60 mg / kg, at least 80 mg / kg, at least 100 mg / kg), such as after intravenous administration. In some instances, a compound described herein (e.g., a mixed VI AR agonistantagonist, such as Compound 1) provides an initial apparent volume of the central compartment (Vc) in an individual (e.g., a mammal) of at most 150 mg / kg (e.g., at most 130 mg / kg, at most 110 mg / kg, at most 90 mg / kg), such as after intravenous administration.

[0469] In some instances, a compound described herein (e.g., a mixed VI AR agonistantagonist, such as Compound 1) provides a volume of distribution at steady state (Vss) 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), such as after intravenous administration. In some instances, a compound described herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1) provides a volume of distribution at steady state (Vss) 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), such as after intravenous administration.

[0470] In some instances, a compound described herein (e.g., a mixed VI AR agonistantagonist, such as Compound 1) provides a maximum plasma concentration (Cmax) per unit dose in an individual (e.g., a mammal) of at least 200 ng / mL per mg / kg (e.g., at least 300 ng / mLper mg / kg, at least 500 ng / mL per mg / kg, at least 600 ng / mL per mg / kg, at least 700 ng / mL per mg / kg), such as after subcutaneous administration. In some instances, a compound described herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1) provides a maximum plasma concentration (Cmax) 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), such as after subcutaneous administration. In some instances, a compound described herein (e.g., a mixed VI AR agonistantagonist, such as Compound 1) provides a time of maximum plasma concentration (Tmax) in an individual (e.g., a mammal) of at least 5 minutes (e.g., at least 10 minutes, at least 20 minutes, at least 30 minutes), such as after subcutaneous administration In some instances, a compound described herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1) provides a time of maximum plasma concentration (Tmax) in an individual (e.g., a mammal) of at most 60 minutes (e.g., at most 50 minutes, at most 40 minutes, at most 30 minutes, at most 20 minutes), such as after subcutaneous administration.

[0471] In some instances, a compound described herein (e.g., a mixed VI AR agonistantagonist, such as Compound 1) provides an area under the curve (AUC) per unit dose in an individual (e.g., a mammal) of at least 40,000 mhrng / mL per mg / kg (e.g., at least 45,000 mhrng / mL per mg / kg, at least 50,000 mhrng / mL per mg / kg, at least 55,000 mhrng / mL per mg / kg, at least 60,000 minmg / mL per mg / kg), such as after subcutaneous administration. In some instances, a compound described herein (e.g., a mixed V 1 AR agonist-antagonist, such as Compound 1) provides an area under the curve (AUC) per unit dose in an individual (e.g., a mammal) of at most 70,000 minmg / mL per mg / kg (e.g., 65,000 minmg / mL per mg / kg, 60,000 minmg / mL per mg / kg, 55,000 minmg / mL per mg / kg, 50,000 minmg / mL per mg / kg), such as after subcutaneous administration.

[0472] In some instances, a compound described herein (e.g., a mixed VI AR agonistantagonist, such as Compound 1) provides an apparent total body clearance (CL / F) in an individual (e.g., a mammal) of at least 10 mL / min / kg (e.g., at least 12 mL / min / kg, at least 15 mL / min / kg, at least 18 mL / min / kg), such as after subcutaneous administration. In some instances, a compound described herein (e.g., a mixed VI AR agonist-antagonist, such as Compound 1) provides an apparent total body clearance (CL / F) in an individual (e.g., a mammal) of at most 30 mL / min / kg (e.g., at most 28 mL / min / kg, at most 25 mL / min / kg, at most 22 mL / min / kg, at most 20 mL / min / kg), such as after subcutaneous administration.

[0473] Provided in some embodiments herein are methods of treating complications of endstage liver disease, such as, ascites (e.g., refractory ascites), in an individual (e.g., in needthereof), the method comprising administering a therapeutically effective amount of a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., an acetate salt), to the individual.

[0474] In some embodiments, an individual described herein has cirrhotic portal hypertension. In some embodiments, an individual described herein end-stage liver disease (ESLD). In some embodiments, an individual described herein has ascites. In some embodiments, an individual described herein has refractory ascites. In some embodiments, an individual described herein has developed ascites as a complication of ESLD. In some embodiments, an individual described herein has developed refractory ascites as a complication of ESLD.

[0475] In some embodiments, a compound described herein (e.g., Compound 1) provides a substantially improved therapeutic index (e.g., arising from a lower maximal vasoconstrictive effect and lower risk for tissue hypoxia), such as, when compared to full (VIA) receptor agonists. In some embodiments, a compound described herein (e.g., Compound 1) provides about half of the maximal vasoconstriction produced by full agonists, such as, without any concomitant signs of ischemia. In some embodiments, a compound described herein (e.g., Compound 1) is a (clinically) efficacious vasoconstrictor (e.g., having a favorable benefit / risk profde, such as, having low to no organ toxicities).

[0476] Provided in some embodiments herein is a method of treating end-stage liver disease (ESLD) in an individual (e.g., in need thereof), the method comprising administering a therapeutically effective amount of a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., an acetate salt), to the individual.

[0477] Provided in some embodiments herein is a method of treating a complication of ESLD in an individual (e.g., in need thereof), the method comprising administering a therapeutically effective amount of a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., an acetate salt), to the individual.

[0478] Provided in some embodiments herein is a method of treating ascites in an individual (e.g., in need thereof), the method comprising administering a therapeutically effective amount of a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., an acetate salt), to the individual.

[0479] In some embodiments, the individual has a form of ascites that is difficult to treat. In some embodiments, the individual has recurrent ascites. In some embodiments, the individual has non-responsive ascites. In some embodiments, the individual has partially-responsive ascites. In some embodiments, the individual has treatment-resistant ascites. In someembodiments, the individual has treatment-nonresponsive ascites. In some embodiments, the individual has diuretic-resistant ascites. In some embodiments, the individual has diuretic- intractable ascites.

[0480] Provided in some embodiments herein is a method of treating refractory ascites in an individual (e.g., in need thereof), the method comprising administering a therapeutically effective amount of a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., an acetate salt), to the individual.

[0481] Provided in some embodiments herein is a method of treating ascites in an individual, such as an individual who has developed ascites as a complication of cirrhosis, the method comprising administering a therapeutically effective amount of a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., an acetate salt), to the individual.

[0482] Provided in some embodiments herein is a method of treating acute hepatorenal sydrome-acute kidney injury (HRS-AKI) in an individual, such as an individual who has developed HRS-AKI as a complication of cirrhosis, the method comprising administering a therapeutically effective amount of a compound described herein (e.g., Compound 1), or a pharmaceutically acceptable salt (e.g., an acetate salt), to the individual.

[0483] In some embodiments, the individual has liver disease (ESLD). In some embodiments, the individual has ascites as a complication of end-stage liver disease (ESLD). In some embodiments, the individual has developed refractory ascites as a complication of end-stage liver disease (ESLD).

[0484] 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.

[0485] In some embodiments, the therapeutically effective amount of a compound described herein (e.g., Compound 1), or the pharmaceutically acceptable salt (e.g., the acetate salt), is about 5 pg to about 55 pg. In some embodiments, the therapeutically effective amount of a compound described herein (e.g., Compound 1), or the pharmaceutically acceptable salt (e.g., the acetate salt), is about 8 pg to about 50 pg. In some embodiments, the therapeutically effective amount of a compound described herein (e.g., Compound 1), or the pharmaceutically acceptable salt (e.g., the acetate salt), is about 20 pg to about 35 pg. In some embodiments, the therapeutically effective amount of a compound described herein (e.g., Compound 1), or the pharmaceutically acceptable salt (e.g., the acetate salt), is about 25 pg to about 35 pg. In someembodiments, the therapeutically effective amount of a compound described herein (e.g., Compound 1), or the pharmaceutically acceptable salt (e.g., the acetate salt), is about 30 pg. In some embodiments, the therapeutically effective amount of a compound described herein (e.g., Compound 1), or the pharmaceutically acceptable salt (e.g., the acetate salt), is administered over a period of time, such as over several hours (e.g., continuously for up to 24-hr) for several days (e.g., up to 10 days).

[0486] In some embodiments, a compound described herein (e.g., Compound 1), or the pharmaceutically acceptable salt (e.g., the acetate salt), is administered to the individual intravenously. In some embodiments, Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), is administered to the individual by intravenous infusion.

[0487] In some embodiments, a compound described herein (e.g., Compound 1), or the pharmaceutically acceptable salt (e.g., the acetate salt), is administered to the individual subcutaneously. In some embodiments, Compound 1, or the pharmaceutically acceptable salt (e.g., the acetate salt), is administered to the individual by subcutaneous injection.

[0488] In some embodiments, the therapeutically effective amount of a compound described herein (e.g., Compound 1), or the pharmaceutically acceptable salt (e.g., the acetate salt), is about 5 pg / hr or more. In some embodiments, the therapeutically effective amount of a compound described herein (e.g., Compound 1), or the pharmaceutically acceptable salt (e.g., the acetate salt), is about 55 pg / hr or less. In some embodiments, the therapeutically effective amount of a compound described herein (e.g., Compound 1), or the pharmaceutically acceptable salt (e.g., the acetate salt), is about 5 pg / hr to about 55 pg / hr. In some embodiments, the therapeutically effective amount of a compound described herein (e.g., Compound 1), or the pharmaceutically acceptable salt (e.g., the acetate salt), is about 8 pg / hr to about 50 pg / hr. In some embodiments, the therapeutically effective amount of a compound described herein (e.g., Compound 1), or the pharmaceutically acceptable salt (e.g., the acetate salt), is about 20 pg / hr to about 35 pg / hr. In some embodiments, the therapeutically effective amount of a compound described herein (e.g., Compound 1), or the pharmaceutically acceptable salt (e.g., the acetate salt), is about 25 pg / hr to about 35 pg / hr. In some embodiments, the therapeutically effective amount of a compound described herein (e.g., Compound 1), or the pharmaceutically acceptable salt (e.g., the acetate salt), is about 30 pg / hr.

[0489] In some embodiments, a compound described herein (e.g., Compound 1), or the pharmaceutically acceptable salt (e.g., the acetate salt), is administered to the individual on a first day and a second day. In some embodiments, a compound described herein (e.g.,-I l l-Compound 1), or the pharmaceutically acceptable salt (e.g., the acetate salt), is (e.g., subcutaneously) administered to the individual one or more days after the first day. In some embodiments, the individual receives an initial (e.g., intravenous infusion) dose of a compound described herein (e.g., Compound 1), or the pharmaceutically acceptable salt (e.g., the acetate salt), on the first day. In some embodiments, the individual receives an initial (e.g., intravenous infusion) dose of a compound described herein (e.g., Compound 1), or the pharmaceutically acceptable salt (e.g., the acetate salt), on the first day to acclimate the individual to vasoconstriction before receiving a first assigned (e.g., subcutaneous) treatment dose, such as on the second day.

[0490] 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 ...

Claims

CLAIMSWe claim:

1. A method of treating end-stage liver disease (ESLD) or a symptom (e.g., complication) thereof in an individual (e.g., in need thereof), the method comprising subcutaneously infusing into the individual (e.g., in need thereof) a composition comprising an (effective) amount of a compound, the compound being a mixed vasopressin receptor 1A (VI AR) agonist-antagonist.

2. The method of claim 1, wherein the mixed vasopressin receptor 1A (VI AR) agonistantagonist is selective for V 1 AR over V2R.

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

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

5. The method of any one of the preceding claims, wherein the compound has a structure represented by Formula I:D1-L-D2Formula I or a pharmaceutically acceptable salt thereof, wherein:DI is a vasopressin receptor 1A (VI AR) agonist;D2 is a VI AR antagonist; andL is a linker.

6. A method of treating end-stage liver disease (ESLD) or a symptom (e.g., complication) thereof in an individual (e.g., in need thereof), the method comprising subcutaneously infusing into the individual (e.g., in need thereof) a composition comprising an (effective) amount of a compound having a structure represented by Formula I:D1-L-D2Formula I or a pharmaceutically acceptable salt thereof, wherein:DI is a vasopressin receptor 1A (VI AR) agonist;D2 is a VI AR antagonist; andL is a linker.

7. The method of claim 6, wherein DI is selective for V 1 AR over V2R.The method according to claim 6 or 7, wherein DI is or comprises a (e.g., cyclic) peptide. The method of any one of claims 6-8, wherein DI is or comprises a cyclic nonapeptide. The method of any one of claims 6-9, wherein DI has or comprises the following structure:The method of any one of claims 6-10, wherein D2 is or comprises a (e.g., linear) peptide. The method of any one of claims 6-11, wherein D2 is a linear polypeptide comprising about seven or more amino acid residues. The method of any one of claims 6-12, wherein D2 has or comprises the following structure:The method of any one of claims 6-13, wherein L is a non-hydro lyzable linker. The method of any one of claims 6-13, wherein L comprises one or more linker group, each linker group being independently selected from the group consisting of a substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl. The method of any one of claims 6-15, wherein L is a bond, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. The method of any one of claims 6-16, wherein L is or comprises substituted or unsubstituted heteroalkyl. The method of any one of claims 6-17, wherein L is heteroalkyl (e.g., alkylamine) substituted with one or more substituent, each substituent being independently selected form the group consisting of oxo, amino, and substituted heteroalkyl (e.g., alkylamine substituted with oxo). The method of any one of claims 6-18, wherein L is or comprises one or more (e.g., modified) amino acid residue. The method of any one of claims 6-19, wherein L has or comprises the following structure:The method of any one of claims 6-20, wherein the compound is Compound 1, or a pharmaceutically acceptable salt thereof. A method of treating end-stage liver disease (ESLD) or a symptom (e.g., complication) thereof in an individual (e.g., in need thereof), the method comprising subcutaneously infusing into the individual (e.g., in need thereof) a composition comprising an (effective) amount of Compound 1 , or a pharmaceutically acceptable salt thereof. The method of any one of the preceding claims, wherein the composition further comprises a liquid vehicle or solvent (e.g., water or an aqueous vehicle). The method of any one of the preceding claims, wherein the method further comprises affixing a subcutaneous infusion device to the skin of the individual, the subcutaneous infusion device comprising a chamber body and a hollow tube body, the composition being configured within the chamber body, the hollow tube body comprising a first opening and a second opening, the first opening being in fluid contact with the chamber body, and the second opening being configured subcutaneously within the individual after affixing the subcutaneous infusion device to the skin. The method of claim 24, wherein the subcutaneous infusion device further comprises a pump configured to subcutaneously infuse the composition into the individual at a constant or varying rate. A method of treating end-stage liver disease (ESLD) or a symptom (e.g., complication) thereof in an individual (e.g., in need thereof), the method comprising subcutaneously administering to the individual (e.g., in need thereof) a composition comprising an (effective) amount of a compound, the compound being a mixed vasopressin receptor 1A (VI AR) agonist-antagonist. A method of treating end-stage liver disease (ESLD) or a symptom (e.g., complication) thereof in an individual (e.g., in need thereof), the method comprising subcutaneously administering to the individual (e.g., in need thereof) a composition comprising an (effective) amount of a compound having a structure represented by Formula I:D1-L-D2Formula I or a pharmaceutically acceptable salt thereof, wherein:DI is a vasopressin receptor 1A (VI AR) agonist;D2 is a VI AR antagonist; andL is a linker. A method of treating end-stage liver disease (ESLD) or a symptom (e.g., complication) thereof in an individual (e.g., in need thereof), the method 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. The method of any one of the preceding claims, wherein when the composition is subcutaneously administered to the individual (e.g., by subcutaneous (bolus) injection or subcutaneous infusion), less than 50% of the compound of Formula I degrades (e.g., subcutaneously). The method of any one of the preceding claims, wherein when the composition is subcutaneously administered to the individual (e.g., by subcutaneous (bolus) injection or subcutaneous infusion), less than 30% of the compound of Formula I degrades (e.g., subcutaneously). The method of any one of the preceding claims, wherein when the composition is subcutaneously administered to the individual (e.g., by subcutaneous (bolus) injection or subcutaneous infusion), less than 50% of the compound of Formula I degrades (e.g., subcutaneously) to form Ml. The method of any one of the preceding claims, wherein when the composition is subcutaneously administered to the individual (e.g., by subcutaneous (bolus) injection or subcutaneous infusion), less than 30% of the compound of Formula I degrades (e.g., subcutaneously) to form Ml. The method of any one of the preceding claims, wherein when the composition is subcutaneously infused into the individual less Ml is formed relative to administration of an otherwise identical composition administered by subcutaneous (bolus) injection. The method of any one of the preceding claims, wherein when the composition is subcutaneously infused into the individual less Ml is formed systemically relative to administration of an otherwise identical composition administered by subcutaneous (bolus) injection.The method of any one of the preceding claims, wherein when the composition is subcutaneously infused into the individual less Ml is formed locally (injection / infusion site) relative to administration of an otherwise identical composition administered by subcutaneous (bolus) injection. The method of any one of the preceding claims, wherein subcutaneously infusing the composition into the individual improves tolerability, relative to subcutaneous (bolus) injection (e.g., based on a reduction of Ml formation). The method of any one of the preceding claims, wherein subcutaneously infusing the composition into the individual reduces undesired systemic events (e.g., undesired vasoconstriction, such as resulting in ischemia), reduces undesired administration site events (e.g., local site vasoconstriction, such as resulting in administration site ischemia), or both. The method of any one of the preceding claims, wherein the composition is subcutaneously infused into the individual continuously for at least one hour. The method of any one of the preceding claims, wherein the composition is subcutaneously infused into the individual at a rate of about 0.005 milliliters per hour (mL / hr) to about 1 mL / hr for an administration period. The method of any one of the preceding claims, wherein the composition comprises a buffering agent. The method of claim 40, wherein the buffering agent is selected from the group consisting of acetate buffer, succinate buffer, and citrate buffer. The method of any one of the preceding claims, wherein the composition comprises a buffering agent in a concentration of about 1 millimolar (mM) to about 1 molar (M). The method of any one of the preceding claims, wherein the composition comprises a buffering agent in a concentration of about 5 mM to about 250 mM. The method of any one of the preceding claims, wherein the composition comprises a buffering agent in a concentration of about 5 mM to about 25 mM. The method of any one of claims 1-43, wherein the composition comprises a buffering agent in a concentration of about 50 mM to about 250 mM. The method of any one of the preceding claims, wherein the composition has a pH of about 4 to about 8. The method of any one of the preceding claims, wherein the composition has a pH of about 4 to about 6.. The method of any one of the preceding claims, wherein the composition has a pH of about 4.5 to about 5. . The method of any one of the preceding claims, wherein the compound is administered to the individual (e.g., continuously) in an amount of about 0.001 milligram (mg) to about 100 mg, such as over a period of one or more days. . The method of any one of the preceding claims, wherein the composition comprises the compound in a concentration of about 0.001 milligrams per milliliters (mg / mL) to about 100 mg / mL. . The method of any one of the preceding claims, wherein the composition comprises the compound in a concentration of about 0.1 mg / mL to about 100 mg / mL. . The method of any one of the preceding claims, wherein the composition comprises the compound in a concentration of about 1 mg / mL to about 10 mg / mL. . The method of any one of the preceding claims, wherein the composition further comprises a preservative. . The method of claim 53, wherein the preservative is present in an amount of about 1 mg / mL to about 20 mg / mL. . The method of any one of the preceding claims, wherein the composition further comprises a solubilizing agent. . The method of claim 32, wherein the solubilizing agent is present in an amount of about 1 mg / mL to about 250 mg / mL (e.g., about 60-80 mg / mL). . The method of any one of the preceding claims, the compound is (continuously) administered to the individual in need thereof at a dose of about 0.1 mg / day to about 100 mg / day. . A method of reducing (incidence of) local vasoconstriction, such as (injection site) ischemia, in an individual in need thereof, the method comprising subcutaneously infusing into the individual in need thereof a composition comprising a compound having a structure represented by Formula I, or a pharmaceutically acceptable salt thereof:D1-L-D2Formula I or a pharmaceutically acceptable salt thereof, wherein:D1 is a vasopressin receptor 1A (VI AR) agonist;D2 is a VI AR antagonist; andL is a linker. . A method of treating end-stage liver disease (ESLD) in an individual in need thereof, the method comprising subcutaneously infusing into the individual in need thereof a composition comprising a compound having a structure represented by Formula I, or a pharmaceutically acceptable salt thereof:D1-L-D2Formula I or a pharmaceutically acceptable salt thereof, wherein:DI is a vasopressin receptor 1A (VI AR) agonist;D2 is a VI AR antagonist; andL is a linker, wherein less than 50% of the compound of Formula I degrades (e.g., subcutaneously).. The method of any one of the preceding claims, wherein (e.g., within the first 24-hours, such as within the first 4 hours) urine volume of the individual (significantly) increases (e.g., compared to a vehicle control) following subcutaneous administration of the compound, or the pharmaceutically acceptable salt thereof, of any one of the preceding claims to the individual. . The method of any one of the preceding claims, wherein urine volume of the individual increases by about 25% or more, 50% or more, 100% or more, 200% or more, 300% or more, 400% or more, or 500% or more (e.g., compared to a vehicle control) following subcutaneous administration of the compound, or the pharmaceutically acceptable salt thereof, of any one of the preceding claims to the individual. . The method of any one of the preceding claims, wherein urine volume of the individual is about 50% or more or 100% or more higher at least one day (e.g., 3 days or more) after subcutaneous administration of the compound, or the pharmaceutically acceptable salt thereof, of any one of the preceding claims to the individual. . The method of any one of the preceding claims, wherein urine sodium (excretion) of the individual (significantly) increases (e.g., compared to a vehicle control) followingsubcutaneous administration of the compound, or the pharmaceutically acceptable salt thereof, of any one of the preceding claims to the individual. The method of any one of the preceding claims, wherein urine sodium and / or urine potassium (excretion) of the individual increases by about 100% or more, 250% or more, 500% or more, 750% or more, 1000% or more, 1500% or more, or 2000% or more (e.g., compared to a vehicle control, such as within the first 4 hours of treatment) following subcutaneous administration of the compound, or the pharmaceutically acceptable salt thereof, of any one of the preceding claims to the individual. The method of any one of the preceding claims, wherein ascites volume of the individual (significantly) decreases (e.g., compared to a vehicle control) following subcutaneous administration of the compound, or the pharmaceutically acceptable salt thereof, of any one of the preceding claims to the individual. The method of any one of the preceding claims, wherein ascites volume of the individual decreases by about 25 or more, 50% or more, 100% or more, about 200% or more, or about 300% or more (e.g., compared to a vehicle control, such as when measured after 3 days of treatment) following subcutaneous administration of the compound, or the pharmaceutically acceptable salt thereof, of any one of the preceding claims to the individual. The method of any one of the preceding claims, wherein body weight of the individual (significantly) decreases (e.g., compared to a vehicle control) following subcutaneous administration of the compound, or the pharmaceutically acceptable salt thereof, of any one of the preceding claims to the individual. The method of any one of the preceding claims, wherein body weight of the individual decreases by about 1% or more, 2.5% or more, 5% or more, or about 10% or more (e.g., compared to a vehicle control) following subcutaneous administration of the compound, or the pharmaceutically acceptable salt thereof, of any one of the preceding claims to the individual. The method of any one of the preceding claims, wherein body weight of the individual is at least about 1%, at least about 2.5%, at least about 5%, or at least about 10% less at least one day (e.g., 3 days or more (e.g., 5 days)) after subcutaneous administration of the compound, or the pharmaceutically acceptable salt thereof, of any one of the preceding claims to the individual. The method of any one of the preceding claims, wherein mean arterial pressure (MAP) of the individual increases (e.g., compared to a baseline measurement before treatment)following subcutaneous administration of the compound, or the pharmaceutically acceptable salt thereof, of any one of the preceding claims to the individual. The method of any one of the preceding claims, wherein MAP of the individual increases by about 1% to about 10% (e.g., compared to a baseline measurement before treatment) after administering the compound, or the pharmaceutically acceptable salt thereof, of any one of the preceding claims to the individual. The method of any one of the preceding claims, wherein MAP of the individual dose- dependently increases after administering the compound, or the pharmaceutically acceptable salt thereof, of any one of the preceding claims to the individual. The method of any one of the preceding claims, wherein (subcutaneous) administration of the compound, or the pharmaceutically acceptable salt thereof, of any one of the preceding claims to the individual improves systemic hemodynamics in the individual. The method of any one of the preceding claims, wherein (subcutaneous) administration of the compound, or the pharmaceutically acceptable salt thereof, of any one of the preceding claims to the individual reduces fluid retention and / or overload in the individual. The method of any one of the preceding claims, wherein the method comprises administering the compound, or the pharmaceutically acceptable salt thereof, of any one of the preceding claims to the individual on a first day and a second day (e.g., the second day being one or more days after the first day). The method of any one of the preceding claims, wherein the method further comprises (subcutaneously) administering the compound, or the pharmaceutically acceptable salt thereof, of any one of the preceding claims to the individual on one or more day after the first day. The method of any one of the preceding claims, wherein the method comprises (subcutaneously) administering the compound, or the pharmaceutically acceptable salt thereof, of any one of the preceding claims to the individual daily for two or more days (e.g., after the first day). The method of any one of the preceding claims, wherein the method further comprises (subcutaneously) administering the compound, or the pharmaceutically acceptable salt thereof, of any one of the preceding claims to the individual on consecutive days after the first day.The method of any one of the preceding claims, wherein the method comprises (subcutaneously) administering the compound, or the pharmaceutically acceptable salt thereof, of any one of the preceding claims to the individual on multiple days. The method of any one of the preceding claims, wherein the individual receives repeated subcutaneous injections of the compound, or the pharmaceutically acceptable salt thereof, of any one of the preceding claims. The method of any one of the preceding claims, wherein the method comprises subcutaneously administering the compound, or the pharmaceutically acceptable salt thereof, of any one of the preceding claims to the individual once- or twice-daily (e.g., for two or more consecutive days). The method of any one of the preceding claims, wherein the method comprises administering the compound, or the pharmaceutically acceptable salt thereof, of any one of the preceding claims to the individual by subcutaneous bolus injection. The method of any one of the preceding claims, wherein the method comprises administering the compound, or the pharmaceutically acceptable salt thereof, of any one of the preceding claims to the individual by (e.g., continuous) subcutaneous infusion. The method of any one of the preceding claims, wherein the method comprises (e.g., subcutaneously) administering the compound, or the pharmaceutically acceptable salt thereof, of any one of the preceding claims to the individual in an amount of about 0.01 milligrams (mg) / day to about 100 mg / day (e.g., about 0.01 milligrams (mg) / day to about 10 mg / day (e.g., about 0.01 mg / day to about 1 mg / day)). The method of any one of the preceding claims, wherein the individual has end-stage liver disease (ESLD). The method of any one of the preceding claims, wherein the individual has ascites. The method of any one of the preceding claims, wherein the individual has refractory ascites. The method of any one of the preceding claims, wherein the individual has developed (refractory) ascites as a complication of ESLD. The method of any one of the preceding claims, wherein the method further comprises reducing serum creatinine (sCr) (value) in the individual (e.g., compared to a baseline measurement before treatment). The method of any one of the preceding claims, wherein the method comprises administering the compound, or the pharmaceutically acceptable salt thereof, of anyone of the preceding claims to the individual at least until the individual has a sCr value of 1.5 milligrams (mg) / deciliters (dL) or less. The method of any one of the preceding claims, wherein the individual has an improvement in renal function after administration of the compound, or the pharmaceutically acceptable salt thereof, of any one of the preceding claims. The method of any one of claims 1, 6, 22, 26-28, 58, and 59, wherein the method comprises any one of the elements of claims 2-5, 7-21, 23-25, 29-57, and 60-91. 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 (VI AR) agonist-antagonist, the composition being formulated for subcutaneous administration. The composition of claim 55, wherein the compound has a structure represented by Formula I:D1-L-D2Formula I or a pharmaceutically acceptable salt thereof, wherein:DI is a vasopressin receptor 1A (VI AR) agonist;D2 is a VI AR antagonist; andL is a linker. The composition according to claim 55 or 56, wherein the compound is Compound 1. A pharmaceutical composition comprising an effective amount of a compound having a structure represented by Formula I:D1-L-D2Formula I or a pharmaceutically acceptable salt thereof, wherein:DI is a vasopressin receptor 1A (VI AR) agonist;D2 is a VI AR antagonist; andL is a linker, the composition being formulated for subcutaneous administration. A pharmaceutical composition comprising an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, the composition being formulated for subcutaneous administration.The composition of any one of the preceding claims, wherein the composition is suitable for systemic delivery of an active agent, such as Compound 1. A subcutaneous formulation comprising a compound having a structure represented by Formula I, or a pharmaceutically acceptable salt thereof:D1-L-D2Formula I or a pharmaceutically acceptable salt thereof, wherein:DI is a vasopressin receptor 1A (VI AR) agonist;D2 is a VI AR antagonist; andL is a linker, wherein less than 50% of the compound of Formula I degrades (e.g., subcutaneously).. A subcutaneous formulation comprising a compound having a structure represented by Formula I, or a pharmaceutically acceptable salt thereof:D1-L-D2Formula I or a pharmaceutically acceptable salt thereof, wherein:DI is a vasopressin receptor 1A (VI AR) agonist;D2 is a VI AR antagonist; andL is a linker, the formulation having a concentration of the compound of Formula I of about 0.1 mg / mL to about 100 mg / mL. . A subcutaneous formulation comprising: a. a compound having a structure represented by Formula I, or a pharmaceutically acceptable salt thereof:D1-L-D2Formula I wherein:DI is a vasopressin receptor 1A (VI AR) agonist;D2 is a VI AR antagonist; andL is a linker, and b. a buffering agent at a concentration of about 1 millimolar (mM) to about 1 M.. The subcutaneous formulation of claims 99-101, further comprising a preservative. . A subcutaneous formulation comprising: a. a compound having a structure represented by Formula I, or a pharmaceutically acceptable salt thereof:D1-L-D2Formula I wherein:DI is a vasopressin receptor 1A (VI AR) agonist;D2 is a VI AR antagonist; andL is a linker, and b. a preservative. . A subcutaneous formulation comprising: a. a compound having a structure represented by Formula I, or a pharmaceutically acceptable salt thereof:D1-L-D2Formula I wherein:DI is a vasopressin receptor 1A (VI AR) agonist;D2 is a VI AR antagonist; andL is a linker, and b. a solubilizing agent. . The subcutaneous formulation of claims 99-104, further comprising preservative (e.g., m-cresol) at a concentration of about 1 mg / mL to about 100 mg / mL.. The subcutaneous formulation of claims 99-105, further comprising 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). . The subcutaneous formulation of claims 99-106, wherein the compound of Formula I is less susceptible to degradation, such as in the subcutaneous layer of an individual subcutaneously administered the formulation. . The subcutaneous formulation of claims 99-107, wherein less than 50% of the compound of Formula I degrades (e.g., in a vial and / or subcutaneously), such as over a period of about one or two days.. The subcutaneous formulation of claims 99-108, wherein the compound of Formula I is present in the formulation at a concentration of about 0.1 mg / mL to about 100 mg / mL. . The subcutaneous formulation of claims 99-109, wherein the compound of Formula I is present in the formulation at a concentration of about 1 mg / mL to about 50 mg / mL. . The subcutaneous formulation of claims 99-109, further comprising a buffering agent at a concentration of about 1 millimolar (mM) to about IM. . The subcutaneous formulation of claims 99-111 , further comprising a buffering agent having a pKa of about 3.0 to about 6.0, such as at 25 °C. . The subcutaneous formulation according to claim 111 or 112, wherein the buffering agent is selected from the group consisting of acetate, citrate, succinate, and phosphate. . The subcutaneous formulation of claims 99-113, having a pH sufficient to inhibit (e.g., deactivate or inactivate) a protease (e.g., trypsin), such as in subcutaneous layer of an individual subcutaneously administered the formulation. . The subcutaneous formulation of claims 99- 114, having a pH of about 4 to about 5 (e.g., about 4.5). . The subcutaneous formulation of claims 99-115, having an ionic strength of about 5 mM to about 200 mM (e.g., about 10 mM to about 100 mM). . The subcutaneous formulation of claims 99-116, wherein the pH of the subcutaneous formulation does not (substantially) change when administered subcutaneously to an individual (e.g., by subcutaneous (bolus) injection or subcutaneous infusion). . A system for treating end-stage liver disease (ESLD), the system comprising:(a) a composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof; and(b) a device configured to provide subcutaneous infusion of the composition to an individual when the device is positioned on the skin of the individual. . The system of claim 118, wherein the system comprises an adhesive body for (e.g., reversibly) affixing the (subcutaneous infusion) device to the surface of the skin of the individual.. The system according to claim 118 or 119, wherein the system comprises a chamber body and a hollow tube body, the composition being configured within the chamber body. . The system of any one of claims 118-120, wherein the hollow tube body comprises a first opening and a second opening. . The system of any one of claims 118-121, wherein the first opening is in fluid contact with the chamber body. . The system of any one of claims 118-122, wherein the second opening is configured subcutaneously within the individual after affixing the subcutaneous infusion device to the skin of the individual. . The system of any one of claims 118-123, wherein the (subcutaneous infusion) device further comprises a pump configured to subcutaneously infuse the composition into the individual at a constant or varying rate. . The system of any one of claims 118-124, wherein the system is configured to (continuously) provide the composition to the individual over a period of about 24 hours or more. . The system of any one of claims 118-125, wherein the device is configured to receive a vial and / or a cartridge of the composition. . The system of any one of claims 118-126, wherein the device is a subcutaneous infusion device (e.g., pump). . The system of any one of claims 118-127, wherein the composition is the composition or formulation of any one of the preceding claims.

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