Hybrid vasopressin receptor agonists-antagonists to modulate mean arterial pressure

Abstract

Provided herein are compositions, such as suitable for subcutaneous administration, and methods for modulating mean arterial pressure (MAP) in an individual using a hybrid V1A receptor agonist-antagonist.

Description

[0001] Cross - reference to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 378,010, filed on September 30, 2022, U.S. Provisional Application No. 63 / 432,974, filed on December 15, 2022, and U.S. Provisional Application No. 63 / 471,712, filed on June 7, 2023, each of which is hereby incorporated by reference in its entirety. Background of the Invention

[0003] Complications of end - stage liver disease (ESLD) result in approximately 1 million deaths each year. Patients with end - stage liver disease often develop portal hypertension. ESLD patients are prone to a variety of decompensated events that can impair the perfusion pressure of the kidneys and lead to progressive functional kidney injury. Hepatorenal syndrome with acute kidney injury (HRS - AKI) is a life - threatening complication and decompensated event that occurs in patients with ESLD, with a mortality rate approaching 90% (e.g., within 90 days) for untreated patients and a median survival of less than 4 weeks. However, if treated promptly, HRS - AKI is potentially reversible. Summary of the Invention

[0004] Hepatorenal syndrome with acute kidney injury (HRS - AKI) is a critical and rapidly progressive consequence of end - stage liver disease (ESLD), which leads to acute renal failure and usually results in death. HRS - AKI is estimated to affect up to 75,000 individuals (e.g., globally) each year and is associated with a mortality rate greater than 50% at 90 days after diagnosis. With the increasing incidence of (chronic) liver disease, the prevalence of HRS - AKI is expected to increase. Therapeutic interventions often only have a modest effect and / or fail to achieve the goals of reversing renal failure and prolonging the survival of critically ill patients.

[0005] The management of decompensated cirrhosis typically involves the use of vasoconstrictors that are full vasopressin 1a receptor (V1AR) agonists. Full (vasopressin V2 receptor (V2R) and V1AR) agonists reduce portal venous pressure by increasing splanchnic arteriolar vasoconstriction, thereby redistributing blood volume into the systemic circulation, which in turn can lead to an increase in glomerular filtration rate and improved renal perfusion. However, (non-selective) full (V1AR, V2R) agonists (e.g., those having only an agonist moiety without an antagonist moiety) may cause unwanted events, such as unwanted systemic events like vasoconstriction leading to ischemia (e.g., organ ischemia and / or local (injection) site ischemia); administration (e.g., injection) site events (e.g., reactions), such as local (site) vasoconstriction leading to ischemia at the administration site; or both (e.g., when administered subcutaneously). Such events may preclude the use of such compounds in an outpatient setting (e.g., home use), such as restricting their use to intravenous administration and short-term application in a hospital setting under close expert monitoring (e.g., thus being unsuitable for chronic diseases and outpatient settings). In addition, given the risk profile of full (V2R, V1AR) agonists, careful titration and monitoring are generally required to prevent the occurrence of critical adverse events (AEs) (such as those associated with tissue hypoxia and ischemia caused by excessive vasoconstriction).

[0006] In addition, it is difficult to increase the mean arterial pressure (MAP) by 10 - 15 mmHg (which is strongly associated with reversal of HRS-AKI) using (non-selective) full (V1AR, V2R) agonists like vasopressin. In some cases, achieving and / or maintaining a 10 - 15 mmHg increase in MAP is the treatment goal of current therapies. Due to the pharmacokinetics of the vasopressin system and the very steep concentration-response curve, it may be easier to under-dose (and lose clinical efficacy) or produce excessive vasoconstriction, which can lead to serious, potentially life-threatening adverse events (AEs). Second, individuals with decompensated cirrhosis may already have high endogenous vasopressin levels, which promote water retention through V2-mediated antidiuresis. Clinical vasopressin agonists are first and foremost V2 agonists and secondarily act as V1a agonists at pharmacological concentrations. The inherent V2 activity may lead to an adverse event profile associated with fluid overload and respiratory complications with clinical vasopressin agonists.

[0007] In some embodiments, compounds are provided herein that are selective for the V1a receptor (e.g., mixed agonist-antagonists). In some embodiments, the compounds achieve and maintain a (target) vasoconstriction level and avoid fluid retention, such as through a uniform dosing profile. In some instances, the compounds have a reduced incidence of (critical) adverse events and improved clinical efficacy (e.g., compared to clinical vasopressin agonists). In some instances, it is not necessary to titrate the compounds, such as to achieve a reduced incidence of (critical) adverse events and improved clinical efficacy (e.g., compared to clinical vasopressin agonists). In some instances, the compounds described herein (e.g., mixed V1a agonist-antagonists) are administered at a higher dose (compared to the necessary dose) and effectively achieve maximal efficacy. In contrast, administration of a relatively high dose of a non-selective full (V1a, V2) agonist (such as terlipressin) can become toxic and result in (critical) adverse events.

[0008] In some instances, after administration of a composition comprising a compound described herein (e.g., a mixed V1a agonist-antagonist, such as Compound 1) to an individual described herein by subcutaneous administration (e.g., subcutaneous infusion or subcutaneous (bolus) injection), the compound is delivered (e.g., systemically) to the individual. In some instances, after administration of a composition comprising a compound described herein (e.g., a mixed V1a agonist-antagonist, such as Compound 1) to an individual described herein by subcutaneous administration (e.g., subcutaneous infusion or subcutaneous (bolus) injection), the compound provides a systemic effect in the individual, such as regulation of mean arterial pressure (MAP).

[0009] In some cases, the compounds described herein (e.g., mixed V1a agonist-antagonists such as Compound 1) are metabolized to full vasopressin agonists, such as when administered subcutaneously. In some cases, the formation of full vasopressin agonists is associated with a higher risk of adverse events in an individual, such as after subcutaneous (bolus) injection of a mixed V1a agonist-antagonist. In some cases, the adverse events are systemic events, local administration site events, or both. In some embodiments, the adverse events are associated with excessive vasoconstriction. In some cases, the full vasopressin agonists have partial activity (compared to the mixed V1a agonist-antagonists). In some cases, subcutaneous administration of the mixed V1a agonist-antagonists described herein (e.g., by subcutaneous (bolus) injection) provides an overproduction of full vasopressin agonists (e.g., in the subcutaneous space of an individual). The overproduction of full vasopressin agonists (e.g., in the subcutaneous space of an individual) is undesirable, for example because less of the parent compound (e.g., the mixed V1a agonist-antagonist described herein such as Compound 1) is delivered systemically, thereby increasing the risk of undesirable (systemic) events (e.g., toxicities associated with excessive (local and / or systemic) vasoconstriction) (such as caused by full agonism of the V1a receptor by the full vasopressin agonist). Additional challenges caused by the overproduction of full vasopressin agonists (e.g., in the subcutaneous space of an individual) after administration of the compositions described herein include reduced efficacy, increased side effects, and / or difficulty in control (e.g., titration) to achieve efficacy. As Figure 15 shown, full agonism of one or more vasopressin receptors may induce critical side effects and / or may be lethal.

[0010] In some embodiments, methods and formulations are described herein for reducing the formation of a full vasopressin agonist (e.g., M1), such as following subcutaneous (bolus) injection of a mixed V1a agonist - antagonist (e.g., Compound 1) described herein. In some embodiments, reducing the formation of a full vasopressin agonist (e.g., M1), such as following subcutaneous administration of a mixed V1a agonist - antagonist described herein, reduces the risk of an individual experiencing an unwanted (systemic) event (e.g., toxicity associated with excessive (local and / or systemic) vasoconstriction) (such as caused by full agonism of the V1a receptor by the full vasopressin agonist). In some embodiments, reducing the formation of a full vasopressin agonist (e.g., M1), such as following subcutaneous administration of a mixed V1a agonist - antagonist described herein, increases the effectiveness of the treatment (e.g., mixed V1a agonist - antagonist) described herein, reduces side effects (e.g., associated with overproduction of the full agonist), and / or improves the efficacy control (e.g., titration) of the treatment (e.g., mixed V1a agonist - antagonist) described herein. In some embodiments, subcutaneous infusion of a mixed V1a agonist - antagonist reduces metabolite (M1) formation (e.g., as measured systemically, such as by serum / plasma concentration). In some embodiments, increasing the buffer concentration of a composition comprising a mixed V1a agonist - antagonist reduces metabolite (M1) formation (e.g., as measured systemically, such as by serum / plasma concentration), such as in vitro and in vivo (e.g., following subcutaneous administration). In some embodiments, increasing the concentration of the mixed V1a agonist - antagonist in the composition reduces metabolite (M1) formation (e.g., as measured systemically, such as by serum / plasma concentration), such as in vitro and in vivo (e.g., following subcutaneous administration). In some embodiments, such as when the composition described herein is administered at a relatively slow infusion rate, subcutaneous infusion of a mixed V1a agonist - antagonist and increasing its concentration in the composition reduces metabolite (M1) formation (e.g., as measured systemically, such as by serum / plasma concentration), such as in vitro and in vivo (e.g., following subcutaneous administration). In some embodiments, any combination of subcutaneous infusion, increased buffer concentration of the composition, and increased drug concentration in the composition reduces metabolite (M1) formation following subcutaneous administration (e.g., as measured systemically, such as by serum / plasma concentration). In some embodiments, subcutaneous infusion of the compounds described herein, increasing the buffer concentration of the composition described herein, and / or increasing the drug concentration in the composition described herein improves the systemic delivery of the mixed agonist - antagonist described herein.

[0011] In some embodiments, the present disclosure provides compounds (e.g., hybrid V1AR receptor agonists - antagonists, such as Compound 1), which reduce the portal pressure (PP) in an individual (e.g., in need thereof), such as after subcutaneous administration, without excessive vasoconstriction within a wide dose range (such as 10 μg / kg to 500 μg / kg).

[0012] In some embodiments, the present disclosure provides compounds (e.g., hybrid V1a receptor agonists - antagonists, such as Compound 1), which increase the mean arterial pressure (MAP) in an individual (e.g., in need thereof), such as after subcutaneous administration. In some embodiments, the increase in MAP reaches a peak plateau, such as a peak plateau of about +10 to +15 mmHg (e.g., even at doses up to 100 to 500 μg / kg). In contrast, administration of the fully non - selective (V2, V1a) receptor agonists (such as terlipressin) described herein at similarly high doses provides a significantly higher increase in MAP, such as well beyond the therapeutic window of +10 to +15 mmHg. Such a large increase in MAP can significantly increase the likelihood of (critical) side effects (in the treated individuals).

[0013] In some embodiments, the compounds described herein (e.g., hybrid V1AR receptor agonists - antagonists, such as Compound 1) reach a therapeutic ceiling (e.g., when administered subcutaneously), such that even after increasing the dose of the compound (e.g., to doses up to 100 to 500 μg / kg), the effect (e.g., increasing MAP) is not (significantly) altered (e.g., increased or decreased).

[0014] In some cases, increasing the dose of the compounds described herein (e.g., fully non - selective (V2R, V1AR) agonists, such as terlipressin) does provide a (significant) change (e.g., increase) in the effect (e.g., MAP). In some cases, increasing the dose of the compounds described herein (e.g., fully non - selective (V2R, V1AR) agonists, such as terlipressin) continues to push the effect (e.g., MAP) to levels that may be harmful and / or may cause (severe) side effects in the individuals receiving the compound.

[0015] In some cases, increasing the dose of the hybrid V1a agonist-antagonist described herein (such as Compound 1) does not continue to increase the MAP of an individual (e.g., even at doses up to 100 to 500 μg / kg), while increasing the dose of a completely non-selective (V2, V1a) agonist (such as terlipressin) does continue to increase the MAP of an individual. In some cases, the hybrid agonist-antagonist described herein (such as Compound 1) can be safely administered subcutaneously to treat ESLD or its symptoms and / or complications, such as without the individual experiencing (critical) side effects and / or having a risk of an effect (such as MAP) developing to a dangerous or harmful level. In some cases, the therapeutic window (and safety profile) of the hybrid V1AR agonist-antagonist described herein (such as Compound 1) is significantly improved compared to a V1AR agonist (e.g., which does not contain a separate V1AR antagonist moiety) (such as terlipressin).

[0016] In some embodiments, the compounds described herein have an agonist moiety (e.g., D1). In some embodiments, the compounds described herein have an antagonist moiety (e.g., D2). In some embodiments, the compounds described herein have an agonist moiety (e.g., D1) and an antagonist moiety (e.g., D2). In some embodiments, the antagonist moiety (e.g., D2) has no (agonist) activity or has significantly lower (agonist) activity than the agonist moiety (e.g., D1), such as having agonist activity that is at least about 1.5x lower than the agonist moiety (e.g., D1), at least about 2x lower than the agonist moiety (e.g., D1), at least about 3x lower than the agonist moiety (e.g., D1), 5x lower than the agonist moiety (e.g., D1), at least about 10x lower than the agonist moiety (e.g., D1), or at least about 100x lower than the agonist moiety (e.g., D1). In some embodiments, the agonism and / or antagonism is agonism and / or antagonism of V1AR.

[0017] In some embodiments, the compounds described herein (e.g., mixed V1a agonist-antagonists such as Compound 1) are not full or non-selective (V2, V1a) receptor agonists. In some embodiments, administration (subcutaneously) of the compounds described herein (e.g., mixed V1a agonist-antagonists such as Compound 1) is non-toxic (at therapeutic levels), e.g., even at doses up to 100 to 500 μg / kg. In some embodiments, the compounds described herein (e.g., mixed V1a agonist-antagonists such as Compound 1) have a wide therapeutic index and are selective for the V1a receptor, such as at therapeutic doses. In some embodiments, the compounds described herein (e.g., mixed V1a agonist-antagonists such as Compound 1) are suitable for subcutaneous administration. In some embodiments, the compounds described herein (e.g., mixed V1a agonist-antagonists such as Compound 1) increase the mean arterial pressure (MAP) of an individual receiving one or more (subcutaneously administered) doses of the compound. In some embodiments, the compounds described herein (e.g., mixed V1a agonist-antagonists such as Compound 1) decrease the portal venous pressure (PP) of an individual receiving one or more (subcutaneously administered) doses of the compound. In some embodiments, the compounds described herein (e.g., mixed V1a agonist-antagonists such as Compound 1) increase the MAP of an individual receiving one or more (subcutaneously administered) doses of the compound and decrease their PP. In some embodiments, such as after subcutaneous administration of the compounds described herein (e.g., mixed V1a agonist-antagonists such as Compound 1), the change in MAP tends to plateau or reach a therapeutic maximum after a period of time (e.g., after about 10 minutes). In some cases, such as after subcutaneous administration of the compounds described herein (e.g., full non-selective (V2, V1a) agonists such as terlipressin), the MAP rapidly increases and reaches a peak after a period of time (e.g., after about 20 minutes). In some embodiments, such as after subcutaneous administration of the compounds described herein (e.g., mixed V1a agonist-antagonists such as Compound 1), the change in PP tends to plateau. In some embodiments, such as after subcutaneous administration of the compounds described herein (e.g., mixed V1a agonist-antagonists such as Compound 1), the changes in MAP and PP tend to plateau or reach a therapeutic maximum after a period of time (e.g., after about 10 minutes).

[0018] In some cases, systemic hemodynamic complications such as portal hypertension and reflex splanchnic arteriolar vasodilation are signs of decompensated cirrhosis. In some cases, splanchnic vasodilation causes blood to pool in the splanchnic circulation, allowing fluid to leak into the abdomen and surrounding organs (ascites), and causing arterial blood pressure to drop. In some cases, such as in decompensated cirrhosis, these hemodynamic changes can lead to systemic complications, including hepatorenal syndrome - acute kidney injury (HRS-AKI).

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

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

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

[0022] In some cases, a mixed V1A agonist - antagonist is suitable for systemic delivery, such as if the mixed agonist - antagonist properties of the mixed V1A agonist - antagonist prevent (significant) injection site reactions (e.g., local vasoconstriction), such as at a subcutaneous injection site. In some cases, the mixed V1A agonist - antagonist provided herein has no (functional) vasopressin 2 (V2) receptor activity, such as at therapeutic concentrations. In some embodiments, the mixed V1A receptor agonist - antagonist is Compound 1.

[0023] In some embodiments, treating ESLD includes treating the disease itself and / or its associated symptoms or complications, such as ascites. In some embodiments, treating ESLD includes improving or managing quality of life, prolonging life, such as by treating its associated symptoms and / or complications (e.g., ascites and hepatic decompensation events).

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

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

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

[0027] In some embodiments, the mixed V1A agonist - antagonist provided herein is used to treat ESLD (e.g., cirrhotic portal hypertension) or its complications, such as HRS - AKI.

[0028] In some embodiments, Compound 1 is used to treat complications of ESLD (e.g., cirrhotic portal hypertension), such as HRS - AKI.

[0029] In some cases, the hybrid V1A agonist-antagonists provided herein (e.g., compound 1) provide a significantly improved therapeutic index (e.g., caused by lower maximal vasoconstrictor effects and lower risk of tissue hypoxia), such as when compared to a completely non-selective (V2, V1A) receptor agonist. In some cases, the hybrid V1A agonist-antagonists provided herein (e.g., compound 1) provide approximately half of the maximal vasoconstriction produced by a full agonist, such as without any accompanying signs of ischemia. In some cases, the hybrid V1A agonist-antagonists provided herein (e.g., compound 1) (such as when administered subcutaneously) are (clinically) effective vasoconstrictors, such as having low to no local toxicity. In some cases, the hybrid V1A agonist-antagonists provided herein (e.g., compound 1) are (clinically) effective vasoconstrictors (e.g., having a favorable benefit / risk profile (e.g., when administered subcutaneously), such as having low to no local toxicity). In some cases, the hybrid V1A agonist-antagonists provided herein (e.g., compound 1) provide sufficient splanchnic vasoconstriction to reduce elevated portal venous pressure while minimizing the risk of excessive vasoconstriction in other vascular beds with associated adverse events (such as mesenteric ischemia).

[0030] In some embodiments, provided herein is a method of modulating mean arterial pressure (MAP) in an individual (e.g., in need thereof), the method comprising subcutaneously administering to the individual (e.g., in need thereof) an effective amount of a compound that is a hybrid vasopressin receptor 1A (V1AR) agonist-antagonist.

[0031] In some embodiments, provided herein is a method of modulating mean arterial pressure (MAP) in an individual (e.g., in need thereof), the method comprising subcutaneously infusing into the individual (e.g., in need thereof) a composition comprising a certain (effective) amount of a compound that is a hybrid vasopressin receptor 1A (V1AR) agonist-antagonist.

[0032] In some embodiments, provided herein is a method of modulating mean arterial pressure (MAP) in an individual (e.g., in need thereof), the method comprising subcutaneously injecting into the individual (e.g., in need thereof) a composition comprising a certain (effective) amount of a compound that is a hybrid vasopressin receptor 1A (V1AR) agonist-antagonist.

[0033] In some embodiments, the hybrid vasopressin receptor 1A (V1AR) agonist-antagonist is more selective for V1AR than for V2R. In some embodiments, the hybrid vasopressin receptor 1A (V1AR) agonist-antagonist has no V2R activity, such as at therapeutic concentrations.

[0034] In some embodiments, the compound comprises a first moiety having agonist activity and a second moiety having antagonist activity.

[0035] In some embodiments, the regulation of the mean arterial pressure (MAP) of an individual comprises increasing the MAP by at least 5% relative to the baseline. In some embodiments, the regulation of the mean arterial pressure (MAP) of an individual comprises increasing the MAP by at least 5 mmHg (e.g., 5 mmHg or more or 10 mmHg or more) relative to the baseline.

[0036] In some embodiments, the compound has a structure represented by Formula I:

[0037] D1-L-D2

[0038] Formula I

[0039] or a pharmaceutically acceptable salt thereof,

[0040] wherein:

[0041] D1 is a vasopressin receptor 1A (V1AR) agonist;

[0042] D2 is a V1AR antagonist; and

[0043] L is a linker.

[0044] In some embodiments, provided herein is a method of regulating the mean arterial pressure (MAP) of 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:

[0045] D1-L-D2

[0046] Formula I

[0047] or a pharmaceutically acceptable salt thereof,

[0048] wherein:

[0049] D1 is a vasopressin receptor 1A (V1AR) agonist;

[0050] D2 is a V1AR antagonist; and

[0051] L is a linker.

[0052] In some embodiments, provided herein is a method of regulating the mean arterial pressure (MAP) of an individual (e.g., in need thereof), the method comprising subcutaneously infusing into the individual (e.g., in need thereof) a composition comprising an amount (effective) of a compound having a structure represented by Formula I:

[0053] D1-L-D2

[0054] Formula I

[0055] or a pharmaceutically acceptable salt thereof,

[0056] wherein:

[0057] D1 is a vasopressin receptor 1A (V1AR) agonist;

[0058] D2 is a V1AR antagonist; and

[0059] L is a linker.

[0060] In some embodiments, D1 is more selective for V1AR than for V2R.

[0061] In some embodiments, D1 is or comprises (e.g., a cyclic) peptide. In some embodiments, D1 is or comprises a cyclic nonapeptide. In some embodiments, D1 has or comprises the following structure:

[0062]

[0063] In some embodiments, D1 has or comprises the following structure:

[0064]

[0065] In some embodiments, D2 is or comprises (e.g., a 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:

[0066]

[0067] In some embodiments, D2 has or comprises the following structure:

[0068]

[0069] In some embodiments, L is a non-hydrolyzable linker. In some embodiments, L comprises one or more linker groups, each linker group independently selected from the group consisting of substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl. In some embodiments, L is a bond, a substituted or unsubstituted alkyl or a substituted or unsubstituted heteroalkyl. In some embodiments, L is or comprises a substituted or unsubstituted heteroalkyl. In some embodiments, L is a heteroalkyl substituted with one or more substituents (e.g., alkylamine), each substituent independently selected from the group consisting of oxo group, amino group and substituted heteroalkyl (e.g., alkylamine substituted with oxo group). In some embodiments, L is or comprises one or more (e.g., modified) amino acid residues. In some embodiments, L has or comprises the following structure:

[0070]

[0071] In some embodiments, L has or comprises the following structure:

[0072]

[0073] In some embodiments, the compound is Compound 1 or a pharmaceutically acceptable salt thereof.

[0074] In some embodiments, provided herein is a method of modulating mean arterial pressure (MAP) in an individual (e.g., in need thereof), the method comprising subcutaneously administering to the individual (e.g., in need thereof) an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof.

[0075] In some embodiments, provided herein is a method of modulating mean arterial pressure (MAP) in an individual (e.g., in need thereof), the method comprising subcutaneously infusing into the individual (e.g., in need thereof) a composition comprising a defined (effective) amount of Compound 1 or a pharmaceutically acceptable salt thereof.

[0076] In some embodiments, provided herein is a method of reducing the incidence of local vasoconstriction (such as (at the 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.

[0077] In some embodiments, the composition further comprises a liquid vehicle or solvent (e.g., water or an aqueous vehicle).

[0078] In some embodiments, the method further comprises attaching a subcutaneous infusion device to the skin of the individual, the subcutaneous infusion device comprising a cavity and a hollow tube, the composition being configured within the cavity, the hollow tube comprising a first opening and a second opening, the first opening being in fluid communication with the cavity, and after attaching the subcutaneous infusion device to the skin, the second opening being subcutaneously disposed within the individual.

[0079] 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.

[0080] In some embodiments, subcutaneous infusion of the composition into the individual improves tolerance (e.g., based on a reduction in overproduction of M1, such as subcutaneous). In some embodiments, subcutaneous infusion of the composition into the individual reduces unwanted systemic events (e.g., unwanted vasoconstriction, such as leading to ischemia), reduces unwanted site-of-administration events (e.g., local site vasoconstriction, such as leading to site-of-administration ischemia), or both.

[0081] In some embodiments, provided herein are methods of modulating mean arterial pressure (MAP) in an individual in need thereof, the method comprising subcutaneously infusing a composition comprising a compound having a structure represented by Formula I or a pharmaceutically acceptable salt thereof to an individual in need thereof, wherein less than 50% of the compound of Formula I degrades (e.g., subcutaneously).

[0082] In some embodiments, provided herein are methods of modulating mean arterial pressure (MAP) in an individual in need thereof, the method comprising subcutaneously injecting a composition comprising a compound having a structure represented by Formula I or a pharmaceutically acceptable salt thereof to an individual in need thereof, wherein less than 50% of the compound of Formula I degrades (e.g., subcutaneously).

[0083] In some embodiments, such as when the composition is administered subcutaneously to an individual (e.g., by subcutaneous (bolus) injection or subcutaneous infusion), less than 50% of the compound of Formula I degrades (e.g., subcutaneously). In some embodiments, such as when the composition is administered subcutaneously to an individual (e.g., by subcutaneous (bolus) injection or subcutaneous infusion), less than 30% of the compound of Formula I degrades (e.g., subcutaneously). In some embodiments, such as when the composition is administered subcutaneously to an individual (e.g., by subcutaneous (bolus) injection or subcutaneous infusion), less than 50% of the compound of Formula I degrades (e.g., subcutaneously) to form M1. In some embodiments, such as when the composition is administered subcutaneously to an individual (e.g., by subcutaneous (bolus) injection or subcutaneous infusion), less than 30% of the compound of Formula I degrades (e.g., subcutaneously) to form M1. In some embodiments, such as when the composition is subcutaneously infused to an individual, less M1 is formed relative to the administration of an otherwise identical composition administered by subcutaneous (bolus) injection. In some embodiments, such as when the composition is subcutaneously infused to an individual, less M1 is formed systemically relative to the administration of an otherwise identical composition administered by subcutaneous (bolus) injection. In some embodiments, such as when the composition is subcutaneously infused to an individual, less M1 is formed locally (at the injection / infusion site) relative to the administration of an otherwise identical composition administered by subcutaneous (bolus) injection.

[0084] In some embodiments, the composition is subcutaneously infused continuously to the individual for at least one hour. In some embodiments, the composition is subcutaneously infused to the individual at a rate of from about 0.005 milliliters per hour (mL / h) to about 1 mL / h for the duration of the administration period.

[0085] In some embodiments, the compound is administered to the individual in an amount of from about 0.001 milligrams (mg) to about 100 mg (e.g., continuously), such as over a period of one or more days.

[0086] In some embodiments, the composition comprises a compound at a concentration of from about 0.001 milligrams per milliliter (mg / mL) to about 100 mg / mL. In some embodiments, the composition comprises a compound at a concentration of from about 0.1 mg / mL to about 100 mg / mL. In some embodiments, the composition comprises a compound at a concentration of from about 1 mg / mL to about 10 mg / mL.

[0087] In some embodiments, the compound is administered (continuously) to an individual in need thereof at a dose of from about 0.1 mg / day to about 100 mg / day.

[0088] In some embodiments, the composition further comprises a preservative. In some embodiments, the preservative is present in an amount of from about 1 mg / mL to about 20 mg / mL.

[0089] In some embodiments, the composition further comprises a solubilizer. In some embodiments, the solubilizer is present in an amount of from about 1 mg / mL to about 100 mg / mL (e.g., about 60 - 80 mg / mL).

[0090] In some embodiments, the composition comprises a buffer. In some embodiments, the buffer is selected from the group consisting of acetate buffer, succinate buffer, and citrate buffer. In some embodiments, the composition comprises a buffer at a concentration of from about 1 millimolar (mM) to about 1 molar (M). In some embodiments, the composition comprises a buffer at a concentration of from about 5 mM to about 250 mM. In some embodiments, the composition comprises a buffer at a concentration of from about 5 mM to about 25 mM. In some embodiments, the composition comprises a buffer at a concentration of from about 50 mM to about 250 mM.

[0091] In some embodiments, the composition has a pH of from about 4 to about 8. In some embodiments, the composition has a pH of from about 4 to about 6. In some embodiments, the composition has a pH of from about 4.5 to about 5.

[0092] In some embodiments, after subcutaneous administration of Compound 1, the mean arterial pressure (MAP) of the individual increases (e.g., compared to the pre - treatment baseline measurement). In some embodiments, after administration of the compound or a pharmaceutically acceptable salt thereof described herein to an individual, the MAP of the individual increases by about 1% to about 10% (e.g., compared to the pre - treatment baseline measurement). In some embodiments, after administration of the compound or a pharmaceutically acceptable salt thereof described herein to an individual, the MAP of the individual increases in a dose - dependent manner.

[0093] In some embodiments, after administration of the compound or a pharmaceutically acceptable salt thereof described herein to an individual, the diastolic blood pressure of the individual increases (e.g., compared to the pre - treatment baseline measurement).

[0094] In some embodiments, after administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the systolic blood pressure of the individual increases (e.g., compared to a baseline measurement prior to treatment).

[0095] In some embodiments, after administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the diastolic blood pressure and / or systolic blood pressure of the individual increases in a dose-dependent manner.

[0096] In some embodiments, after administration of a compound or a pharmaceutically acceptable salt thereof described herein to an individual, the pulse rate and / or peripheral blood flow of the individual decreases.

[0097] In some embodiments, administration (subcutaneously) of a compound or a pharmaceutically acceptable salt thereof described herein to an individual improves the systemic hemodynamics of the individual.

[0098] In some embodiments, administration (subcutaneously) of a compound or a pharmaceutically acceptable salt thereof described herein to an individual reduces fluid retention and / or overload in the individual.

[0099] In some embodiments, the method comprises administering to an individual a compound or a pharmaceutically acceptable salt thereof described herein on a first day and a second day (e.g., the second day is one or more days after the first day).

[0100] In some embodiments, on the first day, an individual receives an initial (e.g., intravenous infusion) dose of a compound or a pharmaceutically acceptable salt thereof described herein (e.g., to acclimatize the individual to vasoconstriction and then receives a first subcutaneous therapeutic dose). In some embodiments, the initial (e.g., intravenous infusion) dose is from about 0.01 milligram (mg) to about 100 mg. In some embodiments, the initial (e.g., intravenous infusion) dose is from about 0.01 mg to about 10 mg. In some embodiments, on the first day, the compound or a pharmaceutically acceptable salt thereof described herein is administered to the individual (e.g., by intravenous infusion) for a period of about 4 h to about 8 h (e.g., about 6 h). In some embodiments, the initial (e.g., intravenous infusion) dose of the compound or a pharmaceutically acceptable salt thereof described herein is a low dose, such as a dose of about 5 μg / h to about 15 μg / h (e.g., about 8 μg / h). In some embodiments, the method further comprises administering (subcutaneously) to the individual the compound or a pharmaceutically acceptable salt thereof described herein on one or more days after the first day. In some embodiments, the method comprises administering (subcutaneously) to the individual the compound or a pharmaceutically acceptable salt thereof described herein daily for two or more days (e.g., 4 to 10 days) (e.g., after the first day). In some embodiments, the method further comprises administering (subcutaneously) to the individual the compound or a pharmaceutically acceptable salt thereof described herein on consecutive days after the first day. In some embodiments, the method comprises administering (subcutaneously) to the individual the compound or a pharmaceutically acceptable salt thereof described herein on multiple days. In some embodiments, the individual receives repeated subcutaneous injections of the compound or a pharmaceutically acceptable salt thereof described herein.

[0101] In some embodiments, the compound or a pharmaceutically acceptable salt thereof described herein is administered subcutaneously to the individual multiple times, such as over a period of several days. In some embodiments, the compound is administered to the individual continuously, such as over a period of several days.

[0102] In some embodiments, the method comprises administering subcutaneously to the individual the compound or a pharmaceutically acceptable salt thereof described herein once daily (e.g., for two or more consecutive days (e.g., five or more consecutive days)).

[0103] In some embodiments, the method will comprise administering to the individual the compound or a pharmaceutically acceptable salt thereof described herein by subcutaneous (bolus) injection, such as wherein the compound is administered to the individual as a single dose (e.g., all at once).

[0104] In some embodiments, the method comprises administering to the individual the compound or a pharmaceutically acceptable salt thereof described herein by subcutaneous infusion. In some embodiments, the method comprises administering to the individual the compound or a pharmaceutically acceptable salt thereof described herein by continuous subcutaneous infusion.

[0105] In some embodiments, the method comprises administering to an individual (e.g., subcutaneously) a compound or a pharmaceutically acceptable salt thereof described herein in an amount of from about 0.01 milligram (mg) / day to about 100 mg / day (e.g., from about 0.01 mg / day to about 10 mg / day (e.g., from about 0.01 mg / day to about 1 mg / day)).

[0106] In some embodiments, the individual has hepatorenal syndrome with HRS-AKI.

[0107] In some embodiments, the individual has end-stage liver disease (ESLD).

[0108] In some embodiments, the individual has developed HRS-AKI as a complication of ESLD.

[0109] In some embodiments, the method further comprises reducing the serum creatinine (sCr) (value) of the individual (e.g., compared to a baseline measurement prior to treatment). In some embodiments, the method comprises administering to the individual a compound or a pharmaceutically acceptable salt thereof described herein, at least until the individual has an sCr value of 1.5 milligrams (mg) / deciliter (dL) or less. In some embodiments, a compound or a pharmaceutically acceptable salt thereof described herein (e.g., Compound 1) is administered to the individual (e.g., as described herein) (e.g., subcutaneously), at least until the sCr value of the individual returns to normal (e.g., baseline).

[0110] In some embodiments, there is provided a pharmaceutical composition comprising an effective amount of a compound or a pharmaceutically acceptable salt thereof, wherein the compound is a mixed vasopressin receptor 1A (V1AR) agonist-antagonist, and the composition is formulated for subcutaneous administration.

[0111] In some embodiments, the compound has a structure represented by Formula I:

[0112] D1-L-D2

[0113] Formula I

[0114] or a pharmaceutically acceptable salt thereof,

[0115] wherein:

[0116] D1 is a vasopressin receptor 1A (V1AR) agonist;

[0117] D2 is a V1AR antagonist; and

[0118] L is a linker.

[0119] In some embodiments, there is provided a pharmaceutical composition comprising an effective amount of a compound having a structure represented by Formula I:

[0120] D1-L-D2

[0121] Formula I

[0122] or a pharmaceutically acceptable salt thereof,

[0123] wherein:

[0124] D1 is a vasopressin receptor 1A (V1AR) agonist;

[0125] D2 is a V1AR antagonist; and

[0126] L is a linker,

[0127] the composition is formulated for subcutaneous administration.

[0128] In some embodiments, the pharmaceutical composition comprises an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof, and the composition is formulated for subcutaneous administration.

[0129] In some embodiments, the composition is suitable for an administration route other than intravenous administration, such as subcutaneous administration.

[0130] In some cases, the hybrid V1A agonist - antagonist provided herein (e.g., Compound 1) is administered in the form described in Example 1.

[0131] In some embodiments, there is provided a pharmaceutical composition that comprises an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof, and the composition is formulated for subcutaneous administration.

[0132] In some embodiments, there is provided a subcutaneous formulation that comprises 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).

[0133] In some embodiments, there is provided a subcutaneous formulation that comprises a compound having a structure represented by Formula I or a pharmaceutically acceptable salt thereof, and the formulation has a concentration of the Compound of Formula I of about 0.1 mg / mL to about 100 mg / mL.

[0134] In some embodiments, there is provided a subcutaneous formulation that comprises a compound having a structure represented by Formula I or a pharmaceutically acceptable salt thereof and a buffer at a concentration of about 1 millimolar (mM) to about 1 M.

[0135] In some embodiments, the formulation comprises a buffer at a concentration of from about 1 millimolar (mM) to about 1 M. In some embodiments, the buffer has a pKa of from about 3.0 to about 6.0, such as at 25 °C. In some embodiments, the buffer is selected from the group consisting of acetate, citrate, succinate, and phosphate.

[0136] In some embodiments, the formulation has a pH sufficient to inhibit a protease (e.g., trypsin) (e.g., inactivate or deactivate it), such as in the subcutaneous layer of an individual to whom the formulation is administered subcutaneously. In some embodiments, the pH of the formulation is from about 4 to about 5 (e.g., about 4.5).

[0137] In some embodiments, when administered subcutaneously to an individual (e.g., by subcutaneous (bolus) injection or subcutaneous infusion), the pH of the subcutaneous formulation does not change (significantly).

[0138] In some embodiments, the formulation has an ionic strength of from about 5 mM to about 200 mM (e.g., from about 10 mM to about 100 mM).

[0139] In some embodiments, the subcutaneous formulation further comprises a preservative.

[0140] In some embodiments, provided herein is a subcutaneous formulation that comprises a compound having a structure represented by Formula I or a pharmaceutically acceptable salt thereof and a preservative.

[0141] In some embodiments, the preservative is any suitable preservative, such as m-cresol. In some embodiments, the formulation comprises the preservative (e.g., m-cresol) at a concentration of from about 1 mg / mL to about 100 mg / mL.

[0142] In some embodiments, provided herein is a subcutaneous formulation that comprises a compound having a structure represented by Formula I or a pharmaceutically acceptable salt thereof and a solubilizer.

[0143] In some embodiments, the solubilizer is any suitable solubilizer, such as cyclodextrin. In some embodiments, the formulation comprises the solubilizer (e.g., cyclodextrin) at a concentration of from about 1 mg / mL to about 100 mg / mL (e.g., about 60 - 80 mg / mL).

[0144] In some embodiments, the compound of Formula I is less prone to degradation, such as in the subcutaneous layer of an individual to whom the formulation is administered subcutaneously.

[0145] In some embodiments, less than 50% of the compound of Formula I degrades (e.g., in the vial and / or subcutaneously), such as over a period of about one day or more (e.g., about one day, about two days, or longer).

[0146] 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.

[0147] In some embodiments, the compound is Compound 1.

[0148] In some embodiments, the composition is suitable for systemic delivery of an active agent, such as Compound 1.

[0149] In some cases, the mixed V1A agonist - antagonist provided herein (e.g., Compound 1) is administered in the form of an acetate salt.

[0150] In some cases, the mixed V1A agonist - antagonist provided herein (e.g., Compound 1) is administered in the form described in any of the examples provided herein (such as any one of Examples 1 - 6).

[0151] In some embodiments, provided herein is a system for regulating mean arterial pressure (MAP), the system comprising a composition that includes a compound of Formula I or a pharmaceutically acceptable salt thereof; and a device configured to provide subcutaneous infusion of the composition to an individual when the device is positioned on the skin of the individual.

[0152] In some embodiments, the system includes an adhesive body for (reversibly) fixing the (subcutaneous infusion) device to the skin surface of the individual. In some embodiments, the system includes a cavity and a hollow tube body, and the composition is configured within the cavity. In some embodiments, the hollow tube body includes a first opening and a second opening. In some embodiments, the first opening is in fluid communication with the cavity. In some embodiments, after the subcutaneous infusion device is fixed to the skin of the individual, the second opening is subcutaneously disposed within the individual.

[0153] In some embodiments, the (subcutaneous infusion) device further includes a pump configured to subcutaneously infuse the composition to the individual at a constant or varying rate.

[0154] In some embodiments, the system is configured to continuously provide the composition to the individual over a period of about 24 hours or longer.

[0155] In some embodiments, the device is configured to receive a vial and / or cartridge of the composition.

[0156] In some embodiments, the device is a subcutaneous infusion device (e.g., a pump). Description of the Drawings

[0157] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings (also referred to herein as "Figure" and "FIG."), in which:

[0158] Figure 1 The study design described in Example 1 is shown for each subject in Phase 1 (intravenous infusion) and Phase 2 (subcutaneous injection).

[0159] Figure 2 The time course of compound 1 concentration after intravenous administration is shown, Phase 1.

[0160] Figure 3A The time course of compound 1 concentration after the first subcutaneous administration is shown, Phase 2.

[0161] Figure 3B The time course of compound 1 concentration after the fifth subcutaneous administration is shown, Phase 2.

[0162] Figure 4A The diastolic blood pressure (mean) of the intravenous infusion is shown.

[0163] Figure 4B The diastolic blood pressure (percent mean change) of the intravenous infusion is shown.

[0164] Figure 5A The diastolic blood pressure (mean) of the repeated subcutaneous injections is shown.

[0165] Figure 5B The diastolic blood pressure (percent mean change) of the repeated subcutaneous injections is shown.

[0166] Figure 6A The systolic blood pressure (mean) of the intravenous infusion is shown.

[0167] Figure 6B The systolic blood pressure (percent mean change) of the intravenous infusion is shown.

[0168] Figure 7A The systolic blood pressure (mean) of the subcutaneous injection is shown.

[0169] Figure 7B The systolic blood pressure (percent mean change) of the subcutaneous injection is shown.

[0170] Figure 8A The change in mean arterial pressure over time (percent mean change in mean arterial pressure relative to baseline after intravenous infusion) is shown.

[0171] Figure 8BShows the change in mean arterial pressure over time (mean percentage change in mean arterial pressure relative to baseline after repeated subcutaneous injections).

[0172] Figure 9A Shows the pulse rate (mean value) after intravenous infusion.

[0173] Figure 9B Shows the pulse rate (mean percentage change) after intravenous infusion.

[0174] Figure 10A Shows the pulse rate (mean value) after subcutaneous injection.

[0175] Figure 10B Shows the pulse rate (mean percentage change) after subcutaneous injection.

[0176] Figure 11 Shows the amount of Compound 1 excreted intact in urine after intravenous infusion.

[0177] Figure 12A Shows the amount of Compound 1 excreted after the 1st subcutaneous injection.

[0178] Figure 12B Shows the amount of Compound 1 excreted after the 5th subcutaneous injection.

[0179] Figure 13A Shows the mean plasma concentration of metabolite M1 after the 1st subcutaneous injection of Compound 1.

[0180] Figure 13B Shows the mean plasma concentration of metabolite M1 after the 5th subcutaneous injection of Compound 1.

[0181] Figure 14 Shows the structure of M1 (circled) relative to Compound 1.

[0182] Figure 15 Shows exemplary dose - response curves for full agonists, partial agonists, and weak agonists. Figure 15 Overall, shows that a wider therapeutic window for vasoconstriction can be achieved with Curve 2 compared to Curve 1 or 3. Panel A shows the full agonist levels at which vasoconstriction can be lethal. Panel A shows the full agonist levels at which vasoconstriction can induce critical side effects.

[0183] Figure 16 Shows the change in portal vein pressure over time (ΔPP) in rats with bile duct ligation (BDL) after subcutaneous administration of different doses of a mixed V1a agonist - antagonist.

[0184] Figure 17Shows the change in mean arterial pressure over time (ΔMAP) in rats on a methionine / choline-deficient (MCD) diet after subcutaneous administration of a fully non-selective (V2, V1a) agonist and different doses of a mixed V1a agonist-antagonist.

[0185] Figure 18 Shows the change in portal venous pressure over time (ΔPP) in rats on a methionine / choline-deficient (MCD) diet after subcutaneous administration of a fully non-selective (V2, V1a) agonist and different doses of a mixed V1a agonist-antagonist.

[0186] Figure 19 Shows an exemplary dose-response curve of the maximum possible effect of a fully non-selective (V2, V1a) agonist and a mixed V1a agonist-antagonist on the human V1a (hV1a) receptor.

[0187] Figure 20 Shows an exemplary dose-response curve of the maximum possible effect of a mixed V1a agonist-antagonist on the human V1a (hV1a) receptor and the human V2 (hV2) receptor.

[0188] Figure 21 Shows an exemplary dose-response curve of the contractility of human mesenteric resistance arteries in response to a mixed V1a agonist-antagonist.

[0189] Figure 22A Illustrates the normalized plasma concentration-time curve of Compound 1 after intravenous administration (10 mg / kg) in an individual (e.g., a mammal).

[0190] Figure 22B Illustrates the normalized plasma concentration-time curve of Compound 1 after subcutaneous administration (1.0 mg / kg) in an individual (e.g., a mammal).

[0191] Figure 23A Illustrates the dose-response (baseline %) of Compound 1, vasopressin, and vehicle on skin blood flow (SBF) in an individual (e.g., a mammal) after intravenous administration.

[0192] Figure 23B Illustrates the dose-response of Compound 1, vasopressin, and vehicle on blood lactate concentration (mM) in an individual (e.g., a mammal) after intravenous administration.

[0193] Figure 23C Illustrates the comparison of blood lactate concentration in an individual (e.g., a mammal) after administration of vehicle, Compound 1, or vasopressin (AVP).

[0194] Figure 24AShows the mean arterial pressure (MAP) in an individual (e.g., a mammal) after subcutaneous administration of Compound 1.

[0195] Figure 24B Shows the systolic arterial pressure in an individual (e.g., a mammal) after subcutaneous administration of Compound 1.

[0196] Figure 24C Shows the diastolic arterial pressure in an individual (e.g., a mammal) after subcutaneous administration of Compound 1.

[0197] Figure 24D Shows the heart rate in an individual (e.g., a mammal) after subcutaneous administration of Compound 1.

[0198] Figure 25A Shows the time curve of the normalized plasma concentration (ng / mL) of Compound 1 after intravenous bolus (0.05 mg / kg) administration in an individual (e.g., a mammal).

[0199] Figure 25B Shows the time curve of the normalized plasma concentration of Compound 1 after subcutaneous bolus (0.5 mg / kg) administration in an individual (e.g., a mammal).

[0200] Figure 26A Shows the change in mean arterial pressure relative to baseline (ΔMAP) within 480 minutes after administration of Compound 1 in an individual (e.g., a mammal).

[0201] Figure 26B Shows the change in mean arterial pressure relative to baseline (ΔMAP) within 480 minutes after administration of terlipressin in an individual (e.g., a mammal).

[0202] Figure 27 Shows that after intravenous (IV) infusion, little metabolism of Compound 1 occurs in healthy humans (inset A), and after subcutaneous (bolus) injection, the concentrations of Compound 1 and M1 are approximately equimolar in healthy humans (inset B).

[0203] Figure 28 Shows that after subcutaneous (SC) infusion of relatively low (insets A and B) and high (insets C and D) doses of Compound 1, little metabolism of Compound 1 occurs in minipigs.

[0204] Figure 29 Depicts Figure 28 The Compound 1 / M1 ratio of insets A and B.

[0205] Figure 30It is shown that little metabolism of Compound 1 occurred in minipigs after relatively slow subcutaneous (SC) infusion of relatively low (Panel A and Panel B) and high (Panel C and Panel D) doses of Compound 1.

[0206] Figure 31 Panel A - Panel D depict Figure 30 the Compound 1 / M1 ratios. DETAILED DESCRIPTION

[0207] Certain Definitions

[0208] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an agent” includes a plurality of such agents, and reference to “the cell” includes reference to one or more cells (or cell populations) known to those skilled in the art and their equivalents, etc. When ranges are used herein for physical properties (such as molecular weight) or chemical properties (such as chemical formula), all combinations and sub - combinations of the ranges and specific embodiments therein are intended to be included. When referring to a number or numerical range, the term “about” means that the recited number or numerical range is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary between 1% and 15% of the stated number or numerical range. Any recitation of “about” provided herein also includes disclosure of the number itself. The term “comprising” (and related terms such as “comprise,” “comprises,” “having,” or “including”) is not intended to exclude that in certain other embodiments (e.g., embodiments of any substance composition, composition, method, or process described herein), it may “consist of the described features” or “consist essentially of the described features.”

[0209] As used herein, the terms “treat,” “treating,” or “treatment” include reducing, attenuating, alleviating, ameliorating, managing, relieving, or mitigating symptoms associated with a disease, disease state, disorder, or indication (e.g., as provided herein) in chronic or acute treatment scenarios. Additionally, treatment of a disease or disease state described herein includes disclosure of treating such disease, disease state, disorder, or indication with such compounds or compositions.

[0210] As used herein, the term "modulate" or "modulating" refers to a change in a biological, chemical, and / or biochemical reaction (such as a physiological reaction) in an individual. In some cases, the change is an increase in the biological, chemical, and / or biochemical reaction of the individual. In some cases, the change is a decrease in the biological, chemical, and / or biochemical reaction of the individual. In some cases, the change is observed after administration of a compound described herein to an individual (e.g., immediately, 30 min or longer, 1 hour or longer, 6 hours or longer, 12 hours or longer, 24 hours or longer, or 1 week or longer).

[0211] As used herein, the term "adverse event" or "AE" refers to an untoward medical event in an individual (such as an individual participating in a clinical trial). In some cases, an AE is an adverse and / or unexpected sign, symptom, or disease (such as temporally related to the use of an investigational medicinal product (IMP)), whether or not considered to be caused by the IMP. For example, an AE can include accidental injury, a cause for any change in medication (drug and / or dose), a cause for any medical, nursing, or pharmacy consultation, or a cause for hospitalization or surgery, as well as over-dosing and medication errors with or without clinical consequences. In some cases, an AE is expected based on the pharmacological action of the IMP. In some cases, an AE is an abnormal laboratory finding, a vital sign, or a physical or gynecological examination finding evaluated by the investigator as clinically significant. In some cases, a pre-treatment adverse event is any untoward medical event that occurs or is observed between signing the informed consent form and the first administration of the IMP. In some cases, an adverse event occurring during treatment is an AE that occurs after administration of the IMP and within the residual drug effect period, or a pre-treatment adverse event or pre-existing medical condition that worsens in intensity after administration of the IMP and within the residual drug effect period. In some cases, the residual drug effect period is an estimated time period after administration of the IMP during which the effect of the product is still considered to be present based on PK, PD, or other product characteristics. In some cases, the residual drug effect is 5 times the terminal half-life. In some cases, the terminal half-life of Compound 1 is about 1.5 - 2 hours. In some cases, the residual drug effect is within the time between the last assessment in Phase 1 and the follow-up visit in Phase 2 (as described in the examples below). In some cases, an adverse event occurring after treatment is an AE that occurs after the residual drug effect period of the IMP (e.g., before the first administration in Phase 2 after the last assessment in Phase 1, and after the follow-up visit in Phase 2).

[0212] "Amino" refers to the -NH2 group.

[0213] "Cyano" refers to the -CN group.

[0214] "Nitro" refers to the -NO2 group.

[0215] "Oxo group" refers to the =O group.

[0216] "Hydroxyl group" refers to the -OH group.

[0217] "Alkyl" generally refers to an acyclic hydrocarbon (e.g., straight-chain or branched-chain) or cycloalkyl group (e.g., ring) composed of only carbon and hydrogen atoms, such as having one to fifteen carbon atoms (e.g., C1-C 15 alkyl). Unless otherwise specified, the alkyl is saturated or unsaturated (e.g., alkenyl, which contains at least one carbon-carbon double bond). The disclosure of "alkyl" provided herein is intended to include independent recitations of "alkyl" unless otherwise specified. The alkyl groups described herein are generally monovalent, but can also be divalent (which can also be described herein as "alkylene" or "alkylenyl" groups). In certain embodiments, the alkyl contains one to thirteen carbon atoms (e.g., C1-C 13 alkyl). In certain embodiments, the alkyl contains one to eight carbon atoms (e.g., C1-C8 alkyl). In other embodiments, the alkyl contains one to five carbon atoms (e.g., C1-C5 alkyl). In other embodiments, the alkyl contains one to four carbon atoms (e.g., C1-C4 alkyl). In other embodiments, the alkyl contains one to three carbon atoms (e.g., C1-C3 alkyl). In other embodiments, the alkyl contains one to two carbon atoms (e.g., C1-C2 alkyl). In other embodiments, the alkyl contains one carbon atom (e.g., C1 alkyl). In other embodiments, the alkyl contains five to fifteen carbon atoms (e.g., C5-C 15 alkyl). In other embodiments, the alkyl contains five to eight carbon atoms (e.g., C5-C8 alkyl). In other embodiments, the alkyl contains two to five carbon atoms (e.g., C2-C5 alkyl). In other embodiments, the alkyl contains three to five carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (isopropyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl is attached to the rest of the molecule by a single bond. Generally, the alkyl groups are each independently substituted or unsubstituted. Each recitation of "alkyl" provided herein (unless otherwise specified) includes a specific and explicit recitation of the unsaturated "alkyl" group. Similarly, unless otherwise specifically stated in the specification, the alkyl group is optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oxime, trimethylsilyl, -OR a, -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), wherein each R a is independently hydrogen, alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, carbocyclic group (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), carbocyclic alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic group (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl).

[0218] "Alkoxy" refers to a group of the formula -O-alkyl bonded through an oxygen atom, wherein the alkyl is an alkyl chain as defined above.

[0219] "Alkenyl" refers to a straight-chain or branched hydrocarbon chain group consisting of only carbon and hydrogen atoms, containing at least one carbon-carbon double bond and having two to twelve carbon atoms. In certain embodiments, the alkenyl contains two to eight carbon atoms. In other embodiments, the alkenyl contains two to four carbon atoms. The alkenyl is optionally substituted as described for the "alkyl" group.

[0220] "Alkylene" or "alkylene chain" generally refers to a straight or branched divalent alkyl group that connects the remainder of the molecule to a group, such as having one to twelve carbon atoms, for example, methylene, ethylene, propylene, isopropylidene, n-butylene, etc. Unless otherwise specifically stated in the specification, the alkylene chain is optionally substituted, as described herein for alkyl groups.

[0221] "Aryl" refers to a group derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or polycyclic hydrocarbon ring system contains only carbon with one hydrogen and five to eighteen carbon atoms, where at least one ring in the ring system is completely unsaturated, i.e., according to Hückel's theory, it contains a system of cyclic delocalized (4n + 2) π electrons. Ring systems from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin, and naphthalene. Unless otherwise specifically stated in the specification, the term "aryl" or the prefix "ar" (such as in "aralkyl") is intended to include aryl groups optionally substituted with one or more substituents independently selected from the following: alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclic group, optionally substituted carbocyclic group alkyl, optionally substituted heterocyclic group, optionally substituted heterocyclic group alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl alkyl, -R b -OR a 、-R b -OC(O)-R a 、-R b -OC(O)-OR a 、-R b -OC(O)-N(R a )2、-R b -N(R a )2、-R b -C(O)R a 、-R b -C(O)OR a 、-R b -C(O)N(R a )2、-R b -O-R c -C(O)N(R a )2、-R b -N(R a )C(O)OR a 、-R b -N(R a )C(O)R a 、-R b -N(R a )S(O) tR a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2(where t is 1 or 2), where each R a is independently hydrogen, alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), cycloalkylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic group (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), each R b is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, and wherein each of the above substituents is unsubstituted unless otherwise indicated.

[0222] "Aralkyl" or "aryl-alkyl" refers to a group of the formula -R c -aryl, where R c is an alkylene chain as defined above, such as methylene, ethylene, etc. The alkylene chain portion of the aralkyl group is optionally substituted as described above for alkylene chains. The aryl portion of the aralkyl group is optionally substituted as described above for aryl groups.

[0223] "Carbocyclic group" or "cycloalkyl group" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms, which includes fused or bridged ring systems and has from three to fifteen carbon atoms. In certain embodiments, the carbocyclic group contains from three to ten carbon atoms. In other embodiments, the carbocyclic group contains from five to seven carbon atoms. The carbocyclic group is attached to the remainder of the molecule by a single bond. The carbocyclic group or cycloalkyl group is saturated (i.e., contains only single C-C bonds) or unsaturated (i.e., contains one or more double or triple bonds). Examples of saturated cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Unsaturated carbocyclic groups are also referred to as "cycloalkenyl groups". Examples of monocyclic cycloalkenyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclic groups include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptyl), norbornenyl, decahydronaphthyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, etc. Unless specifically stated otherwise in the specification, the term "carbocyclic group" is intended to include carbocyclic groups optionally substituted with one or more substituents independently selected from the following: alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thiocarbonyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclic group, optionally substituted carbocyclic alkyl, optionally substituted heterocyclic group, optionally substituted heterocyclic alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl alkyl, -R b -OR a 、-R b -OC(O)-R a 、-R b -OC(O)-OR a 、-R b -OC(O)-N(R a )2、-R b -N(R a )2、-R b -C(O)R a 、-R b -C(O)OR a 、-R b -C(O)N(R a )2、-R b -O-R c -C(O)N(R a )2、-R b -N(R a )C(O)OR a 、-R b -N(R a )C(O)R a 、-R b -N(R a)S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2(where t is 1 or 2), where each R a is independently hydrogen, alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), cycloalkylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), arylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic group (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic group alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), each R b is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0224] "Cycloalkylalkyl" means a group of the formula -R c -cycloalkyl, where R c is an alkylene chain as defined above. The alkylene chain and the cycloalkyl group are optionally substituted as defined above.

[0225] "Cycloalkylalkenyl" means a group of the formula -R c -cycloalkyl, where R c is an alkenylene chain as defined above. The alkenylene chain and the cycloalkyl group are optionally substituted as defined above.

[0226] "Cycloalkylalkoxy" means a group of the formula -O-R c -cycloalkyl bonded through an oxygen atom, where R c is an alkylene chain as defined above. The alkylene chain and the cycloalkyl group are optionally substituted as defined above.

[0227] "Halogen" or "halo" means a fluoro, bromo, chloro or iodo substituent.

[0228] "Halogenated alkyl" refers to an alkyl group as defined above that is substituted with one or more halogen groups as defined above, such as trifluoromethyl, dichloromethyl, chloromethyl, etc. In some embodiments, the halogenated alkyl is a fluoroalkyl, such as trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the fluoroalkyl group is optionally substituted as defined above for alkyl groups.

[0229] The term "heteroalkyl" refers to an alkyl group as defined above, wherein one or more backbone carbon atoms of the alkyl are replaced by heteroatoms (with an appropriate number of substituents or valences - for example, -CH2- can be replaced by -NH- or -O-). For example, each substituted carbon atom is independently replaced by a heteroatom, such as where carbon is replaced by nitrogen, oxygen, sulfur, or other suitable heteroatoms. In some cases, each substituted carbon atom is independently replaced by oxygen, nitrogen (e.g., -NH-, -N(alkyl)-, or -N(aryl)- or having another substituent contemplated herein) or sulfur (e.g., -S-, -S(=O)-, or -S(=O)2-). In some embodiments, the heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In some embodiments, the heteroalkyl is attached to the remainder of the molecule at a heteroatom of the heteroalkyl. In some embodiments, the heteroalkyl is a C1-C 18 heteroalkyl. In some embodiments, the heteroalkyl is a C1-C 12 heteroalkyl. In some embodiments, the heteroalkyl is a C1-C6 heteroalkyl. In some embodiments, the heteroalkyl is a C1-C4 heteroalkyl. In some embodiments, the heteroalkyl includes alkylamino, alkylaminoalkyl, aminoalkyl, heterocycloalkyl, heterocycloalkyl, heterocyclic group, and heterocycloalkylalkyl as defined herein. Unless specifically stated otherwise in the specification, heteroalkyl does not include alkoxy as defined herein. Unless specifically stated otherwise in the specification, the heteroalkyl group is optionally substituted as defined above for alkyl groups.

[0230] "Heteroalkylene" refers to a divalent heteroalkyl group as defined above that connects one part of a molecule to another part of the molecule. Unless specifically stated otherwise, the heteroalkylene is optionally substituted as defined above for alkyl groups.

[0231] "Heterocyclic group" means a stable 3- to 18-membered non-aromatic ring group containing two to twelve carbon atoms and one to six heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise specifically stated in the specification, the heterocyclic group is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which optionally includes a fused or bridged ring system. The heteroatoms in the heterocyclic group are optionally oxidized. One or more nitrogen atoms (if present) are optionally quaternized. The heterocyclic group is partially or fully saturated. The heterocyclic group is saturated (i.e., contains only single C-C bonds) or unsaturated (e.g., contains one or more double or triple bonds in the ring system). In some cases, the heterocyclic group is saturated. In some cases, the heterocyclic group is saturated and substituted. In some cases, the heterocyclic group is unsaturated. Examples of such heterocyclic groups include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidinonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thioxomorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless otherwise specifically stated in the specification, the term "heterocyclic group" is intended to include heterocyclic groups as defined above that are optionally substituted with one or more substituents selected from the following: alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thiocarbonyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclic group, optionally substituted carbocyclic alkyl, optionally substituted heterocyclic group, optionally substituted heterocyclic alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl alkyl, -R b -OR a 、-R b -OC(O)-R a 、-R b -OC(O)-OR a 、-R b -OC(O)-N(R a )2、-R b -N(R a )2、-R b -C(O)R a 、-R b -C(O)OR a 、-R b -C(O)N(R a )2、-R b -O-R c -C(O)N(Ra ) 2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2), where each R a is independently hydrogen, alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), cycloalkylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), arylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic group (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic group alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), each R b is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0232] “N - heterocyclic group” or “N - attached heterocyclic group” refers to a heterocyclic group as defined above which contains at least one nitrogen and where the point of attachment of the heterocyclic group to the remainder of the molecule is through a nitrogen atom in the heterocyclic group. The N - heterocyclic group is optionally substituted as described above for the heterocyclic group. Examples of such N - heterocyclic groups include but are not limited to 1 - morpholinyl, 1 - piperidinyl, 1 - piperazinyl, 1 - pyrrolidinyl, pyrazolidinyl, imidazolinyl and imidazolidinyl.

[0233] "C - heterocyclic group" or "C - attached heterocyclic group" means a heterocyclic group as defined above, which contains at least one heteroatom and wherein the point of attachment of the heterocyclic group to the remainder of the molecule is through a carbon atom in the heterocyclic group. The C - heterocyclic group is optionally substituted as described above for the heterocyclic group. Examples of such C - heterocyclic groups include, but are not limited to, 2 - morpholinyl, 2 - piperidinyl or 3 - piperidinyl or 4 - piperidinyl, 2 - piperazinyl, 2 - pyrrolidinyl or 3 - pyrrolidinyl, etc.

[0234] "Heterocyclic alkyl" means a group of the formula -R c -heterocyclic, wherein R c is an alkylene chain as defined above. If the heterocyclic group is a nitrogen - containing heterocyclic group, the heterocyclic group is optionally attached to the alkyl group at the nitrogen atom. The alkylene chain of the heterocyclic alkyl group is optionally substituted as defined above for the alkylene chain. The heterocyclic moiety of the heterocyclic alkyl group is optionally substituted as defined above for the heterocyclic group.

[0235] "Heterocyclic alkoxy" means a group of the formula -O - R c -heterocyclic bonded through an oxygen atom, wherein R c is an alkylene chain as defined above. If the heterocyclic group is a nitrogen - containing heterocyclic group, the heterocyclic group is optionally attached to the alkyl group at the nitrogen atom. The alkylene chain of the heterocyclic alkoxy group is optionally substituted as defined above for the alkylene chain. The heterocyclic moiety of the heterocyclic alkoxy group is optionally substituted as defined above for the heterocyclic group.

[0236] "Heteroaryl" refers to a group derived from a 3- to 18-membered aromatic ring group containing two to seventeen carbon atoms and one to six heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, a heteroaryl group is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, wherein at least one ring in the ring system is completely unsaturated, i.e., according to Hückel's theory, it contains a system of (4n + 2) π electrons in cyclic delocalization. Heteroaryl includes fused or bridged ring systems. One or more of the heteroatoms in the heteroaryl group are optionally oxidized. One or more nitrogen atoms (if present) are optionally quaternized. The heteroaryl is attached to the remainder of the molecule through any atom of one or more of the rings.Examples of heteroaryl include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benz[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxazolyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, dibenzodioxinyl, chromenyl, chromenone, benzofuranyl, benzofuranone, benzothienyl (benzothienyl / benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanone, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolinyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinone, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (i.e., thienyl).Unless otherwise specifically stated in the specification, the term "heteroaryl" is intended to include heteroaryl groups as defined above which are optionally substituted with one or more substituents selected from: alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thiocarbonyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclic group, optionally substituted carbocyclic alkyl, optionally substituted heterocyclic group, optionally substituted heterocyclic alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl alkyl, -R. b -OR a 、-R b -OC(O)-R a 、-R b -OC(O)-OR a 、-R b -OC(O)-N(R a )2、-R b -N(R a )2、-R b -C(O)R a 、-R b -C(O)OR a 、-R b -C(O)N(R a )2、-R b -O-R c -C(O)N(R a )2、-R b -N(R a )C(O)OR a 、-R b -N(R a )C(O)R a 、-R b -N(R a )S(O) t R a (where t is 1 or 2)、-R b -S(O) t R a (where t is 1 or 2)、-R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2(where t is 1 or 2), where each R aindependently is hydrogen, alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), cycloalkylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), arylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic group (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic group alkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), each R b independently is a direct bond or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, and wherein each of the above substituents is unsubstituted unless otherwise indicated.

[0237] “N - heteroaryl” means a heteroaryl group as defined above that contains at least one nitrogen and wherein the point of attachment of the heteroaryl group to the remainder of the molecule is through a nitrogen atom in the heteroaryl group. The N - heteroaryl group is optionally substituted as described above for the heteroaryl group.

[0238] “C - heteroaryl” means a heteroaryl group as defined above and wherein the point of attachment of the heteroaryl group to the remainder of the molecule is through a carbon atom in the heteroaryl group. The C - heteroaryl group is optionally substituted as described above for the heteroaryl group.

[0239] “heteroarylalkyl” means a group of the formula - R c - heteroaryl, where R c is an alkylene chain as defined above. If the heteroaryl is a nitrogen - containing heteroaryl, the heteroaryl is optionally attached to the alkyl group at a nitrogen atom. The alkylene chain of the heteroarylalkyl group is optionally substituted as defined above for the alkylene chain. The heteroaryl moiety of the heteroarylalkyl group is optionally substituted as defined above for the heteroaryl group.

[0240] “heteroarylalkoxy” means a group of the formula - O - R c - heteroaryl bonded through an oxygen atom, where R c is an alkylene chain as defined above. If the heteroaryl is a nitrogen - containing heteroaryl, the heteroaryl is optionally attached to the alkyl group at a nitrogen atom. The alkylene chain of the heteroarylalkoxy group is optionally substituted as defined above for the alkylene chain. The heteroaryl moiety of the heteroarylalkoxy group is optionally substituted as defined above for the heteroaryl group.

[0241] In some embodiments, the compounds disclosed herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, which are defined in terms of absolute stereochemistry as (R)- or (S)-. Unless otherwise specified, the present disclosure is intended to contemplate all stereoisomeric forms of the compounds disclosed herein. When the compounds described herein contain an olefinic double bond, and unless otherwise specified, the present disclosure is intended to include both E and Z geometric isomers (e.g., cis or trans). Similarly, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included. The term "geometric isomers" refers to the E or Z geometric isomers of an olefinic double bond (e.g., cis or trans). The term "positional isomers" refers to structural isomers around a central ring, such as ortho, meta, and para isomers around a benzene ring.

[0242] Generally, the optionally substituted groups are each independently substituted or unsubstituted. Each recitation of an optionally substituted group provided herein (unless otherwise specified) includes independent and distinct recitations of both the unsubstituted group and the substituted group (e.g., substituted in certain embodiments and unsubstituted in certain other embodiments). Unless otherwise specified, the substituted groups provided herein (e.g., substituted alkyl) are substituted with one or more substituents, each of which is independently selected from the group consisting of halo, cyano, nitro, oxo, thiocarbonyl, imino, oxime, trimethylsilyl, -OR a 、-SR a 、-OC(O)-R a 、-N(R a )2、-C(O)R a 、-C(O)OR a 、-C(O)N(R a )2、-N(R a )C(O)OR a 、-OC(O)-N(R a )2、-N(R a )C(O)R a 、-N(R a )S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where each R aIndependently is hydrogen, alkyl (e.g., optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, carbocyclic group (e.g., optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), carbocyclic alkyl (e.g., optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aryl (e.g., optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (e.g., optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic group (e.g., optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heterocyclic alkyl (e.g., optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (e.g., optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl) or heteroaryl alkyl (e.g., optionally substituted by halogen, hydroxy, methoxy or trifluoromethyl).

[0243] "Pharmaceutically acceptable salts" include both acid addition salts and base addition salts. Pharmaceutically acceptable salts of any of the pharmacological agents described herein are intended to include any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0244] "Pharmaceutically acceptable acid addition salts" refers to those salts which retain the biological effectiveness and properties of the free base and 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, etc.). Also included are salts formed with organic acids (such as aliphatic monocarboxylic and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkane diacids, aromatic acids, aliphatic and aromatic sulfonic acids, etc., and including for example acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc.). Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, octanoates, isobutyrates, oxalates, malonates, succinates, octanedioates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, etc. Also contemplated are amino acid salts, such as arginine salts, gluconates and galacturonates (see for example, Berge S.M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19 (1997)). In some embodiments, the acid addition salts of the basic compound are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt by methods and techniques familiar to those of ordinary skill in the art.

[0245] "Pharmaceutically acceptable base addition salts" refer to those salts that retain the biological effectiveness and properties of the free acid and are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or organic base to the free acid. In some embodiments, the pharmaceutically acceptable base addition salts are formed with metals or amines such as alkali metals, alkaline earth metals, or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, etc. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, N-ethylpiperidine, polyamine resins, etc. See Berge et al., supra.

[0246] In some embodiments, the compounds disclosed herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, which are defined as (R)- or (S)- in terms of absolute stereochemistry. Unless otherwise stated, the present disclosure is intended to contemplate all stereoisomeric forms of the compounds disclosed herein. When the compounds described herein contain an olefinic double bond and unless otherwise stated, the present disclosure is intended to include both E and Z geometric isomers (e.g., cis or trans). Similarly, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included. The term "geometric isomers" refers to the E or Z geometric isomers of an olefinic double bond (e.g., cis or trans). The term "positional isomers" refers to structural isomers around a central ring, such as ortho, meta, and para isomers around a benzene ring.

[0247] In some embodiments, the compounds disclosed herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, which are defined in terms of absolute stereochemistry as (R)- or (S)-. Unless otherwise stated, the present disclosure is intended to contemplate all stereoisomeric forms of the compounds disclosed herein. When the compounds described herein contain an olefinic double bond and unless otherwise stated, the present disclosure is intended to include both E and Z geometric isomers (e.g., cis or trans). Similarly, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included. The term "geometric isomers" refers to the E or Z geometric isomers of an olefinic double bond (e.g., cis or trans). The term "positional isomers" refers to structural isomers around a central ring, such as ortho, meta, and para isomers around a benzene ring.

[0248] Systemic hemodynamic complications may indicate cirrhosis and portal hypertension (PHT). Due to increased intrahepatic resistance, an individual may typically experience an elevation in portal pressure (PP). The combination of increased blood flow and elevated intrahepatic resistance may lead to the common manifestations of PHT and decompensated cirrhosis. Clinical PHT may occur when the hepatic venous pressure gradient (HVPG) > 5 mmHg. PHT may then lead to a hyperdynamic state, characterized by reduced splanchnic and systemic vascular resistance, which may further increase portal blood flow. As advanced cirrhosis progresses, splanchnic arteriolar vasodilation may worsen PHT, which may then lead to a further increase in HVPG, further resulting in inadequate renal perfusion at 10 mmHg or higher. The kidneys may sense low perfusion pressure and reduced glomerular filtration rate as a reduction in blood volume, which may then activate the renin-angiotensin-aldosterone (RAAS) and vasopressin systems, leading to severe vasoconstriction within the kidneys and sodium and water retention. If renal perfusion is inadequate enough, it may lead to the development of ascites and kidney injury in the form of hepatorenal syndrome - acute kidney injury (HRS-AKI).

[0249] The management of HRS-AKI typically focuses on restoring systemic arterial pressure and reducing PHT through splanchnic vasoconstriction, the vasopressin system is the target, and the long-term goal is liver transplantation. Although monitoring and titration are challenging, an increase in vasoconstriction (i.e., mean arterial pressure (MAP)) has been associated with improved hemodynamic parameters. Vasoconstrictors (including terlipressin, norepinephrine, and midodrine / octreotide) have been used as therapies in patients with HRS-AKI in an attempt to restore renal perfusion and function. Terlipressin (a vasopressin analogue) plus albumin has been used as first-line therapy for HRS-AKI because it reduces short-term mortality compared with placebo. Albumin is added to increase the circulating volume. Terlipressin is approved by the US Food and Drug Administration for the treatment of adults with HRS with a rapid decrease in renal function.

[0250] There are three vasopressin receptors: V1a, V1b, and V2. The V1a receptor is found throughout the circulatory system and regulates vasoconstriction. The V2 receptor regulates water excretion (aquaresis) by exerting an antidiuretic effect at the renal level by mediating water reabsorption in the collecting tubules. The V1b receptor is found in the anterior pituitary and peripheral tissues, and one potential role is to mediate the release of adrenocorticotropic hormone, which can stimulate water retention. Vasopressin (also known as arginine vasopressin (AVP) or antidiuretic hormone) is a peptide involved in water balance and vascular tone. At normal physiological concentrations, there is little activity on the V1a system; significant vasoconstriction occurs only at supra-physiological concentrations. In the case of pharmacological application, strong vasoconstriction can be achieved in a concentration-dependent manner.

[0251] Arginine vasopressin (AVP) is the endogenous ligand for the vasopressin V1A, V1B, and V2 G protein-coupled receptors (V1AR, V1BR, V2R). The homeostatic functions of the vasopressin system, such as regulation of blood osmolality and pressor effects, are mediated by the V2 and V1A receptor subtypes. Activation of the V2 receptor located in the renal collecting ducts plays a role in regulating fluid balance through an antidiuretic effect. Activation of the V1A receptor located on vascular smooth muscle cells provides vasoconstriction and increased arterial pressure.

[0252] Lysine vasopressin (LVP) (the active metabolite of terlipressin) is active on V1a, V1b, and V2 receptors and is a full agonist. Although there is a significant improvement in renal function, the use of terlipressin is associated with critical adverse events, including gastrointestinal disorders, sepsis, and respiratory failure. These adverse effects, which may be attributed to the strength of LVP binding to V1a and off-target effects on V2, can lead to further water retention. As a result of the likelihood of critical side effects, terlipressin carries a US FDA black box warning regarding critical or fatal respiratory failure.

[0253] The pressor activity of vasopressin receptor agonists is of clinical interest, as demonstrated by the use of AVP and its analogs (e.g., terlipressin and ornithine vasopressin). However, a significant drawback of existing V1A receptor full agonists is that they may induce severe vasoconstriction and tissue hypoperfusion when used at therapeutic doses. The pharmacological activity of V1AR partial agonists (e.g., compounds with reduced maximal efficacy at the V1A receptor) can be useful in a variety of conditions where a modest increase in blood flow and / or blood pressure without hypoperfusion is desired. For example, such indications can include hepatorenal syndrome, refractory ascites, bleeding esophageal varices, anesthesia-induced hypotension, vasodilatory shock, paracentesis-induced circulatory dysfunction, and spontaneous bacterial peritonitis.

[0254] Individuals with cirrhosis often develop a number of clinical complications, of which ascites accumulation is the most important and indicates a poor prognosis. In some cases, ascites formation is caused by the homeostatic activation of the endogenous sodium and water retention system, attempting to counteract circulatory dysfunction (such as occurs in patients with advanced liver disease). In some cases, circulatory dysfunction is characterized by the presence of splanchnic vasodilation and portal hypertension. In some embodiments, the compounds described herein (e.g., compound 1) have effects on ascites volume, sodium and water excretion, portal hypertension, and systemic hemodynamics after administration of the compound or vehicle to cirrhotic rats with ascites.

[0255] In some embodiments, after intravenous (IV) and / or subcutaneous (SC) administration of a composition comprising a compound described herein (e.g., a mixed V1a agonist / antagonist such as compound 1), the compound is systemically delivered in an individual (see Example 1). In some embodiments, after intravenous and / or subcutaneous administration of the compound, the individual has a systemic effect, such as a change in MAP. In some embodiments, the compound is administered by intravenous infusion. In some embodiments, the compound is administered by subcutaneous (bolus) injection. Although the systemic effects observed after intravenous infusion and subcutaneous (bolus) injection are comparable, more adverse events were measured in individuals receiving the subcutaneous (bolus) injection composition (see Example 1). Overall, the compound is well tolerated by individuals receiving the composition by intravenous infusion.

[0256] In some cases, after subcutaneous (bolus) injection of a composition comprising a compound described herein (e.g., a mixed V1a agonist / antagonist such as compound 1), metabolites are formed (e.g., a large amount of metabolite M1 (e.g., overproduction of M1)) (see Figure 27, small panel B). In some cases, after intravenous infusion of a composition comprising a compound described herein (e.g., a mixed V1a agonist / antagonist such as Compound 1), very small amounts of metabolites are formed (e.g., less than 15% metabolite M1) (see Figure 27 , small panel A). As discussed herein, it is known that the full vasopressin receptor agonists described herein (e.g., terlipressin) cause (critical) adverse events when administered subcutaneously. Thus, the overproduction of the full agonist (M1) after subcutaneous (bolus) injection provides an explanation for the difference in the tolerance profiles of the composition in healthy individuals between intravenous infusion and (subcutaneous) bolus injection.

[0257] As described herein, in some cases, metabolite (M1) formation is reduced by subcutaneous infusion of a composition comprising a compound described herein to an individual (see Example 3). Additionally, in some cases, metabolite (M1) formation is reduced by increasing the buffer concentration of a composition comprising a compound described herein (see Example 4). Further, in some cases, metabolite (M1) formation is reduced by increasing the concentration of the parent drug (e.g., Compound 1) of a composition comprising a compound described herein (see Example 4). In some cases, metabolite (M1) formation is reduced by any one or a combination of subcutaneous infusion, increasing buffer concentration, and increasing drug concentration.

[0258] In some embodiments, provided herein are methods of modulating mean arterial pressure (MAP) in an individual in need thereof, the methods comprising subcutaneous infusion of a composition to an individual in need thereof, the composition comprising a compound described herein (such as a compound having a structure represented by Formula I) or a pharmaceutically acceptable salt thereof. In some embodiments, less than 50% of the compound (such as a compound of Formula I) degrades. In some embodiments, less than 50% of the compound (such as a compound of Formula I) degrades subcutaneously.

[0259] In some embodiments, the composition described herein is administered subcutaneously to an individual and less than 50% of the compound of Formula I degrades (e.g., subcutaneously). In some embodiments, the composition described herein is administered subcutaneously to an individual by subcutaneous (bolus) injection and less than 50% of the compound of Formula I degrades (e.g., subcutaneously). In some embodiments, the composition described herein is administered subcutaneously to an individual by subcutaneous infusion and less than 50% of the compound of Formula I degrades (e.g., subcutaneously). In some embodiments, the compound of Formula I degrades subcutaneously to form M1.

[0260] In some embodiments, such as after subcutaneous (bolus) injection, more than 50% of the parent compound (e.g., Compound 1) degrades (e.g., to form M1). In some embodiments, such as after subcutaneous (bolus) injection, more than 60% of the parent compound (e.g., Compound 1) degrades (e.g., to form M1). In some embodiments, such as after subcutaneous (bolus) injection, more than 70% of the parent compound (e.g., Compound 1) degrades (e.g., to form M1). In some embodiments, such as after subcutaneous (bolus) injection, more than 80% of the parent compound (e.g., Compound 1) degrades (e.g., to form M1).

[0261] In some embodiments, the compositions described herein are administered subcutaneously to an individual, and less than 30% of the compound of Formula I degrades (e.g., subcutaneously). In some embodiments, the compositions described herein are administered subcutaneously to an individual by subcutaneous (bolus) injection, and less than 30% of the compound of Formula I degrades (e.g., subcutaneously). In some embodiments, the compositions described herein are administered subcutaneously to an individual by subcutaneous infusion, and less than 30% of the compound of Formula I degrades (e.g., subcutaneously). In some embodiments, the compound of Formula I degrades subcutaneously to form M1.

[0262] In some embodiments, a composition is administered subcutaneously to an individual, and less M1 is formed relative to administration of an otherwise identical composition administered by subcutaneous (bolus) injection.

[0263] In some embodiments, a composition is administered subcutaneously to an individual, and less M1 is formed systemically relative to administration of an otherwise identical composition administered by subcutaneous (bolus) injection.

[0264] In some embodiments, a composition is administered subcutaneously to an individual, and less M1 is formed locally (at the injection / infusion site) relative to administration of an otherwise identical composition administered by subcutaneous (bolus) injection.

[0265] In some embodiments, administering a composition subcutaneously to an individual improves tolerance. In some embodiments, relative to subcutaneous (bolus) injection, administering a composition subcutaneously to an individual improves tolerance, such as based on a reduction in overproduction of M1, such as subcutaneously.

[0266] In some embodiments, administering a composition subcutaneously to an individual reduces unwanted systemic events, such as unwanted vasoconstriction leading to ischemia. In some embodiments, administering a composition subcutaneously to an individual reduces unwanted site-of-administration events, such as local site vasoconstriction leading to ischemia at the site of administration. In some embodiments, administering a composition subcutaneously to an individual reduces unwanted systemic events and unwanted site-of-administration events.

[0267] In some embodiments, provided herein are methods of reducing the incidence of local vasoconstriction in an individual in need thereof. In some embodiments, the method is a method for reducing the incidence of local vasoconstriction in an individual in need thereof. In some embodiments, the method is a method of reducing the incidence of ischemia in an individual in need thereof. In some embodiments, the method is a method of reducing the incidence of injection site ischemia in an individual in need thereof. In some embodiments, the method comprises subcutaneous infusion into an individual in need thereof of a composition comprising a compound described herein (such as a compound having a structure represented by Formula I) or a pharmaceutically acceptable salt thereof.

[0268] In some cases, a compound described herein (e.g., Compound 1) is used to treat a complication of ESLD.

[0269] In some embodiments, provided herein are methods of modulating mean arterial pressure (MAP) in an individual (e.g., in need thereof), the method comprising subcutaneous infusion into the individual (e.g., in need thereof) of a composition comprising a certain (effective) amount of a compound described herein, such as a mixed vasopressin receptor 1A (V1AR) agonist - antagonist described herein. In some embodiments, the compound has a structure represented by Formula I. In some embodiments, the compound is Compound 1.

[0270] In some embodiments, the method further comprises securing a subcutaneous infusion device to the skin of the individual (e.g., skin surface). In some embodiments, the subcutaneous infusion device comprises a cavity and a hollow tube. In some embodiments, the composition is configured within the cavity. In some embodiments, the hollow tube comprises a first opening and a second opening. In some embodiments, the first opening is in fluid communication with the cavity. In some embodiments, after securing the subcutaneous infusion device to the skin, the second opening is subcutaneously disposed within the individual. In some embodiments, the hollow tube is a needle, such as any needle gauge suitable for subcutaneous administration (e.g., subcutaneous infusion).

[0271] In some embodiments, the subcutaneous infusion device further includes a pump configured to infuse the composition subcutaneously to an individual at a constant rate. In some embodiments, the subcutaneous infusion device further includes a pump configured to infuse the composition subcutaneously to an individual at a varying rate. In some embodiments, the rate is a flow rate. In some embodiments, the continuous infusion is performed at a flow rate insufficient to provide a stream of the composition. In some embodiments, the continuous infusion is performed at a flow rate that provides a continuous drip to the individual. In some embodiments, the composition is infused subcutaneously to the individual at a rate of about 0.001 milliliters per hour (mL / h) or higher. In some embodiments, the composition is infused subcutaneously to the individual at a rate of about 1 mL / h or lower. In some embodiments, the composition is infused subcutaneously to the individual at a rate of about 0.005 mL / h to about 1 mL / h for a period of administration. In some embodiments, the composition is infused subcutaneously to the individual at a rate of about 0.01 mL / h to about 1 mL / h for a period of administration. In some embodiments, the composition is infused subcutaneously to the individual at a rate of about 0.04 mL / h to about 1 mL / h for a period of administration. In some embodiments, the period of administration lasts at least about one hour. In some embodiments, the period of administration lasts at least about one day. In some embodiments, the period of administration lasts at least about one week. In some embodiments, the period of administration lasts at least about one month. In some embodiments, the period of administration is about one month or longer. In some embodiments, the period of administration is about two months or longer. In some embodiments, the period of administration is about three months or longer. In some embodiments, the period of administration is about four months or longer. In some embodiments, the period of administration is about five months or longer. In some embodiments, the period of administration is about six months or longer. In some embodiments, the period of administration is about nine months or longer. In some embodiments, the period of administration is about twelve months or longer.

[0272] In some embodiments, the composition described herein is infused subcutaneously to an individual for at least one hour. In some embodiments, the composition is infused subcutaneously to an individual for at least one day. In some embodiments, the composition is infused subcutaneously to an individual for at least one week. In some embodiments, the composition is infused subcutaneously to an individual for at least one month.

[0273] In some embodiments, the composition described herein is continuously infused subcutaneously to an individual for at least one hour. In some embodiments, the composition is continuously infused subcutaneously to an individual for at least one day. In some embodiments, the composition is continuously infused subcutaneously to an individual for at least one week. In some embodiments, the composition is continuously infused subcutaneously to an individual for at least one month.

[0274] In some embodiments, the compounds described herein are administered to an individual in an amount of from about 0.001 milligrams (mg) to about 100 mg (e.g., continuously). In some embodiments, the compound is administered to the individual in an amount of from about 0.01 mg to about 50 mg (e.g., continuously). In some embodiments, the compound is administered to the individual in an amount of from about 0.01 mg to about 20 mg (e.g., continuously). In some embodiments, the compound is administered to the individual in an amount of from about 0.01 mg to about 10 mg (e.g., continuously). In some embodiments, the compound is administered to the individual in an amount of from about 0.1 mg to about 1 mg (e.g., continuously). In some embodiments, the compound is administered to the individual in an amount of about 0.2 mg (e.g., continuously). In some embodiments, the composition is administered to the individual over a period of one or more days.

[0275] In some embodiments, the composition described herein comprises a compound at a concentration of about 0.001 milligrams per milliliter (mg / mL) or higher. In some embodiments, the composition comprises a compound at a concentration of about 100 mg / mL or lower. In some embodiments, the composition comprises a compound at a concentration of from about 0.001 mg / mL to about 100 mg / mL. In some embodiments, the composition comprises a compound at a concentration of from about 0.01 mg / mL to about 100 mg / mL. In some embodiments, the composition comprises a compound at a concentration of from about 0.1 mg / mL to about 100 mg / mL. In some embodiments, the composition comprises a compound at a concentration of from about 1 mg / mL to about 100 mg / mL. In some embodiments, the composition comprises a compound at a concentration of from about 0.1 mg / mL to about 50 mg / mL. In some embodiments, the composition comprises a compound at a concentration of from about 1 mg / mL to about 50 mg / mL. In some embodiments, the composition comprises a compound at a concentration of from about 0.1 mg / mL to about 10 mg / mL. In some embodiments, the composition comprises a compound at a concentration of from about 1 mg / mL to about 10 mg / mL.

[0276] In some embodiments, the compounds described herein are administered to the described individuals in need thereof at a dose of about 0.1 milligram (mg) / day. In some embodiments, the compounds described herein are administered to the described individuals in need thereof at a dose of about 100 mg / day. In some embodiments, the compounds described herein are administered to the described individuals in need thereof at a dose of about 0.1 mg / day to about 100 mg / day. In some embodiments, the compounds described herein are administered to the described individuals in need thereof at a dose of about 0.1 mg / day to about 50 mg / day. In some embodiments, the compounds described herein are administered to the described individuals in need thereof at a dose of about 1 mg / day to about 50 mg / day. In some embodiments, the compounds described herein are administered to the described individuals in need thereof at a dose of about 1 mg / day to about 10 mg / day. In some embodiments, the compounds are administered to the individual continuously.

[0277] In some embodiments, provided herein are methods of modulating the mean arterial pressure (MAP) of an individual, the methods comprising subcutaneously administering to the individual an effective amount of a compound that is a mixed vasopressin receptor 1A (V1AR) agonist - antagonist. In some embodiments, the individual is in need of an increase in MAP. In some embodiments, the individual has end - stage liver disease (ESLD) or a complication thereof.

[0278] In some embodiments, after subcutaneously administering the compounds described herein (e.g., compound 1), the MAP of the individual increases (e.g., as compared to baseline measurements prior to treatment). In some embodiments, after subcutaneously administering compound 1, the MAP of the individual increases (e.g., as compared to baseline measurements prior to treatment).

[0279] In some embodiments, after administration of a compound or a pharmaceutically acceptable salt thereof described herein (e.g., Compound 1), the MAP of an individual increases by about 1% or more (e.g., compared to a pre-treatment baseline measurement). In some embodiments, after administration of a compound or a pharmaceutically acceptable salt thereof described herein (e.g., Compound 1), the MAP of an individual increases by about 5% or more (e.g., compared to a pre-treatment baseline measurement). In some embodiments, after administration of a compound or a pharmaceutically acceptable salt thereof described herein (e.g., Compound 1), the MAP of an individual increases by about 10% or more (e.g., compared to a pre-treatment baseline measurement). In some embodiments, after administration of a compound or a pharmaceutically acceptable salt thereof described herein (e.g., Compound 1), the MAP of an individual increases by about 15% or more (e.g., compared to a pre-treatment baseline measurement). In some embodiments, after administration of a compound or a pharmaceutically acceptable salt thereof described herein (e.g., Compound 1), the MAP of an individual increases by about 20% or more (e.g., compared to a pre-treatment baseline measurement). In some embodiments, after administration of a compound or a pharmaceutically acceptable salt thereof described herein (e.g., Compound 1), the MAP of an individual increases by about 1% to about 20% (e.g., compared to a pre-treatment baseline measurement). In some embodiments, after administration of a compound or a pharmaceutically acceptable salt thereof described herein (e.g., Compound 1), the MAP of an individual increases by about 5% to about 20% (e.g., compared to a pre-treatment baseline measurement). In some embodiments, after administration of a compound or a pharmaceutically acceptable salt thereof described herein (e.g., Compound 1), the MAP of an individual increases by about 10% to about 20% (e.g., compared to a pre-treatment baseline measurement). In some embodiments, after administration of a compound or a pharmaceutically acceptable salt thereof described herein (e.g., Compound 1), the MAP of an individual increases by about 1% to about 10% (e.g., compared to a pre-treatment baseline measurement). In some embodiments, the increase in MAP occurs about one hour or more after administration of the compound or a pharmaceutically acceptable salt thereof to the individual. In some embodiments, the increase in MAP occurs about two hours or more after administration of the compound or a pharmaceutically acceptable salt thereof to the individual. In some embodiments, the increase in MAP occurs about three hours or more after administration of the compound or a pharmaceutically acceptable salt thereof to the individual. In some embodiments, the increase in MAP occurs about four hours or more after administration of the compound or a pharmaceutically acceptable salt thereof to the individual. In some embodiments, the increase in MAP occurs about five hours or more after administration of the compound or a pharmaceutically acceptable salt thereof to the individual. In some embodiments, the increase in MAP occurs about six hours or more after administration of the compound or a pharmaceutically acceptable salt thereof to the individual. In some embodiments, the increase in MAP occurs about twelve hours or more after administration of the compound or a pharmaceutically acceptable salt thereof to the individual.In some embodiments, the increase in MAP occurs about one to twelve hours after administration of the compound or a pharmaceutically acceptable salt thereof to an individual. In some embodiments, the increase in MAP occurs about one to six hours after administration of the compound or a pharmaceutically acceptable salt thereof to an individual. In some embodiments, the increase in MAP occurs about four to six hours after administration of the compound or a pharmaceutically acceptable salt thereof to an individual.

[0280] In some embodiments, after administration of the compound or a pharmaceutically acceptable salt thereof to an individual, the MAP of the individual increases in a dose-dependent manner.

[0281] In some embodiments, the compounds provided herein have a maximum therapeutic concentration. In some embodiments, the maximum therapeutic concentration includes a concentration increase that does not provide a dose-dependent increase in MAP. In some embodiments, the compounds provided herein have a non-linear dose-dependence, such as above the maximum therapeutic concentration. In some embodiments, the dose-dependent increase in MAP includes the maximum therapeutic concentration. In some embodiments, dose-dependence includes a situation where the effect increases with the dose for at least a certain dose range. For example, a higher dose may not provide or may provide a lower dose-dependent increase.

[0282] In some embodiments, the compounds described herein (e.g., Compound 1) are selective vasopressin V1a receptor partial agonists. In some embodiments, the compounds described herein (e.g., Compound 1) are mixed agonist-antagonists. In some embodiments, the compounds described herein (e.g., Compound 1) are selective for V1AR. In some embodiments, the compounds described herein (e.g., Compound 1) are more selective for V1AR than vasopressin 2 (V2) receptor (V2R). In some cases, the compounds described herein (e.g., Compound 1) do not have functional V2R activity. In some cases, the compounds described herein (e.g., Compound 1) do not have functional V2R activity at therapeutic concentrations. In some embodiments, the therapeutic concentration is a concentration sufficient to modulate V1AR.

[0283] In some cases, the activity and selectivity of the compounds described herein (e.g., mixed agonist-antagonists such as Compound 1) are shown in Table 14 and Table 15. In some cases, the activity and selectivity of the compounds described herein (e.g., mixed agonist-antagonists such as Compound 1) are shown by Figures 19 - 21 shown.

[0284] In some embodiments, the compounds described herein (e.g., Compound 1) are more than 10-fold selective for V1AR over V2R. In some embodiments, the compounds described herein (e.g., Compound 1) are more than 100-fold selective for V1AR over V2R. In some embodiments, the compounds described herein (e.g., Compound 1) are more than 1,000-fold selective for V1AR over V2R. In some embodiments, the compounds described herein (e.g., Compound 1) are more than 10,000-fold selective for V1AR over V2R. In some embodiments, the compounds described herein (e.g., Compound 1) are inactive against V2R.

[0285] In some embodiments, the compounds described herein (e.g., Compound 1) comprise a first moiety having agonist activity. In some embodiments, the compounds described herein (e.g., Compound 1) comprise a second moiety having antagonist activity. In some embodiments, the compounds described herein (e.g., Compound 1) comprise a first moiety having agonist activity and a second moiety having antagonist activity.

[0286] In some embodiments, the compounds provided herein have a ratio of agonist activity to antagonist activity of from about 90:10 to about 10:90. In some embodiments, the compounds provided herein have a ratio of agonist activity to antagonist activity of about 50:50.

[0287] In some embodiments, an agonist-antagonist refers to a compound having an agonist moiety and an antagonist moiety. In a specific embodiment, the agonist moiety and the antagonist moiety are separate.

[0288] In some embodiments, the V1AR agonist-antagonist has a wider therapeutic window than a V1AR agonist. In some embodiments, the V1AR agonist-antagonist described herein has a selective V1a agonist moiety and a selective V1a antagonist moiety. In some instances, the selective V1a agonist moiety or the selective V1a antagonist moiety binds to V1AR such that both the selective V1a agonist moiety and the selective V1a antagonist moiety do not bind to V1AR simultaneously. In some instances, the V1a antagonist moiety competes with the selective V1a agonist moiety for binding to V1AR. In some instances, V1AR agonism provides the (desired) vasoconstrictive effect. In some instances, V1AR antagonism prevents maximal activation of the V1a pathway.

[0289] In some instances, Figure 15 Curve 1 shows the concentration-response curve of a compound (e.g., a completely non-selective (V2, V1a) agonist such as terlipressin), which provides a lethal level of vasoconstriction (e.g., at relatively high doses, depicted as Figure 15Part A) and / or critical adverse events (e.g., at doses above the therapeutic level and at doses of vasoconstriction below the lethal level, depicted as Figure 15 Part B) in. In some embodiments, the compounds described herein (e.g., fully non-selective (V2, V1a) agonists such as terlipressin) have Figure 15 the concentration-response curve shown in line 1. In some cases, Figure 15 Line 1 shows that the compounds described herein (e.g., fully non-selective (V2, V1a) agonists such as terlipressin) have a relatively narrow therapeutic window. In some cases, Figure 15 Line 1 shows that at relatively high doses, the compounds described herein (e.g., fully non-selective (V2, V1a) agonists such as terlipressin) provide lethality (depicted as Figure 15 Part A) and / or vasoconstriction at levels associated with critical adverse events (depicted as Figure 15 Part B) (such as elevated lactate and / or vasoconstriction with ischemia).

[0290] In some embodiments, Figure 15 Curve 2 shows the concentration-response curve of a compound having a safe and effective profile (e.g., a mixed V1a agonist-antagonist such as Compound 1). In some embodiments, the compounds described herein (e.g., a mixed V1a agonist-antagonist such as Compound 1) have Figure 15 the concentration-response curve shown in line 2. In some cases, Figure 15 Line 2 shows that even at high doses, the compounds described herein (e.g., a mixed V1a agonist-antagonist such as Compound 1) have a relatively large therapeutic window. In some cases, Figure 15 Line 2 shows that even at high doses, the compounds described herein (e.g., a mixed V1a agonist-antagonist such as Compound 1) are safe and effective.

[0291] In some cases, Figure 15 Curve 3 shows the concentration-response curve of a compound that does not reach the therapeutic level. In some cases, Figure 15 Curve 3 shows the concentration-response curve of a fully non-selective (V2, V1a) agonist or a partial V1a agonist (such as a compound with relatively low activity against V1AR).

[0292] In some cases, Figures 15 - 21 It is shown that the compounds described herein (e.g., a mixed V1a agonist-antagonist such as Compound 1) can be safely used (in a large dose range) to treat ESLD or its symptoms and / or complications. In some cases, Figure 15Demonstrate that even at supra - physiological concentrations, the compounds described herein (e.g., mixed V1a agonist - antagonists such as Compound 1) provide maximal effects (e.g., change (increase) in MAP) in an individual (e.g., after subcutaneous administration). In some cases, Figures 15 - 21 Demonstrate that the compounds described herein (e.g., mixed V1a agonist - antagonists such as Compound 1) provide robust effects (e.g., change (increase) in MAP) in an individual (e.g., after subcutaneous administration). In some cases, Figures 15 - 21 Demonstrate that the compounds described herein (e.g., mixed V1a agonist - antagonists such as Compound 1) achieve, maintain and do not exceed a safe and effective therapeutic effect (e.g., change (increase) in MAP), such as after subcutaneous administration. In some cases, Figures 15 - 21 Demonstrate that the compounds described herein (e.g., mixed V1a agonist - antagonists such as Compound 1) (e.g., after subcutaneous administration) maintain (a safe level of) therapeutic efficacy over an extended period of time (such as for at least 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 70 minutes, 80 minutes, 90 minutes or 100 minutes or longer). In some cases, Figures 15 - 21 Demonstrate that the compounds described herein (e.g., fully non - selective (V2, V1a) agonists such as terlipressin) rapidly reach toxic and potentially harmful concentrations, such as at relatively high doses. In some cases, Figures 15 - 21 Demonstrate that the compounds described herein (e.g., fully non - selective (V2, V1a) agonists such as terlipressin), the effects of the fully non - selective (V2, V1a) agonists rapidly wane, such as dropping below the therapeutic level rapidly after a relatively short period of time (e.g., after about 80 min or longer).

[0293] In some embodiments, the compounds described herein (e.g., Compound 1) modulate (e.g., increase) mean arterial pressure (MAP). In some embodiments, the compounds described herein (e.g., Compound 1) are administered subcutaneously and modulate (e.g., increase) MAP. In some embodiments, the compounds described herein (e.g., Compound 1) are administered subcutaneously and modulate (e.g., increase) MAP without (significant) injection site reactions (e.g., local vasoconstriction), such as at the subcutaneous injection site. In some embodiments, the compounds described herein (e.g., Compound 1) are suitable for subcutaneous administration for treating one or more complications of ESLD, such as HRS - AKI.

[0294] In some embodiments, the regulation of an individual's mean arterial pressure (MAP) includes increasing the MAP by at least 5% relative to a baseline (e.g., the level such as before administering a compound described herein (e.g., Compound 1)). In some embodiments, the regulation of an individual's MAP includes increasing the MAP by at least 10% relative to a baseline (e.g., the level such as before administering a compound described herein (e.g., Compound 1)). In some embodiments, the regulation of an individual's MAP includes increasing the MAP by at least 15% relative to a baseline (e.g., the level such as before administering a compound described herein (e.g., Compound 1)). In some embodiments, the baseline is the level before administering a compound described herein (e.g., Compound 1). In some cases, the baseline is the level compared to a control (such as a placebo).

[0295] In some embodiments, the regulation of an individual's mean arterial pressure (MAP) includes increasing the MAP by at most 5% relative to a baseline (e.g., the level such as before administering a compound described herein (e.g., Compound 1)). In some embodiments, the regulation of an individual's MAP includes increasing the MAP by at most 10% relative to a baseline (e.g., the level such as before administering a compound described herein (e.g., Compound 1)). In some embodiments, the regulation of an individual's MAP includes increasing the MAP by at most 15% relative to a baseline (e.g., the level such as before administering a compound described herein (e.g., Compound 1)). In some embodiments, the baseline is the level before administering a compound described herein (e.g., Compound 1). In some cases, the baseline is the level compared to a control (such as a placebo).

[0296] In some embodiments, the regulation of an individual's MAP includes increasing the MAP by at least 5 mmHg relative to a baseline (e.g., the level such as before administering a compound described herein (e.g., Compound 1)). In some embodiments, the regulation of an individual's MAP includes increasing the MAP by 1 mmHg or more relative to a baseline (e.g., the level such as before administering a compound described herein (e.g., Compound 1)). In some embodiments, the regulation of an individual's MAP includes increasing the MAP by 5 mmHg or more relative to a baseline (e.g., the level such as before administering a compound described herein (e.g., Compound 1)). In some embodiments, the regulation of an individual's MAP includes increasing the MAP by 10 mmHg or more relative to a baseline (e.g., the level such as before administering a compound described herein (e.g., Compound 1)). In some embodiments, the regulation of an individual's MAP includes increasing the MAP by about 20 mmHg or more relative to a baseline (e.g., the level such as before administering a compound described herein (e.g., Compound 1)). In some embodiments, the baseline is the level before administering a compound described herein (e.g., Compound 1).

[0297] In some embodiments, provided herein are methods of modulating the mean arterial pressure (MAP) of an individual (e.g., as described above), the methods comprising subcutaneously administering to the individual an effective amount of a compound having a structure represented by Formula I: D1-L-D2. In some embodiments, D1 is a vasopressin receptor 1A (V1AR) agonist. In some embodiments, D2 is a V1AR antagonist. In some embodiments, L is a linker. In some embodiments, the compound is administered to the individual as a pharmaceutically acceptable salt.

[0298] In some embodiments, the compounds described herein (e.g., Compound 1) have a structure represented by Formula I: D1-L-D2. In some embodiments, D1 is a vasopressin receptor 1A (V1AR) agonist. In some embodiments, D2 is a V1AR antagonist. In some embodiments, L is a linker. In some embodiments, the compound is administered to the individual as a pharmaceutically acceptable salt.

[0299] In some embodiments, D1 is selective for V1AR. In some embodiments, D1 is more selective for V1AR than for V2R. In some embodiments, D1 is more than 10-fold more selective for V1AR than for V2R. In some embodiments, D1 is more than 100-fold more selective for V1AR than for V2R. In some embodiments, D1 is more than 1,000-fold more selective for V1AR than for V2R. In some embodiments, D1 is more than 10,000-fold more selective for V1AR than for V2R. In some embodiments, D1 is inactive against V2R.

[0300] In some embodiments, D1 comprises a peptide. In some embodiments, D1 is a peptide. In some embodiments, D1 comprises a cyclic peptide. In some embodiments, D1 is a cyclic peptide. In some embodiments, D1 comprises a cyclic nonapeptide. In some embodiments, D1 is a cyclic nonapeptide.

[0301] In some embodiments, D1 has or comprises the following structure:

[0302]

[0303] In some embodiments, D1 has or comprises the following structure:

[0304]

[0305] In some cases, D2 is selective for V1AR. In some embodiments, D2 is more selective for V1AR than for V2R. In some cases, D2 is more than 10-fold more selective for V1AR than for V2R. In some cases, D2 is more than 100-fold more selective for V1AR than for V2R. In some cases, D2 is more than 1,000-fold more selective for V1AR than for V2R. In some cases, D2 is more than 10,000-fold more selective for V1AR than for V2R. In some cases, D2 is inactive against V2R.

[0306] In some embodiments, at least one of D1 and D2 is selective for V1AR. In some embodiments, at least one of D1 and D2 is more selective for V1AR than for V2R.

[0307] In some embodiments, D2 comprises a peptide. In some embodiments, D2 is a peptide. In some embodiments, D2 comprises a linear peptide. In some embodiments, D2 is a linear peptide. In some embodiments, it is a linear polypeptide comprising about seven or more amino acid residues. In some embodiments, D2 comprises seven to twelve amino acid residues.

[0308] In some embodiments, D2 has or comprises the following structure:

[0309]

[0310] In some embodiments, D2 has or comprises the following structure:

[0311]

[0312] In some embodiments, L is a non-hydrolyzable linker.

[0313] In some embodiments, L comprises a peptide bond. In some embodiments, L comprises one or more amino acid residues. In some embodiments, L is one or more amino acid residues. In some embodiments, L comprises one or more modified amino acid residues. In some embodiments, L is one or more modified amino acid residues.

[0314] In some embodiments, L comprises one or more linker groups, each linker group independently selected from the group consisting of substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl. In some embodiments, L is a bond, a substituted or unsubstituted alkyl, or a substituted or unsubstituted heteroalkyl. In some embodiments, L is or comprises a substituted or unsubstituted heteroalkyl. In some embodiments, L is a heteroalkyl substituted with one or more substituents, each substituent independently selected from the group consisting of oxo, amino, and substituted heteroalkyl. In some embodiments, L is an alkylamine substituted with one or more substituents, each substituent independently selected from the group consisting of oxo, amino, and substituted heteroalkyl. In some embodiments, L is an alkylamine substituted with an oxo group.

[0315] In some embodiments, L has or comprises the following structure:

[0316]

[0317] In some embodiments, L has or comprises the following structure:

[0318]

[0319] In some embodiments, the compounds described herein are Compound 1 or a pharmaceutically acceptable salt thereof.

[0320] In some instances, Compound 1 is glycyl-L-cysteinyl-L-phenylalanyl-L-isoleucyl-L-glutaminyl-L-asparaginyl-L-cysteinyl-L-prolyl-N4-(phenylacetyl-O-methyl-D-tyrosyl-L-phenylalanyl-L-glutaminyl-L-asparaginyl-L-alanyl-L-prolyl-L-arginyl-L-isoglutamyl-N5-acetyl-L-lysyl-L-ε-lysyl)-L-2,4-diaminobutyryl-, cyclo(1→6)-disulfide.

[0321] In some instances, Compound 1 has C 110 H 161 N 31 O 27 S2 as its empirical formula.

[0322] In some instances, Compound 1 has an average molecular weight of 2413.78 u.

[0323] In some instances, the hybrid V1A agonist-antagonist provided herein (e.g., Compound 1) is a white to off-white powder.

[0324] In some cases, the hybrid V1A agonist-antagonists provided herein (e.g., Compound 1) have a solubility of at least 10 mg / mL in water.

[0325] In some embodiments, Compound 1 has a structure represented by Formula (I-A):

[0326]

[0327] or a pharmaceutically acceptable salt thereof.

[0328] In some cases, the hybrid V1A agonist-antagonists provided herein (e.g., Compound 1) are 20-mer monocyclic branched peptides containing natural and non-natural amino acids (such as from non-animal sources). In some cases, the hybrid V1A agonist-antagonists provided herein (e.g., Compound 1) have an S-S bridge between Cys 1 and Cys 6 residues. In some cases, the branched chain is linked through the side chain amino functional group at position 8.

[0329] In some cases, compounds having a structure represented by Formula (I-B) are provided herein:

[0330]

[0331] or a pharmaceutically acceptable salt thereof,

[0332] wherein:

[0333] Dab is 2,4-diaminobutyric acid, D-Tyr(Me) is O-methyl-D-tyrosine, and

[0334] PhAc is phenylacetic acid (e.g., wherein L-2,4-diaminobutyric acid, N-ε-acetyl-L-lysine, L-isoglutamine, and O-methyl-D-tyrosine are non-natural, and the N-terminal portion is substituted with phenylacetic acid).

[0335] In some cases, the hybrid V1A agonist-antagonists provided herein (e.g., Compound 1) are provided as a pharmaceutically acceptable salt. In some cases, the hybrid V1A agonist-antagonists provided herein (e.g., Compound 1) are provided as the acetate salt. In some cases, the hybrid V1A agonist-antagonists provided herein (e.g., Compound 1) are administered in the form described in Example 1.

[0336] In some embodiments, the compounds described herein are any of the compounds described in either U.S. Patent No. 9,644,000 or U.S. Patent No. 9,388,214, each of which is incorporated herein by reference in its entirety (specifically for the compounds provided herein).

[0337] In some cases, Compound 1 has the empirical formula C 110 H 161 N 31 O 27 S2(AcOH) z where z is any integer (e.g., from 1 - 100).

[0338] In some embodiments, provided herein are methods of modulating mean arterial pressure (MAP) in an individual (e.g., as described herein), the methods comprising subcutaneously administering to the individual an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof.

[0339] In some embodiments, provided herein are pharmaceutical compositions comprising an amount of a compound or a pharmaceutically acceptable salt thereof (e.g., Compound 1) described herein. In some embodiments, the amount of the compound is an effective amount of the compound. In some embodiments, the compound is a mixed vasopressin receptor 1A (V1AR) agonist - antagonist. In some embodiments, the composition is formulated for subcutaneous administration. In some embodiments, the compound has a structure represented by Formula I. In some embodiments, the compound is Compound 1.

[0340] In some embodiments, provided herein are subcutaneous formulations comprising a compound described herein (such as a compound having a structure represented by Formula I) or a pharmaceutically acceptable salt thereof.

[0341] In some embodiments, less than 50% of the compound (such as a compound of Formula I) degrades. In some embodiments, less than 50% of the compound (such as a compound of Formula I) degrades to form M1. In some embodiments, less than 50% of the compound (such as a compound of Formula I) degrades subcutaneously. In some embodiments, less than 50% of the compound (such as a compound of Formula I) degrades subcutaneously to form M1.

[0342] In some embodiments, less than 30% of the compound (such as a compound of Formula I) degrades. In some embodiments, less than 30% of the compound (such as a compound of Formula I) degrades to form M1. In some embodiments, less than 30% of the compound (such as a compound of Formula I) degrades subcutaneously. In some embodiments, less than 30% of the compound (such as a compound of Formula I) degrades subcutaneously to form M1.

[0343] In some embodiments, the compositions described herein further comprise a liquid vehicle or solvent (e.g., water or an aqueous vehicle).

[0344] In some embodiments, provided herein are subcutaneous formulations having a compound as described herein, such as a compound having a structure represented by Formula I, at a concentration of about 0.001 milligrams (mg) per milliliter (mL) or higher. In some embodiments, the subcutaneous formulation has a compound as described herein, such as a compound having a structure represented by Formula I, at a concentration of about 100 mg / mL or lower. In some embodiments, the subcutaneous formulation has a compound as described herein, such as a compound having a structure represented by Formula I, at a concentration of about 0.001 mg / mL to 100 mg / mL. In some embodiments, the subcutaneous formulation comprises a compound at a concentration of about 0.01 mg / mL to about 100 mg / mL. In some embodiments, the subcutaneous formulation comprises a compound at a concentration of about 0.1 mg / mL to about 100 mg / mL. In some embodiments, the subcutaneous formulation comprises a compound at a concentration of about 1 mg / mL to about 100 mg / mL. In some embodiments, the subcutaneous formulation comprises a compound at a concentration of about 0.1 mg / mL to about 50 mg / mL. In some embodiments, the subcutaneous formulation comprises a compound at a concentration of about 1 mg / mL to about 50 mg / mL. In some embodiments, the subcutaneous formulation comprises a compound at a concentration of about 0.1 mg / mL to about 10 mg / mL. In some embodiments, the subcutaneous formulation comprises a compound at a concentration of about 1 mg / mL to about 10 mg / mL.

[0345] In some embodiments, the compounds are formulated as described in the examples herein. In some embodiments, the compounds are formulated as an aqueous solution. In some embodiments, the compounds are formulated as an aqueous solution having a concentration of at least about 0.01 mg / mL of the compound. In some embodiments, the compounds are formulated as an aqueous solution having a concentration of at least about 0.1 mg / mL of the compound. In some embodiments, the compounds are formulated as an aqueous solution having a concentration of at least about 1 mg / mL of the compound. In some embodiments, the compounds are formulated as an aqueous solution having a concentration of at least about 10 mg / mL of the compound. In some embodiments, the compounds are formulated as an aqueous solution having a concentration of at most about 50 mg / mL of the compound. In some embodiments, the compounds are formulated as an aqueous solution having a concentration of at most about 10 mg / mL of the compound. In some embodiments, the compounds are formulated as an aqueous solution having a concentration of at most about 1 mg / mL of the compound. In some embodiments, the compounds are formulated as an aqueous solution having a concentration of at most about 0.1 mg / mL of the compound. In some embodiments, the compounds are formulated as an aqueous solution having a concentration of at most about 0.01 mg / mL of the compound. In some embodiments, the compounds are formulated as an aqueous solution having a concentration of from about 0.01 mg / mL to about 50 mg / mL of the compound. In some embodiments, the compounds are formulated as an aqueous solution having a concentration of from about 0.01 mg / mL to about 10 mg / mL of the compound. In some embodiments, the compounds are formulated as an aqueous solution having a concentration of from about 1 mg / mL to about 10 mg / mL of the compound. In some embodiments, the composition is formulated with an acetate buffer. In some embodiments, the composition is formulated at a pH of 4.5. In some embodiments, the composition is formulated with mannitol.

[0346] In some embodiments, an additive (e.g., a preservative) is added to the composition (e.g., subcutaneously) having a pH of about 3 - 6 (e.g., 4.5) and comprising at least about 1 millimolar (mM) of an acetate buffer (e.g., from about 5 mM sodium acetate to about 150 mM sodium acetate) and from about 10 milligrams per milliliter (mg / mL) to about 100 mg / mL of mannitol (e.g., about 43.6 mg / mL of mannitol). In some cases, the additive is a preservative. In some cases, a preservative is added to the composition (e.g., subcutaneously) having a pH of about 4.5 and comprising about 10 mM sodium acetate and about 43.6 mg / mL of mannitol.

[0347] In some embodiments, provided herein are compositions comprising Compound 1. In some embodiments, the compositions are suitable for subcutaneous administration. In some embodiments, the formulation is suitable for subcutaneous (bolus) injection. In some embodiments, the subcutaneous (bolus) injection is provided to an individual as a single dose (e.g., all at once). In some embodiments, the formulation is suitable for subcutaneous infusion.

[0348] In some embodiments, the compositions described herein comprise an additive. In some embodiments, the compositions described herein are subcutaneous compositions and comprise an additive. In some embodiments, the additive is selected from the group consisting of preservatives, solubilizers (e.g., cyclodextrins), buffers, and chelating agents (e.g., zinc acetate or ethylenediaminetetraacetic acid (EDTA)). In some embodiments, the additive is a preservative.

[0349] In some embodiments, provided herein is a subcutaneous formulation that comprises a compound having a structure represented by Formula I and a preservative.

[0350] In some embodiments, the compositions described herein further comprise a preservative. In some embodiments, the preservative is any suitable preservative such as m-cresol, phenol, chlorobutanol, or benzyl alcohol. In some embodiments, the preservative is present in the composition in an amount of about 0.1 mg / mL or more. In some embodiments, the preservative is present in the composition in an amount of about 50 mg / mL or less. In some embodiments, the preservative is present in the composition in an amount of about 0.1 mg / mL to about 50 mg / mL. In some embodiments, the preservative is present in the composition in an amount of about 1 mg / mL to about 20 mg / mL.

[0351] In some cases, even at relatively high concentrations of the preservative, the compositions described herein that comprise a preservative do not exhibit a physical interaction (e.g., aggregation) with any of the screened preservatives (e.g., between the preservative and Compound 1).

[0352] In some embodiments, provided herein is a subcutaneous formulation that comprises a compound having a structure represented by Formula I and a solubilizer.

[0353] In some embodiments, the compositions described herein further comprise a solubilizer. In some embodiments, the solubilizer is any suitable solubilizer such as cyclodextrin (e.g., sulfobutyl ether-β-cyclodextrin (SBECD)). In some embodiments, the solubilizer is present in the composition in an amount of about 0.1 mg / mL or more. In some embodiments, the solubilizer is present in the composition in an amount of about 500 mg / mL or less. In some embodiments, the solubilizer is present in the composition in an amount of about 250 mg / mL or less. In some embodiments, the solubilizer is present in the composition in an amount of about 100 mg / mL or less. In some embodiments, the solubilizer is present in the composition in an amount of about 0.1 mg / mL to about 250 mg / mL. In some embodiments, the solubilizer is present in the composition in an amount of about 0.1 mg / mL to about 100 mg / mL. In some embodiments, the solubilizer is present in the composition in an amount of about 1 mg / mL to about 250 mg / mL. In some embodiments, the solubilizer is present in the composition in an amount of about 1 mg / mL to about 100 mg / mL. In some embodiments, the solubilizer is present in the composition in an amount of about 60 mg / mL to about 80 mg / mL.

[0354] In some embodiments, the composition further comprises a buffer. In some embodiments, the buffer has a pKa of about 3.0 to about 6.0, such as at 25 °C. In some embodiments, the buffer is selected from the group consisting of acetate buffer, succinate buffer, phosphate buffer, and citrate buffer. In some embodiments, the composition further comprises acetate buffer. In some embodiments, the acetate buffer is a combination of acetate and acetic acid. In some embodiments, the composition further comprises succinate buffer. In some embodiments, the succinate buffer is a combination of succinate and succinic acid. In some embodiments, the composition further comprises citrate buffer. In some embodiments, the citrate buffer is a combination of citrate and citric acid.

[0355] In some embodiments, provided herein is a subcutaneous formulation that comprises a compound having a structure represented by Formula I and a buffer at a concentration of about 1 millimolar (mM) to about 1 M.

[0356] In some embodiments, the compositions described herein comprise a buffer at a concentration of about 1 millimolar (mM) or higher. In some embodiments, the compositions described herein comprise a buffer at a concentration of about 1 molar (M) or lower. In some embodiments, the compositions described herein comprise a buffer at a concentration of from about 1 mM to about 1 M. In some embodiments, the compositions described herein comprise a buffer at a concentration of from about 1 mM to about 500 mM. In some embodiments, the compositions described herein comprise a buffer at a concentration of from about 1 mM to about 250 mM. In some embodiments, the compositions described herein comprise a buffer at a concentration of from about 50 mM to about 250 mM. In some embodiments, the compositions described herein comprise a buffer at a concentration of from about 50 mM to about 150 mM. In some embodiments, the compositions described herein comprise a buffer at a concentration of about 100 mM. In some embodiments, the compositions described herein comprise a buffer at a concentration of from about 1 mM to about 50 mM. In some embodiments, the compositions described herein comprise a buffer at a concentration of from about 5 mM to about 25 mM. In some embodiments, the compositions described herein comprise a buffer at a concentration of about 10 mM.

[0357] In some embodiments, the compositions described herein have a pH sufficient to inhibit a protease (e.g., trypsin) (e.g., inactivate or deactivate it), such as in the subcutaneous layer of an individual to whom the formulation is administered subcutaneously.

[0358] In some embodiments, the pH of the compositions described herein does not change (significantly) when administered subcutaneously to an individual. In some embodiments, the pH of the compositions described herein does not change (significantly) when administered subcutaneously to an individual by subcutaneous (bolus) injection. In some embodiments, the pH of the compositions described herein does not change (significantly) when administered subcutaneously to an individual by subcutaneous infusion.

[0359] In some embodiments, the compositions described herein have a pH of at least about 3. In some embodiments, the compositions described herein have a pH of about 9 or lower, 8 or lower, 7 or lower, 6 or lower, 5 or lower, or 4 or lower. In some embodiments, the compositions described herein have a pH of from about 4 to about 8. In some embodiments, the compositions described herein have a pH of from about 4 to about 6. In some embodiments, the compositions described herein have a pH of from about 4.5 to about 5. In some embodiments, the compositions described herein have a pH of about 4. In some embodiments, the compositions described herein have a pH of about 4.5.

[0360] In some embodiments, the compositions described herein have an ionic strength of about 1 mM or higher. In some embodiments, the compositions described herein have an ionic strength of about 1 M or lower. In some embodiments, the compositions described herein have an ionic strength of about 1 mM to about 500 mM. In some embodiments, the compositions described herein have an ionic strength of about 5 mM to about 200 mM. In some embodiments, the compositions described herein have an ionic strength of about 5 mM to about 10 mM to about 100 mM.

[0361] In some embodiments, the compounds described herein (such as compounds having a structure represented by Formula I) are (e.g., substantially) less susceptible to degradation (e.g., by proteases). In some embodiments, in the subcutaneous layer of an individual to whom a composition comprising the compound is administered subcutaneously, the compounds described herein (such as compounds having a structure represented by Formula I) are (e.g., substantially) less susceptible to degradation (e.g., by proteases).

[0362] In some embodiments, the compounds described herein (such as compounds having a structure represented by Formula I) are stable in the compositions described herein. In some embodiments, less than 50% of the compounds described herein (such as compounds having a structure represented by Formula I) degrade in a vial. In some embodiments, less than 50% of the compounds described herein (such as compounds having a structure represented by Formula I) degrade in a vial over a period of at least about one week (e.g., about one week or longer, two weeks or longer, three weeks or longer, or four weeks or longer). In some embodiments, less than 50% of the compounds described herein (such as compounds having a structure represented by Formula I) degrade subcutaneously. In some embodiments, less than 50% of the compounds described herein (such as compounds having a structure represented by Formula I) degrade subcutaneously over a period of at least about one hour (e.g., about one hour or longer, six hours or longer, twelve hours or longer, or twenty-four hours or longer).

[0363] In some embodiments, the compositions described herein (such as those having an acidic pH, a relatively high buffer (e.g., acetate buffer) concentration, and / or a relatively high concentration of the compounds described herein (e.g., Compound 1)) are well tolerated after subcutaneous (e.g., injection or infusion) administration (see Examples 3 and 4).

[0364] In some embodiments, the compositions described herein have a pH and / or buffer (e.g., acetate buffer) concentration sufficient to inhibit, reduce, or eliminate the formation of undesirable metabolites of the compounds described herein (e.g., Compound 1), such as full (V1a) agonists, like M1. In some cases, compositions containing a relatively high buffer concentration (e.g., 50 mM or more of buffer) extend the amount of time that the local environment (e.g., at or near the injection site) maintains a certain pH (e.g., a pH of about 3 or higher) sufficient to inhibit, reduce, or eliminate the formation of undesirable metabolites of the compounds described herein (e.g., Compound 1), such as full (V1a) agonists, like M1. In some cases, when (subcutaneously) injected, compositions having an acidic pH (e.g., a pH of 1 to 6) produce undesirable effects, such as burning, stinging, pain at the injection site, etc. It is expected that compositions having a relatively acidic pH or a buffer concentration that extends the amount of time that the local environment (e.g., at or near the injection site) maintains a certain (e.g., acidic) pH will prolong such undesirable effects. In contrast, the compositions described herein having a relatively acidic pH (e.g., a pH of 4 or 4.5) and / or a buffer concentration that extends the amount of time that the local environment (e.g., at or near the injection site) maintains a certain (e.g., acidic) pH do not produce (significant) undesirable effects when administered subcutaneously (e.g., by injection or infusion). In some cases, a higher buffer concentration inhibits, reduces, or eliminates the formation of M1 to provide sufficient time for absorption of the compounds described herein, such as due to an extended period of time during which the pH of the local environment is acidic (e.g., 4.5) after administration. In some embodiments, the buffer concentration of the compositions provided herein that extends the amount of time that the local environment (e.g., at or near the injection site) maintains a certain (e.g., acidic) pH is about 50 mM or higher. In some embodiments, when administered subcutaneously (e.g., by injection or infusion), the pH of the compositions provided herein sufficient to inhibit, reduce, or eliminate the formation of undesirable metabolites of the compounds described herein (e.g., Compound 1), such as full (V1a) agonists, like M1, is acidic. In some embodiments, when administered subcutaneously (e.g., by injection or infusion), the pH of the compositions provided herein sufficient to inhibit, reduce, or eliminate the formation of undesirable metabolites of the compounds described herein (e.g., Compound 1), such as full (V1a) agonists, like M1, is about 3 or higher. In some embodiments, when administered subcutaneously (e.g., by injection or infusion), the pH of the compositions provided herein sufficient to inhibit, reduce, or eliminate the formation of undesirable metabolites of the compounds described herein (e.g., Compound 1), such as full (V1a) agonists, like M1, is about 4 or 4.5.

[0365] In some embodiments, the compositions described herein (e.g., compositions suitable for intravenous or subcutaneous administration) comprise acetate buffer at a concentration of about 10 mM or higher. In some embodiments, the compositions described herein comprise acetate buffer at a concentration of about 50 mM or higher.

[0366] In some embodiments, the compositions described herein (e.g., compositions suitable for intravenous or subcutaneous administration) have a pH of about 3 or higher.

[0367] In some embodiments, the compositions described herein (e.g., compositions suitable for intravenous or subcutaneous administration) comprise acetate buffer at a concentration of 10 mM and have a pH of 4.5. In some embodiments, the composition is suitable for intravenous administration. In some embodiments, the composition does not contain a preservative. In some embodiments, the composition is suitable for subcutaneous administration. In some embodiments, the composition is suitable for subcutaneous infusion.

[0368] In some embodiments, the compositions described herein (e.g., compositions suitable for subcutaneous administration) comprise acetate buffer at a concentration of 100 mM (or higher) and have a pH of about 4 or 4.5. In some embodiments, the composition is suitable for subcutaneous administration. In some embodiments, the composition is suitable for subcutaneous (bolus) injection. In some embodiments, the composition is suitable for subcutaneous infusion.

[0369] In some embodiments, the compositions described herein (e.g., compositions suitable for intravenous or subcutaneous administration) comprise acetate buffer at a concentration of about 10 mM or higher. In some embodiments, the compositions described herein comprise acetate buffer at a concentration of about 50 mM or higher.

[0370] In some embodiments, the compositions described herein comprise a compound at a concentration sufficient to inhibit, reduce, or eliminate the formation of unwanted metabolites of the compounds described herein (e.g., Compound 1), such as full (V1a) agonists like M1. In some cases, compositions containing a relatively high drug concentration (e.g., 0.1 milligram per milliliter (mg / mL) or higher) saturate the local environment (e.g., at or near the injection site) with the drug, such that more drug is absorbed before significant formation of unwanted metabolites of the drug, such as full (V1a) agonists. In some embodiments, when administered subcutaneously (e.g., by injection or infusion), the compositions described herein having a relatively high concentration of the compounds provided herein are sufficient to inhibit, reduce, or eliminate the formation of unwanted metabolites of the compounds described herein (e.g., Compound 1), such as full (V1a) agonists like M1. In some embodiments, the drug concentration in the composition (e.g., the concentration of the compounds described herein) is about 0.1 mg / mL or higher.

[0371] In some embodiments, the compositions provided herein have a concentration of the compounds described herein of about 0.1 mg / mL or higher. In some embodiments, the compositions provided herein have a concentration of the compounds described herein of about 1 mg / mL or higher. In some embodiments, the compositions provided herein have a concentration of the compounds described herein of about 100 mg / mL or lower. In some embodiments, the compositions provided herein have a concentration of the compounds described herein of from about 0.1 mg / mL to about 100 mg / mL. In some embodiments, the compositions provided herein have a concentration of the compounds described herein of from about 0.1 mg / mL to about 10 mg / mL. In some embodiments, the composition is suitable for subcutaneous administration. In some embodiments, the composition is suitable for subcutaneous (bolus) injection. In some embodiments, the composition is suitable for subcutaneous infusion. In some embodiments, the compositions provided herein have a concentration of the compounds described herein of about 0.1 mg / mL or lower. In some embodiments, the composition is suitable for intravenous administration.

[0372] In some embodiments, the compositions described herein are suitable for subcutaneous infusion. In some embodiments, the composition suitable for subcutaneous infusion is administered to an individual in a manner that reduces (injection site) injury or trauma. In some embodiments, the composition suitable for subcutaneous infusion is administered to an individual over a (prolonged) period of time. In some embodiments, the composition suitable for subcutaneous infusion is administered to an individual at a (relatively slow) rate (such as by infusion). In some embodiments, the composition is administered at a rate sufficient to provide an infusion (e.g., not a stream) of the composition. In some embodiments, the composition is administered at a rate of about 0.1 milliliter per hour (mL / h) or lower over a (prolonged) period of time (e.g., a period of about 24 hours or longer).

[0373] In some embodiments, there are provided pharmaceutical compositions that comprise an amount of a compound having a structure represented by Formula I. In some embodiments, the composition is formulated for subcutaneous administration. In some embodiments, the amount of the compound is an effective amount of the compound.

[0374] In some embodiments, there are provided pharmaceutical compositions that comprise an amount of Compound 1 or a pharmaceutically acceptable salt thereof, and the composition is formulated for subcutaneous administration. In some embodiments, the amount of the compound is an effective amount of the compound.

[0375] In some embodiments, the compositions described herein are suitable for systemic delivery of the active agents described herein, such as compounds having a structure represented by Formula I. In some embodiments, the compositions described herein are suitable for administration of the active agents described herein, such as compounds having a structure represented by Formula I, in an outpatient setting (such as at home). In some embodiments, the compositions described herein are suitable for systemic delivery of Compound 1. In some embodiments, the compositions described herein are suitable for administration of Compound 1 in an outpatient setting (such as at home).

[0376] In some embodiments, provided herein is a system for regulating mean arterial pressure, the system comprising a composition that includes a compound of Formula I or a pharmaceutically acceptable salt thereof; and a device configured to provide subcutaneous infusion of the composition to an individual when the device is positioned on the skin of the individual.

[0377] In some embodiments, the system includes an adhesive body for securing the (subcutaneous infusion) device to the skin surface of the individual. In some embodiments, the system includes an adhesive body for reversibly securing the (subcutaneous infusion) device to the skin surface of the individual.

[0378] In some embodiments, the system includes a cavity and a hollow tube. In some embodiments, the composition is configured within the cavity. In some embodiments, the hollow tube includes a first opening and a second opening. In some embodiments, the first opening is in fluid communication with the cavity. In some embodiments, after the subcutaneous infusion device is secured to the skin of the individual, the second opening is subcutaneously disposed within the individual. In some embodiments, the hollow tube is a needle, such as any needle gauge suitable for subcutaneous administration (e.g., subcutaneous infusion).

[0379] In some embodiments, the system does not include an adhesive body. In some embodiments, the device is not attached to the skin surface of the individual. In some embodiments, the cavity is attached to an injection port. In some embodiments, the system does not include an adhesive body and the cavity is attached to an injection port.

[0380] In some embodiments, the (subcutaneous infusion) device further includes a pump configured to subcutaneously infuse the composition to the individual at a constant or varying rate (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 longer. In some embodiments, the system is configured to continuously provide the composition to the individual over a period of about 24 hours or longer.

[0381] In some embodiments, the device is configured to receive a vial and / or cartridge of the composition.

[0382] In some embodiments, the device is a subcutaneous infusion device. In some embodiments, the device is a pump.

[0383] In some cases, the present disclosure provides a pharmaceutical composition comprising an effective amount of a first compound or a pharmaceutically acceptable salt thereof and an effective amount of a second compound or a pharmaceutically acceptable salt thereof, wherein the first compound is a vasoconstrictor and wherein the second compound sufficiently blocks the (e.g., local) vasoconstrictive action of the first compound, such as providing sufficient uptake of the first compound to the circulatory system and / or internal organs (e.g., kidneys) of an individual (e.g., in need). In some embodiments, the pharmaceutical composition is injectable. In some cases, the pharmaceutical composition is suitable for intravitreal administration. In some cases, the pharmaceutical composition is suitable for subcutaneous administration. In some cases, the first compound is a vasopressin receptor 1A (V1AR) agonist. In some cases, the first compound is a selective V1AR agonist. In some cases, the second compound is a V1AR antagonist. In some cases, the second compound is a selective V1AR antagonist. In some cases, the second compound is a vasodilator.

[0384] In some embodiments, the compounds described herein (e.g., compound 1) are safe (e.g., in humans) (e.g., see Example 1). In some embodiments, the compounds described herein (e.g., compound 1) are well tolerated (e.g., in humans) (e.g., see Example 1). In some embodiments, the compounds described herein (e.g., compound 1) are safe and well tolerated (e.g., in humans) (e.g., see Example 1). In some embodiments, the compounds described herein (e.g., compound 1) have a pharmacodynamic profile with submaximal partial agonism consistent with that of a mixed agonist - antagonist at the V1a receptor.

[0385] In some cases, the compounds described herein (e.g., compound 1) are tested in a Phase 1, double - blind, placebo - controlled, dose - group - randomized trial to study the safety, tolerability, and pharmacokinetic and pharmacodynamic (PD) profiles of the compound administered to healthy adults aged 18 to 45 years (see Example 1). In some cases, the trial comprises two treatment periods: a Phase 1 (6 - h intravenous [IV] infusion of the compound or placebo in the dose range of 0.1 to 0.9 mg) and a Phase 2 (once - daily subcutaneous [SC] injection of the compound at 0.1, 0.3 mg or placebo for 5 consecutive days). In some cases, Phase 1 includes 32 males and females. In some cases, 8 males and 5 females proceed to Phase 2. In some cases, such as after intravenous administration, the exposure, as measured by AUC and C max is approximately dose - proportional within the dose range studied. In some cases, such as after subcutaneous administration, T maxFor 0.3 h, the exposure is disproportionately high and the bioavailability is 18%, with no significant accumulation after repeated administration. In some cases, after intravenous and subcutaneous administration, the terminal half-lives (t 1 / 2 ) of the compounds described herein (e.g., Compound 1) are approximately 1.5 h and 1.0 h, respectively, such that absorption is not rate-limiting for elimination after subcutaneous administration. In some cases, in all dose groups, the diastolic blood pressure and (to a lesser extent) the systolic blood pressure (BP) of subjects treated with the compounds described herein (e.g., Compound 1) increase, while the pulse rate decreases. In some cases, the overall change in mean arterial pressure (MAP) after intravenous and subcutaneous administration is similar to the change in diastolic BP. In some cases, the absolute change in cardiac output measured by echocardiography appears to be dose-dependent, decreasing on average by 3% - 12% after a 0.9 mg intravenous dose and ≤20% - 25% individually at any dose. In some cases, adverse events (AEs) include abdominal pain and diarrhea, laboratory tests for mesenteric ischemia are negative, and no cases of mesenteric ischemia are reported. In some cases, the AEs are treatment-related, generally mild or moderate in severity, and attributable to the expected pharmacological effects.

[0386] In some embodiments, after administration of a compound or a pharmaceutically acceptable salt thereof described herein (e.g., Compound 1), the diastolic blood pressure of an individual increases (e.g., compared to a pre-treatment baseline measurement). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein (e.g., Compound 1), the diastolic blood pressure of an individual increases (e.g., compared to a pre-treatment baseline measurement).

[0387] In some embodiments, after administration of a compound or a pharmaceutically acceptable salt thereof described herein (e.g., Compound 1), the systolic blood pressure of an individual increases (e.g., compared to a pre-treatment baseline measurement). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein (e.g., Compound 1), the systolic blood pressure of an individual increases (e.g., compared to a pre-treatment baseline measurement).

[0388] In some embodiments, after administration of a compound or a pharmaceutically acceptable salt thereof described herein (e.g., Compound 1), the diastolic and / or systolic blood pressure of an individual increases in a dose-dependent manner (e.g., compared to a pre-treatment baseline measurement). In some embodiments, after subcutaneous administration of a compound or a pharmaceutically acceptable salt thereof described herein (e.g., Compound 1), the diastolic and / or systolic blood pressure of an individual increases in a dose-dependent manner (e.g., compared to a pre-treatment baseline measurement).

[0389] In some embodiments, the compounds provided herein have a maximum therapeutic concentration. In some embodiments, the maximum therapeutic concentration includes an increase in concentration that does not provide a dose-dependent increase in blood pressure, such as diastolic blood pressure, systolic blood pressure, and / or MAP. In some embodiments, the compounds provided herein have a non-linear dose-dependence, such as above the maximum therapeutic concentration. In some embodiments, the dose-dependent increase in blood pressure, such as diastolic blood pressure, systolic blood pressure, and / or MAP, includes the maximum therapeutic concentration. In some embodiments, the dose-dependence includes a situation where the effect increases with the dose for at least a certain dose range. For example, a higher dose may not provide or may provide a lower dose-dependent increase.

[0390] In some embodiments, MAP is calculated from measurements of systolic and diastolic blood pressures. In some embodiments, MAP is calculated when considering the pressure during a single cardiac cycle. In some embodiments, MAP is 1 / 3 (systolic blood pressure - diastolic blood pressure) + diastolic blood pressure.

[0391] In some embodiments, after administration of the compounds provided herein or a pharmaceutically acceptable salt thereof (e.g., Compound 1), the pulse rate of an individual decreases (e.g., compared to a baseline measurement prior to treatment). In some embodiments, after administration of the compounds provided herein or a pharmaceutically acceptable salt thereof (e.g., Compound 1), the peripheral blood flow of an individual decreases (e.g., compared to a baseline measurement prior to treatment). In some embodiments, after administration of the compounds provided herein or a pharmaceutically acceptable salt thereof (e.g., Compound 1), the pulse rate and peripheral blood flow of an individual decrease (e.g., compared to a baseline measurement prior to treatment).

[0392] In some embodiments, administration of the compounds provided herein or a pharmaceutically acceptable salt thereof (e.g., Compound 1) to an individual (e.g., as described herein) improves the systemic hemodynamics of the individual. In some embodiments, subcutaneous administration of the compounds provided herein or a pharmaceutically acceptable salt thereof (e.g., Compound 1) to an individual (e.g., as described herein) improves the systemic hemodynamics of the individual.

[0393] In some embodiments, administering to an individual (e.g., as described herein) a compound or a pharmaceutically acceptable salt thereof (e.g., Compound 1) as described herein reduces fluid retention in the individual. In some embodiments, administering to an individual (e.g., as described herein) a compound or a pharmaceutically acceptable salt thereof (e.g., Compound 1) as described herein reduces fluid overload in the individual. In some embodiments, administering to an individual (e.g., as described herein) a compound or a pharmaceutically acceptable salt thereof (e.g., Compound 1) as described herein reduces both fluid retention and overload in the individual. In some embodiments, administering subcutaneously to an individual (e.g., as described herein) a compound or a pharmaceutically acceptable salt thereof (e.g., Compound 1) as described herein reduces fluid retention in the individual. In some embodiments, administering subcutaneously to an individual (e.g., as described herein) a compound or a pharmaceutically acceptable salt thereof (e.g., Compound 1) as described herein reduces fluid overload in the individual. In some embodiments, administering subcutaneously to an individual (e.g., as described herein) a compound or a pharmaceutically acceptable salt thereof (e.g., Compound 1) as described herein reduces both fluid retention and overload in the individual.

[0394] In some embodiments, administering to an individual (e.g., as described herein) (e.g., subcutaneously) a compound or a pharmaceutically acceptable salt thereof (e.g., Compound 1) as described herein decreases the serum creatinine (sCr) (value) of the individual (e.g., compared to a pre-treatment baseline measurement). In some embodiments, administering to an individual (e.g., as described herein) (e.g., subcutaneously) a compound or a pharmaceutically acceptable salt thereof (e.g., Compound 1) as described herein until the individual has an sCr value of 1.5 milligrams (mg) / deciliter (dL) or less. In some embodiments, administering to an individual (e.g., as described herein) (e.g., subcutaneously) a compound or a pharmaceutically acceptable salt thereof (e.g., Compound 1) as described herein until the sCr value of the individual returns to normal (e.g., baseline).

[0395] In some cases, intravenous (i.v.) administration of a compound as described herein (e.g., Compound 1) provides a terminal half-life of about 1.5 hours, with a clearance and volume of distribution of about 13 L / h and about 15 - 20 L, respectively. In some cases, after subcutaneous (s.c.) administration of a compound as described herein (e.g., Compound 1), the t max is about 0.3 hours and the terminal half-life is about 1 hour (e.g., without any accumulation upon repeated administration). In some cases, the bioavailability after subcutaneous (s.c.) administration of a compound as described herein (e.g., Compound 1) is about 18%.

[0396] In some cases, a compound as described herein (e.g., Compound 1) has an exposure (by AUC and C max) proportional increase. In some cases, the compounds described herein (e.g., Compound 1) exhibit more than approximate proportionality after subcutaneous administration. In some cases, the compounds described herein (e.g., Compound 1) have higher exposure in females than in males, such as after intravenous infusion and subcutaneous injection.

[0397] In some cases, the compounds described herein (e.g., Compound 1) are metabolized to metabolite M1 (see Figure 14 ). M1 has a free - form structure as the structure circled in Figure 14 . In some embodiments, M1 is a full (V1A) agonist. In some embodiments, M1 has a molecular weight of 1405.68 g / mol. In some embodiments, M1 has the chemical formula C 60 H 98 N 19 O 16 S2 + . Compared to Compound 1, M1 has (significantly) lower activity (towards V1a). Specifically, the activity of M1 towards V1a is approximately one - tenth of that of Compound 1.

[0398] In some cases, such as in a single subject after intravenous administration, M1 is found in the plasma of individuals who have received Compound 1. In some cases, such as in all studied subjects, M1 is found at comparable concentrations after subcutaneous administration. In some cases, the compounds described herein (e.g., Compound 1) are metabolized (e.g., to M1) during the transport to the circulation after subcutaneous injection. As discussed above, it is known that the full agonists described herein are toxic and cause (critical) adverse events when administered subcutaneously. Therefore, the formation of full agonists (e.g., M1), such as when the compounds described herein are administered by subcutaneous (bolus) injection, is not desired, such as when used for the purposes described herein.

[0399] In some cases, compared to intravenous infusion of the compounds described herein (e.g., Compound 1), the non - dose - dependent increase in diastolic blood pressure and (to a lesser extent) systolic blood pressure is more significant (e.g., accompanied by a reflex decrease in pulse rate). In some cases, after intravenous and subcutaneous administration of the compounds described herein (e.g., Compound 1), peripheral blood flow decreases.

[0400] In some cases, individuals receiving a certain dose of the compounds described herein (e.g., Compound 1) have adverse events (AE) (e.g., treatment-related). In some cases, the AE occurs at the start of the subcutaneous treatment period. In some cases, there are more AEs after subcutaneous administration compared to intravenous administration. In some cases, there are more AEs in females compared to males. In some cases, the AE has mild or moderate intensity. In some cases, the AE has severe intensity. In some cases, the AE of severe intensity is a mild elevation of troponin I.

[0401] In some cases, the compounds described herein (e.g., Compound 1) induce a reversible increase in diastolic blood pressure. In some cases, the compounds described herein (e.g., Compound 1) induce a reversible increase in systolic blood pressure. In some cases, the compounds described herein (e.g., Compound 1) induce a reversible increase in MAP. In some cases, the compounds described herein (e.g., Compound 1) induce a reversible increase in diastolic blood pressure and MAP. In some cases, the compounds described herein (e.g., Compound 1) induce a decrease in heart rate and cardiac output. In some cases, the evaluation of ECG, clinical chemistry, hematology, hemostasis, and urine analysis parameters does not provide any safety concerns for the compounds described herein (e.g., Compound 1).

[0402] In some cases, such as when administered as a single intravenous infusion, the compounds described herein (e.g., Compound 1) are safe and well-tolerated (e.g., in both males and females), such as at a dose of about 0.9 mg or less. In some cases, the maximum tolerated subcutaneous dose (MTD) of the compounds described herein (e.g., Compound 1) is about 0.1 mg.

[0403] In some cases, the pharmacokinetic parameters of the compounds described herein (e.g., in plasma for the 0.1 mg to 0.9 mg intravenous dose group) provide dose proportionality. In some cases, the pharmacokinetic parameters of the compounds described herein (e.g., in plasma for the 0.1 mg to 0.9 mg intravenous dose group) provide that non-dose-dependent PK parameters are comparable between dose groups (see Example 1). In some cases, males clear the compounds described herein (e.g., Compound 1) at a higher rate compared to females. In some cases, males administered the compounds described herein (e.g., Compound 1) have lower Compound C max . In some cases, males administered the compounds described herein (e.g., Compound 1) have lower Compound AUC compared to females. In some cases, males administered the compounds described herein (e.g., Compound 1) have lower Compound Cmax and AUC.

[0404] In some cases, such as after subcutaneous administration of the compounds described herein (e.g., Compound 1), t max is consistent between the first and fifth doses. In some cases, such as after subcutaneous administration of the compounds described herein (e.g., Compound 1), t 1 / 2 is consistent between the first and fifth doses. In some cases, such as after subcutaneous administration of the compounds described herein (e.g., Compound 1), t max and t 1 / 2 is consistent between the first and fifth doses. In some cases, such as after subcutaneous administration of the compounds described herein (e.g., Compound 1), the AUC is variable between the first and fifth doses. In some cases, such as after subcutaneous administration of the compounds described herein (e.g., Compound 1), C max is variable between the first and fifth doses. In some cases, such as after subcutaneous administration of the compounds described herein (e.g., Compound 1), the AUC and C max are variable between the first and fifth doses. In some cases, the AUC and C max show dose proportionality (e.g., only for C at the fifth administration max ).

[0405] In some cases, after intravenous administration, the terminal half-life of the compounds described herein (e.g., Compound 1) is about 1.5 hours. In some cases, after subcutaneous administration, the terminal half-life of the compounds described herein (e.g., Compound 1) is about 1 hour. In some cases, the terminal half-life of the compounds described herein (e.g., Compound 1) is comparable in males and females (e.g., indicating that absorption is not rate-limiting for elimination after subcutaneous administration, such as supported by a short time to C max (about 0.3 hours) and similar in both males and females). In some cases, the bioavailability of the compounds described herein (e.g., Compound 1) is about 18%. In some cases, the formation of metabolites after subcutaneous administration (such as producing metabolites and compounds with comparable concentrations) provides a bioavailability of about 18%. In some cases, after intravenous administration, the fraction of the unchanged excreted dose in urine is about <10%. In some cases, after subcutaneous administration, the fraction of the unchanged excreted dose of the compounds described herein (e.g., Compound 1) in urine is about <5%. In some cases, the fraction of the unchanged excreted dose of the compounds described herein (e.g., Compound 1) in urine is constant across the dose range (e.g., of the study provided in Example 1).

[0406] The presence of metabolite M1 (a full agonist) in plasma after subcutaneous administration (but present only at very low concentrations (<1% of Compound 1) after intravenous administration) demonstrates that Compound 1 is metabolized somewhere along the path between the subcutaneous tissue and the systemic circulation. In some cases, the half-life of M1 is longer than that of Compound 1 after intravenous and subcutaneous administrations. In some cases, the half-life of Compound 1 is shorter after subcutaneous administration compared to intravenous administration (e.g., approximately 2 hours and 4 hours, respectively). In some cases, the compounds described herein (e.g., Compound 1) are metabolized in the kidney.

[0407] In some cases, the pharmacodynamic effects of the compounds described herein (e.g., Compound 1) on blood pressure and heart rate are as expected for a vasopressin V1a specific agonist. In some cases, administration of the compounds described herein (e.g., Compound 1) to an individual provides an increase in the diastolic blood pressure of the individual. In some cases, administration of the compounds described herein (e.g., Compound 1) to an individual provides an increase in the systolic blood pressure of the individual. In some cases, administration of the compounds described herein (e.g., Compound 1) to an individual provides an increase in the MAP of the individual. In some cases, administration of the compounds described herein (e.g., Compound 1) to an individual provides a decrease in the pulse of the individual. In some cases, administration of the compounds described herein (e.g., Compound 1) to an individual provides a decrease in the peripheral blood flow of the individual. In some cases, the effects on blood pressure and heart rate are non-dose-dependent (e.g., the changes observed in the lowest dose group are roughly the same as those observed in the higher dose groups). In some cases, subcutaneous injection provides a more significant PD effect compared to the same dose administered intravenously (e.g., although the C max is approximately 50% lower). In some cases, the active metabolite M1 (e.g., a full V1a agonist) in plasma after subcutaneous administration (significantly) contributes to the total (e.g., local and / or systemic) V1a vasopressor activity, such as in individuals who have (critical) adverse events after administration of the compounds described herein by subcutaneous (bolus) injection. In some cases, increased M1 formation (such as after subcutaneous (bolus) injection) provides a significant reduction in the (systemic) delivery of Compound 1, such as resulting in unwanted effects (e.g., due to less delivery of the active agent (e.g., M1 or a mixed V1a agonist-antagonist described herein) and / or increased vasoconstriction, which may increase the risk of ischemia, cyanosis, pain, inflammation, and / or necrosis).

[0408] In some cases, the safety evaluation of the compounds described herein (e.g., Compound 1) provides an improved profile compared to other (e.g., non-selective) vasopressin receptor agonists described herein. In some cases, the absolute change in mean cardiac output is dose-dependent. In some cases, the relative change in mean cardiac output is comparable between doses (e.g., and well separated from placebo). In some cases, the reduction in an individual's cardiac output is about 20%-25% (e.g., as observed in all active agent treatment groups (including the placebo group), after intravenous and subcutaneous administration). In some cases, the reduction in cardiac output is secondary to a reduced heart rate. In some cases, ECG evaluations do not indicate any effects of the compounds described herein (e.g., Compound 1). In some cases, clinical laboratory parameters do not show any signs of cardiac or mesenteric ischemia (e.g., or adverse effects on the liver or kidneys).

[0409] In some cases, the adverse events in individuals receiving a partial agonist described herein (e.g., Compound 1) (e.g., intravenously or subcutaneously) are comparable to the pharmacological vasopressor activity of the compounds described herein (e.g., Compound 1 or vasopressin). For example, subcutaneous administration of the compounds described herein (e.g., Compound 1) provides (significantly) more AEs compared to intravenous administration (see Example 1). Additionally, the frequency of AEs after subcutaneous administration of the compounds described herein (e.g., Compound 1) decreases within 5 days of treatment. For example, in some cases, on Day 1, subcutaneous administration provides about 0.5-fold more AEs / administration compared to intravenous administration (e.g., although there were only 3 subjects receiving 0.3 mg subcutaneously compared to 35 subjects receiving 0.45 mg or higher doses intravenously). Additionally, subcutaneous administration of the partial agonist described herein (e.g., Compound 1) provides about 3-fold more AEs / administration compared to intravenous administration of the same compound (see Example 1). Given (1) the formation of M1 (a full (V1a) agonist) after subcutaneous administration of Compound 1, (2) the known toxicity of full vasopressin agonists and the resulting adverse events, (3) Compound 1 and M1 being present at approximately equimolar concentrations after subcutaneous administration of M1, and (4) the exposure to Compound 1 after subcutaneous administration (by C max and AUC) being lower than after intravenous infusion, the presence of M1 (rather than Compound 1) in plasma after subcutaneous administration results in the total V1a vasopressor activity and (e.g., amplified) pharmacological effects and / or AE profile after subcutaneous administration of Compound 1.

[0410] In addition, in view of the fact that the presence of the vasopressin receptor full agonist M1 results in an increased number of vasoconstriction-related AEs compared to much higher concentrations of Compound 1, further demonstrating (a similar combination of pharmacodynamics and adverse effects to Compound 1 over a wide concentration range), Compound 1 is a partial agonist and / or a mixed agonist-antagonist. In addition, the observations studied in Example 1 also demonstrate that the mechanism of action of the mixed agonist-antagonist caps one or more (local vasoconstriction) effects in an individual (and limits such effects to levels below the maximum possible level). As further support for this interpretation, studies with terlipressin (a V1A receptor full agonist) have demonstrated that the increases in blood pressure are greater than those provided in Example 1 (e.g., further supporting that the maximum pharmacodynamic effect of Compound 1 is "capped" and that Compound 1 is a V1A receptor partial agonist and / or a mixed agonist-antagonist).

[0411] In some cases, the pharmacological effects of the compounds described herein (e.g., Compound 1) are attributed to vasopressin V1a receptor agonism. In some cases, the lack of any effect on diuresis and hemostasis demonstrates a high degree of specificity for the V1a receptor (e.g., providing the desired pharmacological profile).

[0412] In some cases, the terminal half-life of the compounds described herein (e.g., Compound 1) is approximately 1.5 hours (after intravenous administration).

[0413] In some cases, the total clearance of the compounds described herein (e.g., Compound 1) is approximately 13 L / h (after intravenous administration).

[0414] In some cases, the terminal half-life of the compounds described herein (e.g., Compound 1) is approximately 1 hour (after subcutaneous administration). In some cases, the t max of the compounds described herein (e.g., Compound 1) is approximately 0.3 hours (after subcutaneous administration). In some cases, the bioavailability of the compounds described herein (e.g., Compound 1) is approximately 18% (without any apparent accumulation of the compounds described herein (e.g., Compound 1), such as after repeated subcutaneous administration).

[0415] In some cases, after intravenous administration of the compounds described herein (e.g., Compound 1), the increase in exposure of the compounds described herein (e.g., Compound 1) (e.g., by means of AUC and C max ) is approximately proportional for AUC and C max

[0416] In some cases, after intravenous infusion of the compounds described herein (e.g., Compound 1), the exposure of the compounds described herein (e.g., Compound 1) (by means of AUC and C max ​)Higher in females than in males.

[0417] In some cases, administration of a compound described herein (e.g., Compound 1) provides an increase in diastolic blood pressure in an individual receiving the compound. In some cases, administration of a compound described herein (e.g., Compound 1) provides an increase in systolic blood pressure in an individual receiving the compound. In some cases, administration of a compound described herein (e.g., Compound 1) provides an increase in MAP in an individual receiving the compound. In some cases, administration of a compound described herein (e.g., Compound 1) provides a reflex decrease in pulse rate in an individual receiving the compound (e.g., in an apparent non-dose-dependent manner).

[0418] In some cases, peripheral blood flow is reduced after intravenous and subcutaneous administration of a compound described herein (e.g., Compound 1).

[0419] In some cases, such as during subcutaneous administration of a compound described herein (e.g., Compound 1), an active metabolite M1 (a full (V1a) agonist) is produced, such as at concentrations comparable to those of Compound 1.

[0420] In some embodiments, such as those described in the studies provided in Example 6, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) reduces portal pressure (PP) (after subcutaneous administration), and there is no excessive vasoconstriction within a wide dose range (e.g., 10 μg / kg to 500 μg / kg of Compound 1), see Figure 16 and Figure 18 . In some embodiments, such as those described in the studies provided in Example 6, a compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) reduces PP (after subcutaneous administration) within a wide dose range (e.g., 10 μg / kg to 500 μg / kg of Compound 1), see Figure 16 and Figure 18 .

[0421] In some embodiments, the methods provided herein further include evaluating a biological sample (e.g., of an individual). In some embodiments, the method further includes evaluating a biomarker of a biological sample of an individual, such as the biomarker described in Example 6. In some embodiments, the biomarker (e.g., the amount or level of the biomarker) is compared to a control or standard (e.g., the amount or level of the biomarker).

[0422] In some embodiments, the biomarkers described herein, such as those described in Example 6, are evaluated at a first time point and a second time point. In some embodiments, the second time point is used to determine the reactivity or efficacy of a compound such as those described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1). In some embodiments, the second time point is an endpoint. In some instances, the endpoint is used to determine the amount or level of a biomarker sufficient to achieve the desired reactivity or efficacy of a compound such as those described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1). In some embodiments, the methods provided herein further comprise administering to an individual a compound such as those described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) at least until the level or amount of the (individual's) biomarker reaches the endpoint. In some embodiments, the method comprises continuing to administer the compound after the level or amount of the (individual's) biomarker reaches the endpoint.

[0423] In some embodiments, the level or amount of the biomarker described herein (such as those described in Example 6) is higher (e.g., at least 5% higher, at least 15% higher, at least 25% higher, at least 35% higher, at least 45% higher, at least 55% higher, at least 65% higher, at least 75% higher, at least 85% higher, at least 95% higher or more) at the second time point compared to the first time point.

[0424] In some embodiments, the level or amount of the biomarker described herein (such as those described in Example 6) is lower (e.g., up to 95% lower, up to 85% lower, up to 75% lower, up to 65% lower, up to 55% lower, up to 45% lower, up to 35% lower, up to 25% lower, up to 15% lower, up to 5% lower or more) at the second time point compared to the first time point.

[0425] In some embodiments, such as those described in the studies provided in Example 6, the compound described herein (e.g., a mixed V1AR agonist-antagonist such as Compound 1) increases mean arterial pressure (MAP) (after subcutaneous administration), such as within a wide dose range (e.g., 10 μg / kg to 500 μg / kg of Compound 1), see Figure 17 . In some embodiments, such as those described in the studies provided in Example 6, the increase in MAP reaches a peak plateau or therapeutic ceiling (e.g., the MAP increases by about 10 to about 15 mmHg), see Figure 17 . In some embodiments, such as those described in the studies provided in Example 6, the increase in MAP reaches a peak plateau or therapeutic ceiling (e.g., the MAP increases by about 10 to about 15 mmHg), accompanied by a decrease in PP (about 2 to about 14 mmHg), see Figure 17。In some cases, even after a 5-fold increase in dose (e.g., 100 μg / kg or 500 μg / kg of Compound 1), the compounds described herein do not produce a meaningful further change in effect, such as an increase in MAP, see Figure 17 。

[0426] In other cases, administration of a full V1a receptor agonist (such as terlipressin) provides a significantly higher increase in MAP (and outside the therapeutic window of 10 - 15 mmHg), such as although the decrease in PP is similar to those of the compounds described herein (e.g., mixed V1AR agonist - antagonist, such as Compound 1), see Figure 17 。

[0427] In some embodiments, provided herein is a method of treating a complication (such as HRS - AKI) of end - stage liver disease in an individual (e.g., in need), the method comprising administering to the individual a therapeutically effective amount of a compound described herein (e.g., Compound 1) or a pharmaceutically acceptable salt (e.g., acetate).

[0428] In some embodiments, the individual described herein has cirrhotic portal hypertension. In some embodiments, the individual described herein has end - stage liver disease (ESLD). In some embodiments, the individual described herein has HRS - AKI. In some embodiments, the individual described herein has developed HRS - AKI as a complication of ESLD.

[0429] In some embodiments, the compounds described herein (e.g., Compound 1) provide a significantly improved therapeutic index (e.g., caused by lower maximal vasoconstrictor effects and lower risk of tissue hypoxia), such as when compared to full V1A receptor agonists. In some embodiments, the compounds described herein (e.g., Compound 1) provide approximately half of the maximal vasoconstriction produced by the full agonist, such as without any accompanying signs of ischemia. In some embodiments, the compounds described herein (e.g., Compound 1) are (clinically) effective vasoconstrictors (e.g., having a favorable benefit / risk profile, such as having low to no organ toxicity).

[0430] In some embodiments, provided herein is a method of treating hepatorenal syndrome with acute kidney injury (HRS - AKI) in an individual (e.g., in need), the method comprising administering to the individual a therapeutically effective amount of a compound described herein (e.g., Compound 1) or a pharmaceutically acceptable salt (e.g., acetate).

[0431] In some embodiments, provided herein are methods of treating acute hepatorenal syndrome with acute kidney injury (HRS-AKI) in an individual (such as an individual who has developed HRS-AKI as a complication of cirrhosis with ascites), the method comprising administering to the individual a therapeutically effective amount of a compound described herein (e.g., Compound 1) or a pharmaceutically acceptable salt (e.g., acetate).

[0432] In some embodiments, the individual has end-stage liver disease (ESLD). In some embodiments, the individual has HRS-AKI as a complication of end-stage liver disease (ESLD). In some embodiments, the individual has developed HRS-AKI as a complication of end-stage liver disease (ESLD).

[0433] 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.

[0434] In some embodiments, a therapeutically effective amount of the compound described herein (e.g., Compound 1) or a pharmaceutically acceptable salt (e.g., acetate) is from about 5 μg to about 55 μg. In some embodiments, a therapeutically effective amount of the compound described herein (e.g., Compound 1) or a pharmaceutically acceptable salt (e.g., acetate) is from about 8 μg to about 50 μg. In some embodiments, a therapeutically effective amount of the compound described herein (e.g., Compound 1) or a pharmaceutically acceptable salt (e.g., acetate) is from about 20 μg to about 35 μg. In some embodiments, a therapeutically effective amount of the compound described herein (e.g., Compound 1) or a pharmaceutically acceptable salt (e.g., acetate) is from about 25 μg to about 35 μg. In some embodiments, a therapeutically effective amount of the compound described herein (e.g., Compound 1) or a pharmaceutically acceptable salt (e.g., acetate) is about 30 μg. In some embodiments, a therapeutically effective amount of the compound described herein (e.g., Compound 1) or a pharmaceutically acceptable salt (e.g., acetate) is administered for several days (e.g., up to 10 days) over a period of time (such as over several hours (e.g., continuously for up to 24 h)).

[0435] In some embodiments, the compound described herein (e.g., Compound 1) or a pharmaceutically acceptable salt (e.g., acetate) is administered intravenously to the individual. In some embodiments, Compound 1 or a pharmaceutically acceptable salt (e.g., acetate) is administered to the individual by intravenous infusion.

[0436] In some embodiments, the compound described herein (e.g., Compound 1) or a pharmaceutically acceptable salt (e.g., acetate) is administered subcutaneously to the individual. In some embodiments, Compound 1 or a pharmaceutically acceptable salt (e.g., acetate) is administered to the individual by subcutaneous injection.

[0437] In some embodiments, a therapeutically effective amount of the compounds described herein (e.g., Compound 1) or a pharmaceutically acceptable salt thereof (e.g., acetate) is about 5 μg / h or more. In some embodiments, a therapeutically effective amount of the compounds described herein (e.g., Compound 1) or a pharmaceutically acceptable salt thereof (e.g., acetate) is about 55 μg / h or less. In some embodiments, a therapeutically effective amount of the compounds described herein (e.g., Compound 1) or a pharmaceutically acceptable salt thereof (e.g., acetate) is from about 5 μg / h to about 55 μg / h. In some embodiments, a therapeutically effective amount of the compounds described herein (e.g., Compound 1) or a pharmaceutically acceptable salt thereof (e.g., acetate) is from about 8 μg / h to about 50 μg / h. In some embodiments, a therapeutically effective amount of the compounds described herein (e.g., Compound 1) or a pharmaceutically acceptable salt thereof (e.g., acetate) is from about 20 μg / h to about 35 μg / h. In some embodiments, a therapeutically effective amount of the compounds described herein (e.g., Compound 1) or a pharmaceutically acceptable salt thereof (e.g., acetate) is from about 25 μg / h to about 35 μg / h. In some embodiments, a therapeutically effective amount of the compounds described herein (e.g., Compound 1) or a pharmaceutically acceptable salt thereof (e.g., acetate) is about 30 μg / h.

[0438] In some embodiments, the compounds described herein (e.g., Compound 1) or a pharmaceutically acceptable salt thereof (e.g., acetate) are administered to an individual on the first and second days. In some embodiments, the compounds described herein (e.g., Compound 1) or a pharmaceutically acceptable salt thereof (e.g., acetate) are administered to an individual (e.g., subcutaneously) one or more days after the first day. In some embodiments, on the first day, an individual receives an initial (e.g., intravenous infusion) dose of the compounds described herein (e.g., Compound 1) or a pharmaceutically acceptable salt thereof (e.g., acetate). In some embodiments, on the first day, an individual receives an initial (e.g., intravenous infusion) dose of the compounds described herein (e.g., Compound 1) or a pharmaceutically acceptable salt thereof (e.g., acetate) to acclimatize the individual to vasoconstriction, and then, for example, on the second day, receives a first designated (e.g., subcutaneous) therapeutic dose.

[0439] In some embodiments, the compounds provided herein are administered to an individual (e.g., in need) in an amount of about 0.01 milligrams (mg) or more. In some embodiments, the compounds provided herein are administered to an individual (e.g., in need) in an amount of about 0.1 mg or more. In some embodiments, the compounds provided herein are administered to an individual (e.g., in need) in an amount of about 0.3 mg or more. In some embodiments, the compounds provided herein are administered to an individual (e.g., in need) in an amount of about 0.45 mg or more. In some embodiments, the compounds provided herein are administered to an individual (e.g., in need) in an amount of about 0.6 mg or more. In some embodiments, the compounds provided herein are administered to an individual (e.g., in need) in an amount of about 0.9 mg or more. In some embodiments, the compounds provided herein are administered to an individual (e.g., in need) in an amount of about 10 mg or more. In some embodiments, the compounds provided herein are administered to an individual (e.g., in need) in an amount of about 20 mg or more. In some embodiments, the compounds provided herein are administered to an individual (e.g., in need) in an amount of about 30 mg or more. In some embodiments, the compounds provided herein are administered to an individual (e.g., in need) in an amount of about 40 mg or more. In some embodiments, the compounds provided herein are administered to an individual (e.g., in need) in an amount of about 50 mg or more. In some embodiments, the compounds provided herein are administered to an individual (e.g., in need) in an amount of about 0.01 mg to about 50 mg. In some embodiments, the compounds provided herein are administered to an individual (e.g., in need) in an amount of about 0.01 mg to about 10 mg. In some embodiments, the compounds provided herein are administered to an individual (e.g., in need) in an amount of about 0.01 mg to about 1 mg.

[0440] In some embodiments, the initial (e.g., intravenous infusion) dose is about 0.01 milligrams (mg) or more. In some embodiments, the initial (e.g., intravenous infusion) dose is about 0.1 mg or more. In some embodiments, the initial (e.g., intravenous infusion) dose is about 0.3 mg or more. In some embodiments, the initial (e.g., intravenous infusion) dose is about 0.45 mg or more. In some embodiments, the initial (e.g., intravenous infusion) dose is about 0.6 mg or more. In some embodiments, the initial (e.g., intravenous infusion) dose is about 0.9 mg or more. In some embodiments, the initial (e.g., intravenous infusion) dose is about 10 mg or more. In some embodiments, the initial (e.g., intravenous infusion) dose is about 20 mg or more. In some embodiments, the initial (e.g., intravenous infusion) dose is about 30 mg or more. In some embodiments, the initial (e.g., intravenous infusion) dose is about 40 mg or more. In some embodiments, the initial (e.g., intravenous infusion) dose is about 50 mg or more. In some embodiments, the initial (e.g., intravenous infusion) dose is from about 0.01 mg to about 50 mg. In some embodiments, the initial (e.g., intravenous infusion) dose is from about 0.01 mg to about 10 mg. In some embodiments, the initial (e.g., intravenous infusion) dose is from about 0.01 mg to about 1 mg.

[0441] In some embodiments, the dose administered after the initial dose (e.g., subcutaneously) is about 0.01 milligrams (mg) or more. In some embodiments, the dose administered after the initial dose (e.g., subcutaneously) is about 0.1 mg or more. In some embodiments, the dose administered after the initial dose (e.g., subcutaneously) is about 0.3 mg or more. In some embodiments, the dose administered after the initial dose (e.g., subcutaneously) is about 0.45 mg or more. In some embodiments, the dose administered after the initial dose (e.g., subcutaneously) is about 0.6 mg or more. In some embodiments, the dose administered after the initial dose (e.g., subcutaneously) is about 0.9 mg or more. In some embodiments, the dose administered after the initial dose (e.g., subcutaneously) is about 10 mg or more. In some embodiments, the dose administered after the initial dose (e.g., subcutaneously) is about 20 mg or more. In some embodiments, the dose administered after the initial dose (e.g., subcutaneously) is about 30 mg or more. In some embodiments, the dose administered after the initial dose (e.g., subcutaneously) is about 40 mg or more. In some embodiments, the dose administered after the initial dose (e.g., subcutaneously) is about 50 mg or more. In some embodiments, the dose administered after the initial dose (e.g., subcutaneously) is from about 0.01 mg to about 50 mg. In some embodiments, the dose administered after the initial dose (e.g., subcutaneously) is from about 0.01 mg to about 10 mg. In some embodiments, the dose administered after the initial dose (e.g., subcutaneously) is from about 0.01 mg to about 1 mg.

[0442] In some embodiments, the initial (e.g., intravenous infusion) dose of the compounds described herein (e.g., Compound 1) or a pharmaceutically acceptable salt thereof (e.g., acetate) is a low dose. In some embodiments, the initial (e.g., intravenous infusion) dose of the compounds described herein (e.g., Compound 1) or a pharmaceutically acceptable salt thereof (e.g., acetate) is a dose from about 5 μg / h to about 15 μg / h. In some embodiments, the initial (e.g., intravenous infusion) dose of the compounds described herein (e.g., Compound 1) or a pharmaceutically acceptable salt thereof (e.g., acetate) is a dose of about 8 μg / h.

[0443] In some embodiments, on the first day, the compounds described herein (e.g., Compound 1) or a pharmaceutically acceptable salt thereof (e.g., acetate) are administered to an individual (e.g., by intravenous infusion) for a period of about 4 h to about 8 h. In some embodiments, on the first day, the compounds described herein (e.g., Compound 1) or a pharmaceutically acceptable salt thereof (e.g., acetate) are administered to an individual (e.g., by intravenous infusion) for a period of about 6 h.

[0444] In some embodiments, a first dose of a compound or a pharmaceutically acceptable salt thereof is administered to an individual on a first day, and a second dose is administered to the individual on a second day. In some embodiments, the first dose and the second dose comprise the same amount of the compound or a pharmaceutically acceptable salt thereof.

[0445] In some embodiments, the compounds or pharmaceutically acceptable salts thereof (e.g., Compound 1) described herein are administered to an individual (e.g., as described herein) (e.g., subcutaneously) in an amount of about 0.01 milligram (mg) / day or more. In some embodiments, the compounds or pharmaceutically acceptable salts thereof (e.g., Compound 1) described herein are administered to an individual (e.g., as described herein) (e.g., subcutaneously) in an amount of about 0.1 mg / day or more. In some embodiments, the compounds or pharmaceutically acceptable salts thereof (e.g., Compound 1) described herein are administered to an individual (e.g., as described herein) (e.g., subcutaneously) in an amount of about 0.3 mg / day or more. In some embodiments, the compounds or pharmaceutically acceptable salts thereof (e.g., Compound 1) described herein are administered to an individual (e.g., as described herein) (e.g., subcutaneously) in an amount of about 0.45 mg / day or more. In some embodiments, the compounds or pharmaceutically acceptable salts thereof (e.g., Compound 1) described herein are administered to an individual (e.g., as described herein) (e.g., subcutaneously) in an amount of about 0.6 mg / day or more. In some embodiments, the compounds or pharmaceutically acceptable salts thereof (e.g., Compound 1) described herein are administered to an individual (e.g., as described herein) (e.g., subcutaneously) in an amount of about 0.9 mg / day or more. In some embodiments, the compounds or pharmaceutically acceptable salts thereof (e.g., Compound 1) described herein are administered to an individual (e.g., as described herein) (e.g., subcutaneously) in an amount of about 10 mg / day or more. In some embodiments, the compounds or pharmaceutically acceptable salts thereof (e.g., Compound 1) described herein are administered to an individual (e.g., as described herein) (e.g., subcutaneously) in an amount of about 50 mg / day or more. In some embodiments, the compounds or pharmaceutically acceptable salts thereof (e.g., Compound 1) described herein are administered to an individual (e.g., as described herein) (e.g., subcutaneously) in an amount of about 100 mg / day or more. In some embodiments, the compounds or pharmaceutically acceptable salts thereof (e.g., Compound 1) described herein are administered to an individual (e.g., as described herein) (e.g., subcutaneously) in an amount of about 100 mg / day or less. In some embodiments, the compounds or pharmaceutically acceptable salts thereof (e.g., Compound 1) described herein are administered to an individual (e.g., as described herein) (e.g., subcutaneously) in an amount of about 50 mg / day or less. In some embodiments, the compounds or pharmaceutically acceptable salts thereof (e.g., Compound 1) described herein are administered to an individual (e.g., as described herein) (e.g., subcutaneously) in an amount of about 10 mg / day or less. In some embodiments, the compounds or pharmaceutically acceptable salts thereof (e.g., Compound 1) described herein are administered to an individual (e.g., as described herein) (e.g., subcutaneously) in an amount of about 1 mg / day or less. In some embodiments, the compounds or pharmaceutically acceptable salts thereof (e.g., Compound 1) described herein are administered to an individual (e.g., as described herein) (e.g., subcutaneously) in an amount of about 0.1 mg / day or less.In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof (e.g., Compound 1) are administered to an individual (e.g., as described herein) (e.g., subcutaneously) in an amount of from about 0.01 mg / day to about 100 mg / day. In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof (e.g., Compound 1) are administered to an individual (e.g., as described herein) (e.g., subcutaneously) in an amount of from about 0.01 mg / day to about 10 mg / day. In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof (e.g., Compound 1) are administered to an individual (e.g., as described herein) (e.g., subcutaneously) in an amount of from about 0.01 mg / day to about 1 mg / day.

[0446] In some embodiments, the compounds described herein (e.g., Compound 1) or pharmaceutically acceptable salts thereof (e.g., acetate) are administered to an individual (e.g., subcutaneously) over multiple days (e.g., for 5 consecutive days). In some embodiments, the method comprises administering the compounds described herein (e.g., Compound 1) or pharmaceutically acceptable salts thereof (e.g., acetate) to an individual (e.g., subcutaneously) on one or more days. In some embodiments, the compounds described herein (e.g., Compound 1) or pharmaceutically acceptable salts thereof (e.g., acetate) are administered to an individual (e.g., subcutaneously) on subsequent days. In some embodiments, the method comprises administering the compounds described herein (e.g., Compound 1) or pharmaceutically acceptable salts thereof (e.g., acetate) to an individual (e.g., subcutaneously) on consecutive days and / or non-consecutive days. In some embodiments, the method comprises administering the compounds described herein (e.g., Compound 1) or pharmaceutically acceptable salts thereof (e.g., acetate) to an individual (e.g., subcutaneously) on one day or on consecutive multiple days. In some embodiments, the method comprises administering the compounds described herein (e.g., Compound 1) or pharmaceutically acceptable salts thereof (e.g., acetate) to an individual (e.g., subcutaneously) on one day or on non-consecutive multiple days. In some embodiments, the method comprises administering the compounds described herein (e.g., Compound 1) or pharmaceutically acceptable salts thereof (e.g., acetate) to an individual (e.g., subcutaneously) on one day or on consecutive multiple days after the first day. In some embodiments, the method comprises administering the compounds described herein (e.g., Compound 1) or pharmaceutically acceptable salts thereof (e.g., acetate) to an individual (e.g., subcutaneously) on one day or on non-consecutive multiple days after the first day.

[0447] In some embodiments, the method comprises administering to an individual (e.g., subcutaneously) a compound described herein (e.g., Compound 1) or a pharmaceutically acceptable salt (e.g., acetate) for at least two days. In some embodiments, the method comprises administering to an individual (e.g., subcutaneously) a compound described herein (e.g., Compound 1) or a pharmaceutically acceptable salt (e.g., acetate) for five or more days. In some embodiments, the method comprises administering to an individual (e.g., subcutaneously) a compound described herein (e.g., Compound 1) or a pharmaceutically acceptable salt (e.g., acetate) for ten or more days.

[0448] In some embodiments, the method comprises administering to an individual (e.g., subcutaneously) a compound described herein (e.g., Compound 1) or a pharmaceutically acceptable salt (e.g., acetate) for one week or longer.

[0449] In some embodiments, the method comprises administering to an individual (e.g., subcutaneously) a compound described herein (e.g., Compound 1) or a pharmaceutically acceptable salt (e.g., acetate) for one month or longer.

[0450] In some embodiments, the method comprises administering to an individual (e.g., subcutaneously) a compound described herein (e.g., Compound 1) or a pharmaceutically acceptable salt (e.g., acetate) for one year or longer.

[0451] In some embodiments, the method comprises administering to an individual (e.g., subcutaneously) a compound described herein (e.g., Compound 1) or a pharmaceutically acceptable salt (e.g., acetate) for up to 11 days, such as for up to 10 days after the first day. In some embodiments, the method comprises administering to an individual (e.g., subcutaneously) a compound described herein (e.g., Compound 1) or a pharmaceutically acceptable salt (e.g., acetate) for 4 to 10 days. In some embodiments, the method comprises administering to an individual (e.g., subcutaneously) a compound described herein (e.g., Compound 1) or a pharmaceutically acceptable salt (e.g., acetate) for 4 to 10 days after the first day. In some embodiments, the method comprises administering to an individual (e.g., subcutaneously) a compound described herein (e.g., Compound 1) or a pharmaceutically acceptable salt (e.g., acetate) for up to 9 days. In some embodiments, the days are consecutive days. In some embodiments, the days are non - consecutive days. In some embodiments, the method comprises administering to an individual a compound described herein (e.g., Compound 1) or a pharmaceutically acceptable salt (e.g., acetate) (e.g., via continuous intravenous infusion) within a 24 - h time period.

[0452] In some embodiments, the method comprises administering to an individual, via continuous intravenous infusion, the compounds (e.g., Compound 1) or pharmaceutically acceptable salts (e.g., acetate) described herein for up to 9 days within a 24-hour period each day. In some embodiments, the method comprises administering subcutaneously to an individual the compounds (e.g., Compound 1) or pharmaceutically acceptable salts (e.g., acetate) described herein (e.g., for up to 5 days). In some embodiments, the compounds (e.g., Compound 1) or pharmaceutically acceptable salts (e.g., acetate) described herein are administered to an individual in an amount of up to about 2 milligrams (mg) / day. In some embodiments, the compounds (e.g., Compound 1) or pharmaceutically acceptable salts (e.g., acetate) described herein are administered to an individual in an amount of about 0.2 mg / day to about 2 mg / day. In some embodiments, the compounds (e.g., Compound 1) or pharmaceutically acceptable salts (e.g., acetate) described herein are administered to an individual in an amount of about 0.5 mg / day to about 1.5 mg / day. In some embodiments, the compounds (e.g., Compound 1) or pharmaceutically acceptable salts (e.g., acetate) described herein are administered to an individual in an amount of about 1.2 mg / day.

[0453] In some embodiments, an individual (e.g., as described herein) receives repeated subcutaneous injections of the compounds or pharmaceutically acceptable salts thereof (e.g., Compound 1) described herein. In some embodiments, the compounds or pharmaceutically acceptable salts thereof (e.g., Compound 1) described herein are administered subcutaneously to an individual (e.g., as described herein) once daily. In some embodiments, the compounds or pharmaceutically acceptable salts thereof (e.g., Compound 1) described herein are administered subcutaneously to an individual (e.g., as described herein) once daily for two or more consecutive days. In some embodiments, the compounds or pharmaceutically acceptable salts thereof (e.g., Compound 1) described herein are administered subcutaneously to an individual (e.g., as described herein) once daily for three or more consecutive days. In some embodiments, the compounds or pharmaceutically acceptable salts thereof (e.g., Compound 1) described herein are administered subcutaneously to an individual (e.g., as described herein) once daily for four or more consecutive days. In some embodiments, the compounds or pharmaceutically acceptable salts thereof (e.g., Compound 1) described herein are administered subcutaneously to an individual (e.g., as described herein) once daily for five or more consecutive days.

[0454] In some embodiments, in some embodiments, the compounds or pharmaceutically acceptable salts thereof (e.g., Compound 1) described herein are administered to an individual (e.g., as described herein) via subcutaneous bolus injection.

[0455] In some embodiments, the compounds or pharmaceutically acceptable salts thereof (e.g., Compound 1) described herein are administered to an individual (e.g., as described herein) via subcutaneous infusion. In some embodiments, the compounds or pharmaceutically acceptable salts thereof (e.g., Compound 1) described herein are administered to an individual (e.g., as described herein) via continuous subcutaneous infusion.

[0456] Unless otherwise stated, a composition for subcutaneous administration means a composition that is suitable for systemic delivery of an active agent or API (e.g., Compound 1) when administered subcutaneously.

[0457] Unless otherwise stated, formulation means a composition that contains excipients such as stabilizers or diluents.

[0458] Unless otherwise stated, the weight (e.g., dose) of the compounds (e.g., Compound 1) described herein provided herein is calculated based on the free base of the compound (e.g., not the pharmaceutically acceptable salt of the compound). In some cases, an acceptable salt of the compounds (e.g., Compound 1) described herein provided herein is administered to an individual receiving the treatment provided herein.

[0459] In some cases, the compounds described herein (e.g., mixed V1AR agonist - antagonists such as Compound 1) have an effect (e.g., increase or decrease) on the levels of the biomarkers described herein (e.g., the biomarkers described in Examples 5 or 6). In some embodiments, the biomarkers described herein are selected from the group consisting of: mean arterial pressure (MAP), (plasma) aldosterone, (plasma) renin, ascites volume, body weight, urine volume, (net) fluid balance, urinary sodium, urinary potassium, portal venous pressure, cardiac output, systemic vascular resistance, BUN, BUN / CREA, PHOS, spleen weight, skin blood flow (SBF), blood lactate concentration, heart rate, arterial systolic pressure, arterial diastolic pressure, and blood pH. In some embodiments, the biomarker described herein is mean arterial pressure (MAP). In some embodiments, the biomarker described herein is aldosterone. In some embodiments, the biomarker described herein is renin. In some embodiments, the biomarker described herein is ascites volume. In some embodiments, the biomarker described herein is body weight. In some embodiments, the biomarker described herein is urine volume. In some embodiments, the biomarker described herein is net fluid balance. In some embodiments, the biomarker described herein is urinary sodium. In some embodiments, the biomarker described herein is urinary potassium. In some embodiments, the biomarker described herein is spleen weight. In some embodiments, the biomarker described herein is arterial systolic pressure. In some embodiments, the biomarker described herein is arterial diastolic pressure. In some embodiments, the biomarker described herein is heart rate. In some embodiments, the biomarker described herein is portal venous pressure. In some embodiments, the biomarker described herein is skin blood flow (SBF). In some embodiments, the biomarker described herein is blood lactate concentration. In some embodiments, the biomarker described herein is heart rate. In some embodiments, the biomarker described herein is arterial systolic pressure. In some embodiments, the biomarker described herein is arterial diastolic pressure.

[0460] In some embodiments, the compounds described herein (e.g., mixed V1AR agonist - antagonists such as Compound 1) increase the mean arterial pressure, arterial systolic pressure, and arterial diastolic pressure of an individual (e.g., a mammal), such as after subcutaneous administration (e.g., see Figures 24A - 24C)。In some cases, the occurrence and magnitude of the maximum blood pressure increase are related to the dose of the compounds described herein (e.g., mixed V1AR agonist - antagonists such as compound 1) in an individual (e.g., a mammal), such as after subcutaneous administration. In some embodiments, the compounds described herein (e.g., mixed V1AR agonist - antagonists such as compound 1) increase the mean arterial pressure (MAP) of an individual (e.g., a mammal) by at least about 10 mmHg (e.g., at least 15 mmHg, at least 20 mmHg, at least 30 mmHg, at least 40 mmHg), such as after subcutaneous administration (e.g., see Figure 26A )。In some embodiments, the compounds described herein (e.g., mixed V1AR agonist - antagonists such as compound 1) increase the mean arterial pressure (MAP) of an individual (e.g., a mammal) by at most about 50 mmHg (e.g., at most 40 mmHg, at most 30 mmHg, at most 20 mmHg, at most 10 mmHg), such as after subcutaneous administration. In some embodiments, the compounds described herein (e.g., mixed V1AR agonist - antagonists such as compound 1) increase the mean arterial pressure (MAP) of an individual (e.g., a mammal) by about 10 mmHg to about 50 mmHg, such as after subcutaneous administration. In some embodiments, the compounds described herein (e.g., mixed V1AR agonist - antagonists such as compound 1) increase the mean arterial pressure (MAP) of an individual (e.g., a mammal) by about 20 mmHg, such as after subcutaneous administration. In some embodiments, the compounds described herein (e.g., mixed V1AR agonist - antagonists such as compound 1) increase the mean arterial pressure (MAP) of an individual (e.g., a mammal) by about 40 mmHg, such as after subcutaneous administration. In some embodiments, the compounds described herein (e.g., mixed V1AR agonist - antagonists such as compound 1) increase the mean arterial pressure (MAP) of an individual (e.g., a mammal) by about 25 mmHg, such as after subcutaneous administration. In some embodiments, the compounds described herein (e.g., mixed V1AR agonist - antagonists such as compound 1) increase the mean arterial pressure (MAP) of an individual (e.g., a mammal) and maintain the increase for at least 75 minutes (e.g., at least 150 minutes, at least 300 minutes), such as after subcutaneous administration. In some cases, the compounds described herein (e.g., mixed V1AR agonist - antagonists such as compound 1) provide a change in the mean arterial pressure (MAP) of an individual (e.g., a mammal) that is statistically different from that of the vehicle, such as after subcutaneous administration. In some embodiments, the compounds described herein (e.g., mixed V1AR agonist - antagonists such as compound 1) increase the MAP of an individual (e.g., a mammal) and the MAP does not return to the baseline value, such as after subcutaneous administration.

[0461] In some embodiments, a full antagonist (such as terlipressin) increases the mean arterial pressure (MAP) of an individual (e.g., a mammal) (e.g., see Figure 26B ). In some embodiments, after intravenous administration, a full antagonist (such as terlipressin) increases the mean arterial pressure (MAP), and the effect lasts only for a short period of time, such as less than 90 minutes (e.g., not longer than 30, 75, or 90 minutes) (e.g., see Figure 26B ). In some embodiments, a full antagonist (such as terlipressin) provides an instantaneous effect on MAP (e.g., see Figure 26B ). In some embodiments, the compounds described herein (e.g., a mixed V1AR agonist - antagonist, such as Compound 1) provide an increase in MAP across a 50 - fold dose range in an individual (e.g., a mammal), which in some cases can represent the maximal effect on arterial pressure.

[0462] In some embodiments, the compounds described herein (e.g., a mixed V1AR agonist - antagonist, such as Compound 1) decrease the heart rate of an individual (e.g., a mammal), such as after subcutaneous administration, see Figure 24D . In some embodiments, the compounds described herein (e.g., a mixed V1AR agonist - antagonist, such as Compound 1) decrease the heart rate of an individual (e.g., a mammal) by at least 2% (e.g., at least 5%, at least 10%, at least 15%), such as after subcutaneous administration (e.g., see Figure 24D ). In some embodiments, the compounds described herein (e.g., a mixed V1AR agonist - antagonist, such as Compound 1) decrease the heart rate of an individual (e.g., a mammal) by at most 20% (e.g., at most 15%, at most 10%, at most 5%), such as after subcutaneous administration (e.g., see Figure 24D ). In some embodiments, the compounds described herein (e.g., a mixed V1AR agonist - antagonist, such as Compound 1) decrease the heart rate of an individual (e.g., a mammal) by about 5%, such as after subcutaneous administration (e.g., see Figure 24D ). In some cases, the compounds described herein (e.g., a mixed V1AR agonist - antagonist, such as Compound 1) provide a change in MAP associated with a measurable decrease in the heart rate of an individual (e.g., a mammal), such as after subcutaneous administration (e.g., see Figure 24D , Figure 26A ). In some cases, for the compounds described herein (e.g., a mixed V1AR agonist - antagonist, such as Compound 1), changes in systolic and diastolic blood pressure are associated with changes in the MAP of an individual (e.g., a mammal), such as after subcutaneous administration (e.g., see Figures 24A - 24C ).

[0463] In some embodiments, the compounds described herein (e.g., mixed V1AR agonist-antagonists such as Compound 1) have a terminal half-life (t 1 / 2term ) of at least 50 minutes (e.g., at least 70 minutes, at least 90 minutes, at least 110 minutes, at least 130 minutes) in an individual (e.g., a mammal), such as after subcutaneous administration. In some embodiments, the compounds described herein (e.g., mixed V1AR agonist-antagonists such as Compound 1) have a terminal half-life (t 1 / 2term ) of at most 150 minutes (e.g., at most 130 minutes, at most 110 minutes, at most 90 minutes, at most 70 minutes) in an individual (e.g., a mammal), such as after subcutaneous injection. In some embodiments, the compounds described herein (e.g., mixed V1AR agonist-antagonists such as Compound 1) have a terminal half-life (t 1 / 2term ) of about 50 to about 150 minutes in an individual (e.g., a mammal), such as after subcutaneous injection. In some embodiments, the compounds described herein (e.g., mixed V1AR agonist-antagonists such as Compound 1) have a terminal half-life (t 1 / 2term ) of about 110 minutes in an individual (e.g., a mammal), such as after subcutaneous injection. In some embodiments, the compounds described herein (e.g., mixed V1AR agonist-antagonists such as Compound 1) have an elimination half-life (t 1 / 2elim ) of at least 1 minute (e.g., at least 5 minutes, at least 10 minutes, at least 15 minutes, at least 20 minutes) in an individual (e.g., a mammal), such as after intravenous administration. In some embodiments, the compounds described herein (e.g., mixed V1AR agonist-antagonists such as Compound 1) have an elimination half-life (t 1 / 2elim ) of at most 60 minutes (e.g., at most 40 minutes, at most 20 minutes, at most 10 minutes). In some embodiments, the compounds described herein (e.g., mixed V1AR agonist-antagonists such as Compound 1) have an elimination half-life (t 1 / 2elim ) of about 1 minute to about 40 minutes in an individual (e.g., a mammal). In some embodiments, the compounds described herein (e.g., mixed V1AR agonist-antagonists such as Compound 1) have an elimination half-life (t 1 / 2elim ) of about 20 minutes. In some embodiments, after subcutaneous administration, the terminal half-life (t 1 / 2term ) of the compound is greater than the elimination half-life (t 1 / 2elim ).

[0464] In some embodiments, the compounds described herein (e.g., the hybrid V1AR agonist - antagonists such as Compound 1) have a bioavailability of at least 40% (e.g., at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%) in an individual (e.g., a mammal), such as after subcutaneous administration. In some embodiments, the compounds described herein (e.g., the hybrid V1AR agonist - antagonists such as Compound 1) have a bioavailability of at most 75% (e.g., at most 70%, at most 60%, at most 50%, at most 40%) in an individual (e.g., a mammal). In some embodiments, the compounds described herein (e.g., the hybrid V1AR agonist - antagonists such as Compound 1) have a bioavailability of from about 40% to about 70% in an individual (e.g., a mammal). In some embodiments, the compounds described herein (e.g., the hybrid V1AR agonist - antagonists such as Compound 1) have a bioavailability of about 60% in an individual (e.g., a mammal).

[0465] In some embodiments, the compounds described herein (e.g., the hybrid V1AR agonist - antagonists such as Compound 1) have a clearance rate similar to the glomerular filtration rate (e.g., 5 - 15 mL / min / kg) in an individual (e.g., a mammal), such as after subcutaneous administration. In some embodiments, the compounds described herein (e.g., the hybrid V1AR agonist - antagonists such as Compound 1) have a filtration rate of at least 5 mL / min / kg (e.g., at least 7 mL / min / kg, at least 10 mL / min / kg, at least 13 mL / min / kg). In some embodiments, the compounds described herein (e.g., the hybrid V1AR agonist - antagonists such as Compound 1) have a filtration rate of at most 25 mL / min / kg (e.g., at most 22 mL / min / kg, at most 18 mL / min / kg, at most 15 mL / min / kg). In some embodiments, the compounds described herein (e.g., the hybrid V1AR agonist - antagonists such as Compound 1) have a filtration rate of about 20 mL / min / kg. In some embodiments, the compounds described herein (e.g., the hybrid V1AR agonist - antagonists such as Compound 1) have a filtration rate of about 10 mL / min / kg.

[0466] In some embodiments, the compounds described herein (e.g., the hybrid V1AR agonist - antagonists such as Compound 1) reduce the skin blood flow in an individual (e.g., a mammal), such as after intravenous administration (e.g., see Figure 23A)。In some embodiments, the compounds described herein (e.g., mixed V1AR agonist - antagonists such as Compound 1) reduce cutaneous blood flow in an individual (e.g., a mammal) by up to 60% (e.g., up to 55%, up to 50%, up to 45%, up to 40%). In some embodiments, the compounds described herein (e.g., mixed V1AR agonist - antagonists such as Compound 1) reduce cutaneous blood flow in an individual (e.g., a mammal) by at least 10% (e.g., at least 20%, at least 30%, at least 40%, at least 50%). In some embodiments, the compounds described herein (e.g., mixed V1AR agonist - antagonists such as Compound 1) reduce cutaneous blood flow in an individual (e.g., a mammal) by about 20% to about 60%. In some embodiments, the compounds described herein (e.g., mixed V1AR agonist - antagonists such as Compound 1) reduce cutaneous blood flow in an individual (e.g., a mammal) by about 40%. In some embodiments, the compounds described herein (e.g., mixed V1AR agonist - antagonists such as Compound 1) reduce cutaneous blood flow in an individual (e.g., a mammal) less than vasopressin reduces cutaneous blood flow in an individual (e.g., a mammal), such as after intravenous administration, e.g., see Figure 23A . In some cases, the compounds described herein (e.g., mixed V1AR agonist - antagonists such as Compound 1) reduce cutaneous blood flow in an individual (e.g., a mammal) by about 40% after intravenous administration, and vasopressin reduces cutaneous blood flow in an individual (e.g., a mammal) by about 90% after intravenous administration, demonstrating that the mixed V1AR agonist - antagonists described herein (such as Compound 1) are more suitable for intravenous administration compared to a fully non - selective (V2, V1a) agonist (e.g., vasopressin or terlipressin), such as by reducing (significant) injection site reactions (e.g., local vasoconstriction) that prevent systemic delivery of the drug. In some cases, the lesser reduction in cutaneous blood flow of the compounds provided herein (e.g., mixed V1AR agonist - antagonists such as Compound 1) compared to vasopressin demonstrates less local vasoconstriction compared to vasopressin.

[0467] In some cases, increased serum lactate levels are a clinical marker of anaerobic metabolism and tissue hypoxia and are used as a surrogate marker for the development of vasoconstriction and tissue ischemia. In some embodiments, the compounds described herein (e.g., mixed V1AR agonist - antagonists such as Compound 1) do not (significantly) increase the blood lactate concentration in an individual, such as after intravenous administration (e.g., see Figure 23B)。In some embodiments, the compounds described herein (e.g., mixed V1AR agonist-antagonists such as Compound 1) do not (significantly) increase the blood lactate levels of an individual, whereas vasopressin at a similar dose significantly increases the blood lactate levels of an individual, such as after intravenous administration (e.g., see Figures 23B - 23C )。In some cases, vasopressin increases the blood lactate levels of an individual by at least 2-fold (e.g., 3-fold, 4-fold), such as after intravenous administration (e.g., see Figure 23B )。

[0468] In some embodiments, the compounds described herein (e.g., mixed V1AR agonist-antagonists such as Compound 1) decrease the plasma concentration (e.g., linearly) (see, for example, Figures 22A - 22B 、 Figures 25A - 25B )。

[0469] In some embodiments, the compounds described herein (e.g., mixed V1AR agonist-antagonists such as Compound 1) increase the blood pH of an individual, such as after intravenous administration. In some embodiments, the compounds described herein (e.g., mixed V1AR agonist-antagonists such as Compound 1) decrease the blood pH of an individual, such as after intravenous administration.

[0470] In some cases, the compounds described herein (e.g., mixed V1AR agonist-antagonists such as Compound 1) provide an initial apparent volume of the central compartment (V c ) of at least 20 mL / kg (e.g., at least 40 mg / kg, at least 60 mg / kg, at least 80 mg / kg, at least 100 mg / kg) in an individual (e.g., a mammal), such as after intravenous administration. In some cases, the compounds described herein (e.g., mixed V1AR agonist-antagonists such as Compound 1) provide an initial apparent volume of the central compartment (V c ) of at most 150 mg / kg (e.g., at most 130 mg / kg, at most 110 mg / kg, at most 90 mg / kg) in an individual (e.g., a mammal), such as after intravenous administration.

[0471] In some cases, the compounds described herein (e.g., mixed V1AR agonist-antagonists such as Compound 1) provide a steady-state volume of distribution (V ss), such as after intravenous administration. In some cases, the compounds described herein (e.g., mixed V1AR agonist - antagonists such as Compound 1) provide a steady - state volume of distribution (V ss ) in an individual (e.g., a mammal), such as after intravenous administration.

[0472] In some cases, the compounds described herein (e.g., mixed V1AR agonist - antagonists such as Compound 1) provide a maximum plasma concentration (C max ) / unit dose of at least 200 ng / mL / mg / kg (e.g., at least 300 ng / mL / mg / kg, at least 500 ng / mL / mg / kg, at least 600 ng / mL / mg / kg, at least 700 ng / mL / mg / kg) in an individual (e.g., a mammal), such as after subcutaneous administration. In some cases, the compounds described herein (e.g., mixed V1AR agonist - antagonists such as Compound 1) provide a maximum plasma concentration (C max ) / unit dose of at most 1000 ng / mL / mg / kg (e.g., at most 900 ng / mL / mg / kg, at most 700 ng / mL / mg / kg, at most 500 ng / mL / mg / kg, at most 400 ng / mL / mg / kg) in an individual (e.g., a mammal), such as after subcutaneous administration. In some cases, the compounds described herein (e.g., mixed V1AR agonist - antagonists such as Compound 1) provide a time to maximum plasma concentration (T max ) of at least 5 minutes (e.g., at least 10 minutes, at least 20 minutes, at least 30 minutes) in an individual (e.g., a mammal), such as after subcutaneous administration. In some cases, the compounds described herein (e.g., mixed V1AR agonist - antagonists such as Compound 1) provide a time to maximum plasma concentration (T max ) of at most 60 minutes (e.g., at most 50 minutes, at most 40 minutes, at most 30 minutes, at most 20 minutes) in an individual (e.g., a mammal), such as after subcutaneous administration.

[0473] In some cases, the compounds described herein (e.g., mixed V1AR agonist-antagonists such as compound 1) provide an area under the curve (AUC) / unit dose of at least 40,000 min·ng / mL / mg / kg (e.g., at least 45,000 min·ng / mL / mg / kg, at least 50,000 min·ng / mL / mg / kg, at least 55,000 min·ng / mL / mg / kg, at least 60,000 min·ng / mL / mg / kg) in an individual (e.g., a mammal), such as after subcutaneous administration. In some cases, the compounds described herein (e.g., mixed V1AR agonist-antagonists such as compound 1) provide an area under the curve (AUC) / unit dose of at most 70,000 min·ng / mL / mg / kg (e.g., 65,000 min·ng / mL / mg / kg, 60,000 min·ng / mL / mg / kg, 55,000 min·ng / mL / mg / kg, 50,000 min·ng / mL / mg / kg) in an individual (e.g., a mammal), such as after subcutaneous administration.

[0474] In some cases, the compounds described herein (e.g., mixed V1AR agonist-antagonists such as compound 1) provide an apparent total clearance (CL / F) of at least 10 mL / min / kg (e.g., at least 12 mL / min / kg, at least 15 mL / min / kg, at least 18 mL / min / kg) in an individual (e.g., a mammal), such as after subcutaneous administration. In some cases, the compounds described herein (e.g., mixed V1AR agonist-antagonists such as compound 1) provide an apparent total clearance (CL / F) of at most 30 mL / min / kg (e.g., at most 28 mL / min / kg, at most 25 mL / min / kg, at most 22 mL / min / kg, at most 20 mL / min / kg) in an individual (e.g., a mammal), such as after subcutaneous administration.

[0475] In some cases, an individual receiving the treatment described herein achieves one or more outcome measures described herein (such as those described in the examples) during and / or after receiving the treatment. In some cases, an individual receiving the treatment described herein meets one or more inclusion criteria provided in the examples. In some cases, an individual receiving the treatment described herein meets each of the inclusion criteria provided in the examples. In some cases, an individual receiving the treatment described herein fails to meet one or more exclusion criteria provided in the examples. In some cases, an individual receiving the treatment described herein fails to meet each of the exclusion criteria provided in the examples. In some embodiments, the compound described herein (e.g., compound 1) is administered to an individual receiving the treatment described herein until one or more primary and / or secondary outcome measures are met, such as the primary and / or secondary outcome measures provided in the examples. In some cases, the compound described herein (e.g., compound 1) is administered to an individual until the individual has an sCr value of 1.5 milligrams (mg) per deciliter (dL) or lower for a number of consecutive days (e.g., 2 or more consecutive days). In some embodiments, the compound described herein or a pharmaceutically acceptable salt thereof (e.g., compound 1) is administered to an individual (e.g., as described herein) (e.g., subcutaneously) at least until the individual's sCr value returns to normal (e.g., baseline).

[0476] Unless otherwise indicated, the measurements described herein (such as measurements of sCr, MAP, etc.) can be made immediately before, several hours before, several days before, or several weeks before administering the compound described herein (e.g., compound 1) or a pharmaceutically acceptable salt (e.g., acetate) to an individual receiving the treatment described herein.

[0477] In some embodiments, an individual receiving the treatment described herein has a reduction in sCr. In some embodiments, an individual receiving the treatment described herein has a substantial reduction in sCr. In some embodiments, an individual receiving the treatment described herein has a significant reduction in sCr. In some embodiments, an individual receiving the treatment described herein has a reduction of about 10% or more in the sCr value, such as compared to the baseline measurement prior to treatment. In some embodiments, an individual receiving the treatment described herein has a reduction of about 50% or less in the sCr value, such as compared to the baseline measurement prior to treatment. In some embodiments, an individual receiving the treatment described herein has a reduction of about 10% to about 50% in the sCr value, such as compared to the baseline measurement prior to treatment. In some embodiments, an individual receiving the treatment described herein has a reduction of about 20% to about 50% in the sCr value, such as compared to the baseline measurement prior to treatment. In some embodiments, an individual receiving the treatment described herein has a reduction of about 30% to about 50% in the sCr value, such as compared to the baseline measurement prior to treatment. In some embodiments, an individual receiving the treatment described herein has a reduction of about 40% to about 50% in the sCr value, such as compared to the baseline measurement prior to treatment. In some instances, the reduction in the sCr value after treatment with the compound described herein (e.g., Compound 1) or a pharmaceutically acceptable salt (e.g., acetate) is significantly greater compared to the reduction in the sCr value after treatment with other treatment options.

[0478] In some embodiments, the compound described herein (e.g., Compound 1) or a pharmaceutically acceptable salt (e.g., acetate) is administered to an individual receiving the treatment described herein until the individual has an sCr value of 1.5 milligrams (mg) / deciliter (dL) or less for several consecutive days. In some embodiments, the compound described herein (e.g., Compound 1) or a pharmaceutically acceptable salt (e.g., acetate) is administered to an individual receiving the treatment described herein until the individual has an sCr value of 1.5 mg / dL or less for 2 or more consecutive days.

[0479] In some embodiments, the mean arterial pressure (MAP) of an individual receiving the treatment described herein increases. In some embodiments, the MAP of an individual receiving the treatment described herein increases compared to the baseline measurement prior to treatment. In some embodiments, the MAP of an individual receiving the treatment described herein increases (e.g., compared to the baseline measurement prior to treatment) by about 15 mmHg or less.

[0480] In some embodiments, the mean arterial pressure (MAP) of an individual receiving the treatment described herein is decreased. In some embodiments, the MAP of an individual receiving the treatment described herein is decreased compared to a baseline measurement prior to treatment. In some embodiments, the MAP of an individual receiving the treatment described herein is decreased (e.g., compared to a baseline measurement prior to treatment) by about 15 mmHg or less.

[0481] In some embodiments, the MAP of an individual receiving the treatment described herein remains largely (e.g., significantly) unchanged (e.g., compared to a baseline measurement prior to treatment). In some embodiments, the MAP of an individual receiving the treatment described herein remains largely (e.g., significantly) unchanged compared to a baseline measurement prior to treatment.

[0482] In some cases, provided herein are methods of modulating the mean arterial pressure (MAP) of an individual (e.g., in need thereof), the method comprising: (a) administering (e.g., intravenously or subcutaneously) an effective amount of a first compound or a pharmaceutically acceptable salt thereof, the first compound being a vasoconstrictor (e.g., a vasopressin receptor 1A (V1AR) agonist (e.g., a selective V1AR agonist)); and (b) administering (e.g., intravenously or subcutaneously) a second compound (e.g., a V1AR antagonist (e.g., a selective V1AR antagonist) or a vasodilator) or a pharmaceutically acceptable salt thereof, wherein the second compound sufficiently blocks the (local) vasoconstrictive effect of the first compound (on the individual) such that sufficient uptake of the first compound into the circulatory system and / or internal organs (e.g., the kidneys) of the individual is provided. In some cases, such as after administration, the first compound causes one or more blood vessels near or at the site of administration to constrict, thereby preventing sufficient uptake of the first compound into the internal organs (e.g., the kidneys) of the individual. In some cases, the first compound and the second compound are administered to the individual simultaneously. In some cases, administration of the second compound reduces the local vasoconstrictive effect of the first compound, but does not reduce the vasoconstrictive effect of the first compound on the internal organs (e.g., the kidneys) of the individual. In some cases, administration of the second compound reduces the local vasoconstrictive effect of the first compound such that a therapeutically effective amount of the first compound is delivered to the internal organs (e.g., the kidneys) of the individual. In some cases, the individual has HRS-AKI.

[0483] In some embodiments, an individual receiving the treatment described herein has a Model for End-Stage Liver Disease (MELD) score of up to 35 prior to treatment (such as at the time of randomization (such as within days prior to treatment)).

[0484] In some embodiments, an individual receiving the treatment described herein has proteinuria of up to about 500 mg / dL prior to treatment (such as at the time of randomization (such as within days prior to treatment)).

[0485] In some embodiments, an individual receiving the treatment described herein has an oxygen flow rate of at least about 90% at 2 liters (L) or less prior to treatment (such as at the time of randomization (such as within a few days prior to treatment)).

[0486] In some embodiments, an individual receiving the treatment described herein has a pulse oximeter reading of at least about 90% at 2 liters (L) prior to treatment (such as at the time of randomization (such as within a few days prior to treatment)).

[0487] In some embodiments, an individual receiving the treatment described herein has a systolic blood pressure of up to 140 mmHg. In some embodiments, an individual receiving the treatment described herein has a diastolic blood pressure of up to 100 mmHg. In some embodiments, an individual receiving the treatment described herein has a systolic blood pressure of 140 mmHg or less and a diastolic blood pressure of 100 mmHg or less. In some instances, the systolic and / or diastolic blood pressure of the individual is measured prior to treatment (such as at the time of randomization (such as within a few weeks prior to treatment)).

[0488] In some embodiments, an individual receiving the treatment described herein is receiving albumin. In some embodiments, an individual receiving the treatment described herein is receiving albumin and has had appropriate diuretic discontinuation prior to treatment. In some embodiments, an individual receiving the treatment described herein is receiving albumin and has had appropriate diuretic discontinuation within a few days prior to treatment. In some embodiments, an individual receiving the treatment described herein is receiving albumin and has had appropriate diuretic discontinuation at least 48 h prior to treatment.

[0489] In some embodiments, an individual receiving the treatment described herein lacks sustained improvement in renal function. In some embodiments, an individual receiving the treatment described herein lacks sustained improvement in renal function after diuretic discontinuation. In some embodiments, an individual receiving the treatment described herein lacks sustained improvement in renal function after plasma volume expansion with albumin. In some embodiments, an individual receiving the treatment described herein lacks sustained improvement in renal function after diuretic discontinuation and plasma volume expansion with albumin.

[0490] In some instances, an individual receiving the treatment described herein is in need of the treatment described herein.

[0491] While the preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Many variations, changes and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed to practice the invention. The following claims are intended to define the scope of the invention and thereby cover the methods and structures within the scope of these claims and their equivalents.

[0492] Example

[0493] Example 1: Tolerance, Pharmacokinetics (PK), and Pharmacodynamics (PD) of a Mixed V1AR Agonist - Antagonist in Healthy Humans and Rats after Intravenous (IV) and Subcutaneous (SC) Administration Overview

[0494] Figure 1

[0495] Generally, after administration of a composition comprising a compound described herein (e.g., a mixed V1AR agonist - antagonist such as Compound 1) to healthy rats and humans by intravenous infusion and subcutaneous (bolus) injection, the systemic exposure of the compound was measured. Additionally, after administration of the composition to healthy rats and humans by intravenous infusion and subcutaneous (bolus) injection, systemic effects such as the regulation of mean arterial pressure (MAP) were measured.

[0496] While the systemic effects observed after intravenous infusion and subcutaneous (bolus) injection were comparable, more adverse events were measured in individuals receiving the composition by subcutaneous (bolus) injection. Overall, the compound was well tolerated by individuals receiving the composition by intravenous infusion.

[0497] After administration of the composition by subcutaneous (bolus) injection, a large amount of metabolite (M1 - a full (V1a) agonist) was measured in healthy humans and rats. Specifically, in both healthy humans and rats, approximately 80% - 90% of metabolite M1 was measured after subcutaneous (bolus) injection of the composition. In contrast, little M1 was measured after intravenous infusion of the composition. As discussed herein, it is known that full vasopressin receptor agonists described herein (e.g., terlipressin) cause (critical) adverse events when administered subcutaneously. Thus, the substantial metabolic conversion of the compound to the full agonist (M1) after subcutaneous (bolus) injection provides an explanation for the difference in the tolerance profiles of the composition in healthy individuals after intravenous infusion versus (subcutaneous) bolus injection. Additional studies described below demonstrate ways to reduce the formation of the full agonist (M1) after subcutaneous administration of a composition comprising a mixed V1AR agonist - antagonist (such as Compound 1) described herein.

[0498] Summary of the trial design

[0499] A double-blind, placebo-controlled, within-dose-group randomized trial was conducted to study the safety, tolerability, pharmacokinetics, and pharmacodynamics of Compound 1 administered by intravenous infusion and multiple subcutaneous injections in healthy men and women. The trial consisted of two treatment periods, Treatment Period 1 and Treatment Period 2 (see First Treatment Period: ).

[0500] The study was conducted in two phases. In Phase 1, the treatment was administered by intravenous infusion, and in Phase 2, the treatment was administered by subcutaneous injection. The trial included 5 escalating dose panels, each panel consisting of 8 healthy subjects (6 receiving the active agent and 2 receiving the placebo). A new cohort of subjects was used for each dose panel.

[0501] Second Treatment Period: Subjects received a 6-hour intravenous infusion of Compound 1 or placebo. At each dose level, the first two subjects to be infused were randomized to receive Compound 1 or placebo (one each), with a minimum observation period of 24 hours. If no safety issues were identified, as judged by the investigator, the remaining subjects in that dose group were randomized and treated according to a randomized and staggered dosing schedule. Dose escalation included 0.1, 0.3, 0.45, 0.6, and 0.9 milligrams (mg) of Compound 1.

[0502] Exclusion Criteria After a 2- to 18-day resting period, each subject received the same treatment as in Phase 1, once-daily subcutaneous doses for 5 days. Doses were selected to prevent exposure from exceeding the intravenous exposure. Dose escalation was stopped after the 0.3 mg dose panel due to the risk of exceeding the maximum tolerated dose at higher doses. For each subject, the treatment period was 2 days plus 6 days, and the total duration of the study from the screening visit to the post-treatment follow-up visit did not exceed 8 weeks. After all subjects in the dose group had completed, the SRC evaluated the safety and tolerability of the compound.

[0503] In a double-blind setting (i.e., the active agent treatment or placebo treatment was not disclosed to the subjects or personnel participating in the study), all subjects were assigned to the active agent treatment or placebo. Randomization and blinding were performed to reduce any bias in reporting, for example, AEs.

[0504] A single intravenous infusion within 6 hours and once-daily subcutaneous doses for 5 days were selected as the route of administration and treatment duration (e.g., to study the full tentative dose range of Compound 1). The same subjects from the intravenous administration were selected to continue with the subcutaneous administration to obtain the most reliable estimate of the bioavailability (F) in the outlined panels.

[0505] The first two subjects to be infused at each dose level are one who receives Active Compound 1 and one who receives placebo, with a minimum observation period of 24 hours in order to reduce the risks associated with exposure to the substance in early clinical development. A sequential dose escalation design for safety assessment of the previous dose level is chosen, taking into account the safety of the study subjects.

[0506] The initially planned escalating doses are 0.1, 0.3, 1, 3, 6, and 10 mg, respectively. In the aforementioned study, administration of 0.3 mg as a 6-hour intravenous infusion resulted in a C max concentration of up to approximately 6 ng / mL. Based on the data from the aforementioned study, it is estimated that the planned subcutaneous (s.c.) doses (0.1, 0.3, 1, 3, 6, and 10 mg) will achieve but not exceed the C max levels obtained with the corresponding intravenous infusions. Administration of 0.3 mg by subcutaneous injection resulted in a C max concentration of up to approximately 2.5 ng / mL. The dose and / or infusion rate may be adjusted based on recommendations from the SRC.

[0507] The investigator will evaluate injection site reactions only at 0.5, 4, and 24 hours after subcutaneous administration of the study drug on Day 1 to Day 5 in the 2nd treatment period. The injection site reactions to be evaluated are erythema, pain, pruritus, edema, bruising, and pallor, each to be evaluated as none, mild, moderate, or severe. Injection site reactions other than those described above or lasting more than 24 hours are classified as adverse events (AE).

[0508] In Phase 1, at screening, on Day -1, before dosing, and at 1, 2, 4, 6, 8, 12, and 24 hours after starting intravenous administration of Compound 1, blood samples are collected for safety laboratory evaluation of clinical chemistry parameters. At screening, on Day -1, and at 6, 12, and 24 hours after starting intravenous administration of Compound 1, blood samples are collected for hematological and hemostasis parameters.

[0509] For subcutaneous administration in Phase 2, on Day -1, before dosing, and at 2 and 6 hours after administration of Compound 1 and at follow-up, samples are collected for clinical chemistry parameters. On Day -1, and at 2 and 4 hours after administration on Day 1, before dosing and at 3 hours after administration on Days 2 - 4, before dosing and at 2 and 6 hours after administration on Day 5, and at follow-up, blood samples are collected for hematological and hemostasis parameters. The actual sampling times are recorded.

[0510] In Cycle 1, at screening, on Day - 1, urine samples for the safety laboratory evaluation of urine analysis parameters were collected before dosing and during collection periods at 0 - 4 hours, 4 - 8 hours, 8 - 12 hours, and 12 - 24 hours after the start of intravenous administration of Compound 1. For subcutaneous administration in Cycle 2, urine analysis samples were collected on Day - 1, before dosing, at 2 and 6 hours after administration of Compound 1 from Day 1 to Day 5, and at follow - up. Urine analysis was performed locally by means of a dip - stick test. In the case of any abnormal results on the dip - stick, a new urine test was performed. In the case of any abnormal and clinically significant results on the dip - stick, a new urine test was to be performed. If an abnormal result was confirmed, it was at the discretion of the investigator whether to initiate further examinations. Clinically significant abnormal findings were reported as AEs. The metabolite patterns of Compound 1 in plasma and urine were measured.

[0511] A similar study was used in healthy rats to evaluate the differences in metabolite formation of Compound 1 between intravenous bolus and subcutaneous (bolus) injection.

[0512] Eligibility

[0513] Individuals participating in the study met the inclusion criteria provided in Table 1.

[0514] Table 1

[0515]

[0516] Individuals with any of the exclusion criteria provided in Table 2 were excluded from the study.

[0517] Table 2

[0518]

[0519]

[0520] If one or more of the predefined criteria provided in Table 3, as confirmed by a second measurement, were met in at least two subjects receiving active agent treatment in a dose cohort, dose escalation was to be terminated.

[0521] Table 3

[0522] Systolic blood pressure increased by 50% or more relative to the baseline value Systolic blood pressure of 180 mmHg or higher Diastolic blood pressure of 105 mmHg or higher Mean arterial pressure (MAP) of 130 mmHg or higher Cardiac output reduced by 25% or more, as estimated by echocardiogram Signs or symptoms of hypertensive crisis Group

[0523] Subjects

[0524] In this trial, 85 subjects were screened, and 64 of them were randomized and dosed. In the Phase 1 intravenous (i.v.) administration, there were 5 dose groups (0.1, 0.3, 0.45, 0.6, and 0.9 mg), and in the Phase 2 subcutaneous (s.c.) administration, there were 2 dose groups (0.1 and 0.3 mg). The 0.1 mg and 0.3 dose groups (intravenous infusion followed by subcutaneous administration) initially included 8 subjects, 6 of whom received the active agent treatment and 2 of whom received placebo. All subjects in the 0.1 mg dose group received both intravenous and subcutaneous administrations, while in the 0.3 mg dose group, only 3 of the 6 subjects who received the infusion continued with the subcutaneous administration. The 0.45, 0.6, and 0.9 mg dose groups (intravenous administration) each included 16 subjects, 12 of whom received the active agent treatment and 4 of whom received placebo. All subjects who received the active agent treatment in the 0.1, 0.45, 0.6, and 0.9 mg dose groups completed the trial, while 1 subject who received the active agent treatment in the 0.3 mg dose group discontinued the trial due to an AE (1 case of elevated troponin I level) after the first subcutaneous administration. Since it was decided to terminate the subcutaneous administration after 3 subjects in the 0.3 mg dose group, the remaining 3 subjects were defined as having completed. All subjects who received placebo completed the trial.

[0525] Treatment

[0526] In Phase 1, subjects received a single 6-hour intravenous infusion of Compound 1 or placebo at a constant rate. The intravenous dose of the first dose cohort was the lowest dose that gave an apparent pharmacologic activity signal in the aforementioned trial. The planned and actual doses of Compound 1 during the intravenous infusion are provided in Table 4. Administration was carried out using a piston-driven syringe infusion pump. The amount administered was recorded for each subject.

[0527] Table 4

[0528] Planned Dose (milligrams (mg)) Actual Dose (milligrams (mg)) Group 1 Group 2 0.1 0.1 Group 3 0.3 0.3 Group 4 1* 0.45 Group 5 3* 0.6 Group 6 6* 0.9 Group 10* ---

[0529] * Due to the anticipated risk of exceeding the maximum tolerated dose at higher doses, dose escalation for both female and male subjects became in smaller increments after the 0.3 mg dose cohort (i.e., 0.45, 0.6, and 0.9 mg).

[0530] In Phase 2, subjects received the same treatment as in Phase 1 at different locations on the abdomen, once-daily subcutaneous injections for 5 days (Table 5). The subcutaneous doses were selected based on data from previous trials.

[0531] Table 5

[0532] Planned Dose (milligrams (mg)) Actual Dose (milligrams (mg)) Group 1 Group 2 0.1 0.1 Group 3 0.3 0.3 Group 4 1* --- Group 5 3* --- Group 6 6* --- IMP 10* ---

[0533] Both female and male subjects discontinued dose escalation after the 0.3 mg dose cohort due to the likelihood of higher doses exceeding the maximum tolerated dose.

[0534] Formulation

[0535] In some cases, Compound 1 was formulated as a sterile manufactured aqueous solution of Compound 1 in 10 mM acetate buffer pH 4.5 with mannitol (e.g., for isotonicity), 1 mg / mL to about 10 mg / mL. In some cases, the formulation containing Compound 1 was filled into glass vials (1.5 mL withdrawable volume) and sealed with a rubber stopper and plastic cap. In some cases, prior to administration, the formulation containing Compound 1 was diluted to the appropriate concentration with 0.9% sodium chloride injection.

[0536] In some cases, Compound 1 was formulated as an investigational medicinal product (IMP) as shown in Table 6. In some cases, Compound 1 was diluted to the desired concentration with 5% dextrose, and the placebo was diluted to the same extent for each dose group.

[0537] Table 6

[0538] Placebo Compound 1 10 mg / mL Sodium acetate buffer --- 10 mM, pH 4.5 10 mM, pH 4.5 Mannitol 44.3 mg / mL 47.2 mg / mL Figure 2

[0539] Objectives and endpoints

[0540] In some cases, the objective of the study was to characterize the differences between intravenous and subcutaneous administration. In a previous single-blind study, differences in adverse events (AEs) and pharmacodynamic cardiovascular changes were observed after subcutaneous administration compared to intravenous administration, despite the same dose and similar exposure being administered.

[0541] In some cases, the objective of the study was to obtain general data on the safety, tolerance, pharmacokinetics, and pharmacodynamics of Compound 1 in healthy subjects.

[0542] In some cases, the objective of the study was to determine the safety and tolerance of a single dose of Compound 1 administered as a continuous intravenous infusion.

[0543] In some cases, the objective of the study was to determine the safety and tolerance of multiple doses of Compound 1 administered as daily subcutaneous injections.

[0544] In some cases, the objective of the study was to determine the single-dose intravenous and multiple-dose subcutaneous pharmacokinetics of Compound 1.

[0545] In some cases, the objective of the study was to investigate the metabolite pattern of Compound 1 in plasma and urine.

[0546] In some cases, the purpose of the study was to investigate the relationship between the pharmacokinetics and pharmacodynamics of Compound 1 in healthy subjects.

[0547] In some cases, the study endpoints were: vital signs (e.g., supine blood pressure, pulse, and body temperature), electrocardiogram (ECG) (e.g., intervals, rhythm, and morphology), cardiac function (e.g., cardiac output using echocardiography), peripheral blood flow / tissue perfusion (e.g., by skin color), venous blood gas (e.g., lactate), urine output, clinical chemistry, hematology, hemostasis, and urine analysis, adverse events (AE) (e.g., type, frequency, and intensity), pharmacokinetics (e.g., AUC, AUC t 、AUCτ、%Extrap AUC、C max 、t max 、CL、V z 、t 1 / 2 、MRT、V ss 、F、Ae, and CLR), and metabolite patterns in plasma and urine.

[0548] Results

[0549] Overall, when administered to healthy individuals by intravenous infusion and subcutaneous (bolus) injection, Compound 1 was systemically delivered and produced systemic effects. However, while little formation of M1 occurred (e.g., approximately 0 - 15%) after administration of Compound 1 to healthy humans by intravenous infusion (Figure 44, inset A), the concentrations of Compound 1 and M1 were approximately equimolar in healthy humans after administration of Compound 1 by subcutaneous (bolus) injection (Figure 44, inset B). Specifically, both human and rat data indicated that approximately 80% - 90% of Compound 1 was converted to M1 (e.g., in the subcutaneous space) after subcutaneous (bolus) injection. These results demonstrated that a large amount of M1 (a full (V1) agonist) was formed after subcutaneous (bolus) injection but not after intravenous infusion, providing an explanation for why healthy humans receiving Compound 1 by subcutaneous (bolus) injection experienced more adverse events compared to healthy humans receiving Compound 1 by intravenous infusion.

[0550] Summary of tolerance and adverse events (AE):

[0551] In Cycle 1, after intravenous infusion, 94 treatment-emergent adverse events (TEAEs) occurred in 35 of the 48 subjects treated with the active agent, and 8 TEAEs occurred in 5 of the 16 subjects receiving placebo. In Cycle 2, after subcutaneous administration, 87 TEAEs occurred in 9 subjects treated with the active agent, and 4 TEAEs occurred in 3 of the 4 subjects receiving placebo. In Cycle 1, 87 of the TEAEs reported by 34 subjects treated with the active agent and 6 of the TEAEs reported by 3 subjects receiving placebo were considered drug-related adverse reactions (ADRs) (e.g., were assessed as plausibly related to treatment). One AE reported by a subject in the 0.1 mg dose group was judged to be serious. No critical AEs occurred, and no AE led to death or trial discontinuation. In Cycle 2, all 87 TEAEs reported by 9 subjects treated with the active agent and all 4 TEAEs reported by 3 subjects receiving placebo were considered ADRs. Three AEs reported by 3 subjects in the 0.1 mg dose group and 2 AEs reported by 1 subject in the 0.3 mg group were judged to be serious, and 1 AE reported by 1 subject in the 0.3 mg group was judged to be critical and led to discontinuation of this subject's trial. No AE led to death. Most TEAEs during intravenous and subcutaneous administration were of mild or moderate intensity in both females and males. Six events were reported as being of severe intensity; one bradycardia event reported after intravenous infusion of 0.1 mg, 3 abdominal pain events reported after subcutaneous administration of 0.1 mg, and 1 abdominal pain event and 1 back pain event (both reported by the same subject after subcutaneous administration of 0.3 mg). One event of elevated troponin I level reported after subcutaneous administration of 0.3 mg was reported as critical.

[0552] Pharmacokinetics:

[0553] Intravenous: In all dose groups, the median time to reach maximum serum concentration after 6-hour intravenous infusion was between 5 and 6 hours (see Figure 3A ). AUC and C max increased with increasing dose, and dose-proportionality analysis of AUC and C max indicated proportionality of both parameters in the 0.1 - 0.9 mg dose range. The harmonic mean terminal half-life was slightly longer (about 1.5 and 1.7 hours) in the 0.6 and 0.9 mg dose groups compared to other dose groups (which had similar mean t 1 / 2 of about 1.2 - 1.3 hours). Other non-dose-dependent pharmacokinetic parameters were comparable between the five doses.

[0554] The pharmacokinetic results of compound 1 following intravenous infusion are shown in Table 7.

[0555] Table 7

[0556]

[0557]

[0558] Subcutaneous: After the 1st and 5th administrations, both the AUC and C max increased with increasing dose (see Figure 3B and Figure 4A ), with a slightly longer terminal half-life in the 0.3 mg dose group (see Table 8). In any dose group, there was no evidence of accumulation of compound 1 after repeated administration (see Table 8). After the 1st and 5th subcutaneous administrations, in both the 0.1 and 0.3 mg dose groups, the median t max was approximately 0.3 - 0.4 hours (see Table 8). The absolute subcutaneous bioavailability of compound 1 was estimated based on the intravenous data from Phase 1 and the repeated subcutaneous administrations in Phase 2. The bioavailability of compound 1 after repeated subcutaneous injection was estimated to be 18%. The pharmacokinetic results of compound 1 following subcutaneous injection are shown in Table 8. The dose proportionality analysis of AUC and C max after the 1st and 5th subcutaneous doses indicated that only C max might be dose proportional after the 5th dose, while the AUC after the 1st and 5th administrations and C max after the 1st administration indicated greater than proportionality.

[0559] Table 8

[0560]

[0561]

[0562] Pharmacodynamics:

[0563] Diastolic blood pressure (intravenous): During intravenous infusion, the diastolic blood pressure increased in response to all five doses of compound 1 ( Figure 4B and Figure 5A ), reaching a plateau after approximately 2 hours. The absolute and relative increases were comparable between all doses, with maximum mean increases of 15 (25%), 16 (24%), 12 (17%), 13 (19%), and 12 (19%) mmHg for the 0.1, 0.3, 0.45, 0.6, and 0.9 mg doses, respectively, with large inter-individual variability. After the end of the infusion, the diastolic blood pressure returned to near baseline values within approximately two hours.

[0564] Diastolic blood pressure (subcutaneous): After subcutaneous administration, there was a reversible increase in diastolic blood pressure in both the 0.1 mg and 0.3 mg dose groups, and all administrations were similar ( Figure 5B and Figure 5A ). Within 5 days of administration, for the 0.1 and 0.3 mg doses, the maximum mean increases were 16 - 21 (30% - 40%) and 8 - 16 (10% - 22%) mmHg, respectively ( Figure 5B and Figure 6A ), however, there was large inter - individual variation. The mean absolute levels and mean changes after each of the 5 administrations were similar, showing no cumulative effect of this pharmacodynamic effect or signs of sensitization / desensitization.

[0565] Systolic blood pressure (intravenous): Compared with diastolic blood pressure, the effect of Compound 1 on systolic blood pressure was less significant both in absolute terms and relatively. For the 0.1, 0.3, 0.45, 0.6, and 0.9 mg doses, the maximum mean increases after intravenous infusion were 13 (13%), 12 (11%), 12 (11%), 12 (11%), and 13 (13%) mmHg, respectively, and the increases for all doses were comparable ( Figure 6B and Figure 7A ).

[0566] Systolic blood pressure (subcutaneous): After subcutaneous administration of 0.1 and 0.3 mg doses, there was a reversible increase in systolic blood pressure, however, it was less significant compared with diastolic blood pressure ( Figure 7B and Figure 8A ). Within 5 days of administration, for the 0.1 and 0.3 mg doses, the maximum mean increases were 10 - 17 (11% - 18%) and 4 - 19 (4% - 17%) mmHg, respectively, however, there was large inter - individual variation. Similar mean absolute levels and mean changes after each of the 5 administrations indicated that this pharmacodynamic effect had no cumulative effect or sensitization / desensitization.

[0567] Mean arterial pressure: The overall changes in mean arterial pressure after intravenous infusion and subcutaneous injection were similar to those of diastolic blood pressure ( Figure 8B and Figure 9A ) (for example, because in the calculation, the latter parameter has a greater weight compared with systolic blood pressure). Within 5 days of subcutaneous administration, for the 0.1, 0.3, 0.45, 0.6, and 0.9 mg doses, the maximum mean increases after intravenous infusion were 13 (18%), 14 (18%), 12 (14%), 13 (15%), and 12 (16%) mmHg, and for the 0.1 and 0.3 mg doses, they were 14 - 18 (21% - 27%) and 6 - 18 (6% - 21%) mmHg.

[0568] Pulse rate: A reversible decrease in pulse rate was observed after intravenous infusion and after repeated subcutaneous administration ( Figure 9B , Figure 10A, Figure 10B and Figure 9A ). For the 0.1, 0.3, 0.45, 0.6, and 0.9 mg doses, the maximum mean decreases after intravenous infusion were 17 (25%), 17 (21%), 17 (23%), 13 (19%), and 14 (21%) bpm, respectively. During 5 days of subcutaneous administration, for the 0.1 and 0.3 mg doses, the decreases were 18 - 20 (26% - 29%) and 16 - 21 (22% - 28%) bpm, respectively. After the end of the infusion, the pulse rate rapidly returned to baseline. During the infusion, a small decrease in the pulse rate was also shown in the subjects treated with placebo ( Figure 9B , Figure 10A , Figure 10B and Figure 11 ).

[0569] Peripheral blood flow: After intravenous infusion, mainly in the 0.45, 0.6, and 0.9 mg dose groups, pallor was reported in 18 subjects treated with the active agent. Overall, the skin color returned to normal approximately 4 - 6 hours after the end of the intravenous infusion. At 30 and 90 minutes after intravenous infusion, in the 0.45 mg dose group, congestion was reported in 1 subject. Approximately 30% of the subjects in the subcutaneous dose groups (0.1 mg and 0.3 mg) reported pallor after the first dose, and the skin color generally returned to normal 4 hours after administration. During the first 2 hours after the second and third doses were administered, single subjects in both dose groups also reported pallor, but none were reported after the fourth and fifth administrations.

[0570] Cardiac output: Compared with placebo, in the subjects treated with the active agent (except for the subjects in the 0.1 mg dose group), cardiac output decreased during the intravenous infusion in the first period. However, there was no obvious dose - related trend or change in the evaluated echocardiographic parameters. In the 0.1 mg dose group, after intravenous infusion, one moderate cardiac output decrease event was reported as an AE. None of the changes in cardiac output met the predefined stopping criteria. Similarly, after subcutaneous administration, a slight decrease in the cardiac output parameters of the subjects treated with the active agent was observed in both dose groups. No outliers were reported for any of the echocardiographic parameters evaluated after repeated subcutaneous administration.

[0571] Urine volume: In any dose group, there was no obvious dose - related trend or change in urine volume after intravenous infusion or subcutaneous injection. Large individual differences in urine volume were observed within the dose groups in both females and males.

[0572] Excretion of Compound 1 in urine (intravenous): In all five dose groups, Compound 1 was excreted in urine up to 24 hours after intravenous infusion. In each dose group, the largest amount of Compound 1 was excreted during the 4 - 8 hours after the start of infusion (approximately 3, 9, 16, 24, and 37 μg, respectively)( Figure 12A ). Overall, less than 10% of the dose was excreted intact in urine after intravenous administration.

[0573] Injection site reactions: Several subjects treated with the active agent reported erythema, pallor, and pruritus of mild severity, with most events occurring immediately after subcutaneous (bolus) injection. At 30 min after administration, in the 0.1 mg dose group, 1 subject reported moderate edema and mild pain.

[0574] Excretion of Compound 1 in urine (subcutaneous): After subcutaneous injection, Compound 1 was excreted in urine up to 8 hours after the 1st and 5th 0.1 mg doses and up to 24 hours after the 1st and 5th 0.3 mg doses. In both dose groups, the largest amount of Compound 1 was excreted during the first 4 hours after the 1st and 5th administrations( Figure 12B and Figure 12A ). After the 1st administration, approximately 2 and 3 μg of Compound 1 were excreted, and after the 5th administration, approximately 0.3 and 1.5 μg were excreted( Figure 12B and Figure 27 ). Overall, less than 5% of the dose was excreted unchanged in urine.

[0575] Metabolism: Analysis of human plasma from the 0.1, 0.6, and 0.9 mg intravenous dose groups and two subcutaneous groups using high-resolution mass spectrometry indicated the presence of the active metabolite M1 (a full (V1a) agonist) after both intravenous and subcutaneous administration, and metabolite M5 was observed only once. Due to analytical method interference, it was not possible to analyze metabolites in human urine. After intravenous administration, metabolite M1 was present only at low concentrations in one subject among males and 4 subjects among females in the 0.6 mg dose group, while it was present in all females and 5 out of 6 males in the 0.9 mg dose group, despite a few exceptions below the LOQ( Figure 27 , Figure A). The mean C max was just above the LOQ, in the range of 0.1 - 0.25 ng / mL, occurred at approximately 5 hours and corresponded to approximately 1% - 2% of the concomitant Compound 1 concentration, and the harmonic mean terminal half-life was approximately 4 hours. In contrast, after subcutaneous administration of 0.1 mg and 0.3 mg of Compound 1, after the first as well as the last administration, in both dose groups, the M1 concentration and exposure were comparable to those of Compound 1( Figure 13A , Figure B)( Figure 13B 、 Figure 3A, Figure 3B , Example 2: Potent and Selective Mixed V1AR Agonist - Antagonist ; Table 9, compared to Table 7). t max was about 0.5 - 1.5 hours, and the harmonic mean terminal half-life was about 1.5 - 2 hours. A summary of the PK variables for metabolite M1 (subcutaneous injection) is shown in Table 9.

[0576] Table 9

[0577]

[0578]

[0579] Methods and Materials

[0580] In some cases, the binding data provided below demonstrate that Compound 1 binds to a given receptor with its agonist or antagonist moiety, and within the population of vasopressin receptors occupied by Compound 1, a portion is occupied by the agonist moiety and another portion is occupied by the antagonist moiety, such as resulting in a partial agonism of the receptor and limiting the observed maximal vasoconstriction.

[0581] Figure 19

[0582] Cell lines. Studies were performed using cell lines expressing rat (r) or human (h) V1a, V1b, V2, or OT receptors. For experiments with human receptors, human embryonic kidney (HEK)-flp-in cells stably expressing the lacZ-Zeocin TM fusion gene were used for the expression of hV1a and hV1b. These cells were designed to be used in conjunction with a Flp-In TM expression vector containing the gene of interest (here hV1a or hV1b) and the Flp recombinase expression plasmid pOG44. For hV2 and hOTR, HEK-293 cells transiently expressing hV2 were used. For experiments with rat receptors, A7r5 rat thoracic aortic smooth muscle cells (ATCC) endogenously expressing rV1a, FLP-In293 (HEK-293) cells stably expressing rV1b, HEK-293 cells (ATCC) transiently transfected with rV2, and Chinese hamster ovary (CHO)-K1 cells (ATCC) transiently expressing rOTR were used.

[0583] Cell maintenance. HEK-flp-in cells were maintained at 37 °C in a humidified atmosphere with 5% CO2 in a medium containing 10% (v / v) heat-inactivated fetal bovine serum (FBS), 4 mM GlutaMAX TM-I and in Dulbecco's Modified Eagle's Medium (DMEM) containing 25 μg / mL hygromycin B. The medium for hV1b-expressing cells also contains 100 U / mL penicillin and 100 μg / mL streptomycin. HEK-293 cells transiently expressing hV2 are maintained in DMEM containing 10% (v / v) heat-inactivated FBS and 4 mM L-glutamine or GlutaMAX-I at 37 °C in a humidified atmosphere with 5% CO2. CHO-K1 cells stably expressing hOTR are maintained in DMEM-F12 containing 5% (v / v) heat-inactivated FBS, 2 mM L-glutamine or GlutaMAX-I and 900 μg / mL G418 sulfate at 37 °C in a humidified atmosphere with 5% CO2. A7r5 cells are maintained in DMEM containing 10% (v / v) heat-inactivated FBS, 4 mM GlutaMAX-1 at 37 °C in a humidified atmosphere with 5% CO2. One day before the assay, cells are removed from the culture flask using trypsin-EDTA, harvested in the medium used for cell culture, and seeded into 384-well (for V1a) or 96-well (for other receptors) poly-d-lysine-treated plates. For rV1a, cells are seeded at 7.5×10 4 cells per well in 20 μL, for hV1a at 2.5×10 4 cells per well in 20 μL, and for all other receptors at 4 - 5×10 4 cells per well in 100 μL.

[0584] Test compounds. Compound 1 (97.3% peptide purity) and AVP (reference agonist) are used in the cell-based functional assay. The compounds are prepared as 10 mM stock concentrations in 100% DMSO (or 5 mM for AVP), stored at -20 °C, and allowed to thaw just before the assay. The compounds are serially diluted in cell culture medium to 10× working solutions. In each study, a blank consisting of diluted medium supplemented with 0.1% (v / v) DMSO is also used as a control. No inhibitory effect of DMSO is observed at 0.1%. For the contractility assay, Compound 1 is formulated as a 23.5 μM stock solution in physiological saline solution (PSS; 120 mM NaCl, 4.6 mM KCl, 1.5 mM NaH2PO4·1H2O, 0.7 mM Na2HPO4, 11.5 mM D-glucose, 25 mM NaHCO3, 2.4 mM CaCl2, 1.2 mM MgCl2 [pH 7.35 - 7.45]). The stock solution is serially diluted in PSS to such concentrations that allow for a further 1 / 100 dilution after the compounds are added to the test device in a cumulative manner from the lowest to the highest concentration to obtain the final test concentrations.

[0585] Cell-based functional assays. To detect the activity generated by the binding of a test compound to the endogenous rV1a receptor or the stably expressed hV1a receptor, a fluorescence imaging plate reader (FLIPR) calcium assay was performed. Briefly, the real-time fluorescence of an intracellular calcium-sensitive dye was measured immediately after adding different concentrations of the test compound. The endogenous ligand of V1a, AVP, was used as a reference agonist. Reporter gene assays were used to monitor agonist-induced activity on human and rat V1b, V2, and OT receptors. Cells expressing the receptor of interest were transiently transfected with a luciferase reporter gene under the control of a transcriptional regulatory element responsive to receptor activation. The expression of the luciferase gene was determined after incubation with different concentrations of the test compound for 5 h. AVP was used as the reference agonist in the V1b assay, desmopressin (dDAVP) was used as the reference agonist in the V2R assay, and carbetocin was the reference agonist in the OTR assay. For the V1a receptor response, the area under the curve of the real-time calcium trace was determined and expressed as relative fluorescence units. For the V1b, V2, and OT receptor responses, luciferase activity was expressed as light counts / second. Compound potency was expressed as the concentration producing a half-maximal response (EC 50 ), and was calculated by performing a four-parameter non-linear regression analysis of the concentration-response curve using ActivityBase TM software. Effica...

Claims

1. A method of modulating the mean arterial pressure (MAP) of an individual (e.g., in need thereof), the method comprising subcutaneously infusing into the individual (e.g., in need thereof) a composition comprising a certain (effective) amount of a compound that is a mixed vasopressin receptor 1A (V1AR) agonist - antagonist.

2. The method according to claim 1, wherein the mixed vasopressin receptor 1A (V1AR) agonist - antagonist is more selective for V1AR than for V2R.

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

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

5. The method according to any one of the preceding claims, wherein the modulation of the mean arterial pressure (MAP) of the individual comprises increasing the MAP by at least 5% relative to baseline.

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

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

8. A method of modulating the mean arterial pressure (MAP) of an individual (e.g., in need thereof), the method comprising subcutaneously infusing into the individual (e.g., in need thereof) a certain (effective) amount of a compound having a structure represented by Formula I: D1 - L - D2 Formula I or a pharmaceutically acceptable salt thereof, wherein: D1 is a vasopressin receptor 1A (V1AR) agonist; D2 is a V1AR antagonist; and L is a linker.

9. The method according to claim 8, wherein D1 is more selective for V1AR than for V2R.

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

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

12. The method according to any one of claims 8 - 11, wherein D1 has or comprises the following structure:

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

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

15. The method according to any one of claims 8 - 14, wherein D2 has or comprises the following structure:

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

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

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

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

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

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

22. The method according to any one of claims 8-21, wherein L has or comprises the following structure:

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

24. A method of modulating mean arterial pressure (MAP) in an individual (e.g., in need thereof), the method comprising subcutaneous infusion of a composition comprising a certain (effective) amount of Compound 1 or a pharmaceutically acceptable salt thereof into the individual (e.g., in need thereof).

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

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

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

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

29. A method of modulating mean arterial pressure (MAP) in an individual (e.g., in need thereof), the method comprising subcutaneous administration of a composition comprising a certain (effective) amount of a compound that is a mixed vasopressin receptor 1A (V1AR) agonist-antagonist into the individual (e.g., in need thereof).

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

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

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

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

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

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

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

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

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

39. The method according to any one of the preceding claims, wherein subcutaneous infusion of the composition to the individual improves tolerance (e.g., based on a reduction in overproduction of M1, such as subcutaneously) relative to subcutaneous (bolus) injection.

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

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

42. The method according to 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 / h) to about 1 mL / h for the duration of the administration period.

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

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

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

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

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

48. The method according to any one of claims 1 - 46, wherein the composition comprises a buffer at a concentration of about 50 mM to about 250 mM.

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

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

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

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

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

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

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

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

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

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

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

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

61. A method for reducing the incidence of local vasoconstriction, such as ischemia (at the injection site), in an individual in need thereof, the method comprising subcutaneous infusion of a composition into the individual in need thereof, the composition comprising a compound having a structure represented by Formula I or a pharmaceutically acceptable salt thereof: D1-L-D2 Formula I or a pharmaceutically acceptable salt thereof, wherein: D1 is a vasopressin receptor 1A (V1AR) agonist; D2 is a V1AR antagonist; and L is a linker.

62. A method for modulating the mean arterial pressure (MAP) in an individual in need thereof, the method comprising subcutaneous infusion of a composition into the individual in need thereof, the composition comprising a compound having a structure represented by Formula I or a pharmaceutically acceptable salt thereof: D1-L-D2 Formula I or a pharmaceutically acceptable salt thereof, wherein: D1 is a vasopressin receptor 1A (V1AR) agonist; D2 is a V1AR antagonist; and L is a linker, wherein less than 50% of the compound of Formula I degrades (e.g., subcutaneously).

63. The method according to any one of the preceding claims, wherein after subcutaneous administration of Compound 1, the MAP of the individual increases (e.g., compared to a pre-treatment baseline measurement).

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

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

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

67. The method according to any one of the preceding claims, wherein after administration of the compound or a pharmaceutically acceptable salt thereof according to any one of the preceding claims to the individual, the systolic blood pressure of the individual increases (e.g., compared to a pre-treatment baseline measurement).

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

69. The method according to any one of the preceding claims, wherein after administration of the compound or a pharmaceutically acceptable salt thereof according to any one of the preceding claims to the individual, the pulse rate and / or peripheral blood flow of the individual decreases.

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

71. The method according to any one of the preceding claims, wherein administering to the individual (subcutaneously) a compound or a pharmaceutically acceptable salt thereof according to any one of the preceding claims reduces fluid retention and / or overload in the individual.

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

73. The method according to any one of the preceding claims, wherein on the first day the individual receives an initial (e.g., intravenous infusion) dose of a compound or a pharmaceutically acceptable salt thereof according to any one of the preceding claims (e.g., to acclimatize the individual to vasoconstriction and then receive a first subcutaneous therapeutic dose).

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

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

76. The method according to any one of the preceding claims, wherein the initial (e.g., intravenous infusion) dose of a compound or a pharmaceutically acceptable salt thereof according to any one of the preceding claims is a low dose, such as a dose of about 5 μg / h to about 15 μg / h (e.g., about 8 μg / h).

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

98. A subcutaneous formulation comprising a compound having a structure represented by Formula I or a pharmaceutically acceptable salt thereof: D1-L-D2 Formula I or a pharmaceutically acceptable salt thereof, wherein: D1 is a vasopressin receptor 1A (V1AR) agonist; D2 is a V1AR antagonist; and L is a linker, wherein less than 50% of the compound of Formula I degrades (e.g., subcutaneously).

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

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

101. The subcutaneous formulation according to claims 98 - 100, the formulation further comprising: a preservative.

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

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

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

105. The subcutaneous formulation according to claims 98 - 104, the formulation further comprising: a solubilizer (e.g., cyclodextrin) at a quantity of from about 1 mg / mL to about 250 mg / mL (e.g., about 60 - 80 mg / mL).

106. The subcutaneous formulation according to claims 98 - 105, wherein the compound of Formula I is less prone to degradation, such as in the subcutaneous layer of an individual to whom the formulation is administered subcutaneously.

107. The subcutaneous formulation according to claims 98 - 106, wherein less than 50% of the compound of formula I degrades (e.g., in the vial and / or subcutaneously), such as over a period of about one or two days.

108. The subcutaneous formulation according to claims 98 - 107, wherein the compound of formula I is present in the formulation at a concentration of about 0.1 mg / mL to about 100 mg / mL.

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

110. The subcutaneous formulation according to claims 98 - 108, the formulation further comprising: a buffer at a concentration of about 1 millimolar (mM) to about 1 M.

111. The subcutaneous formulation according to claims 98 - 110, the formulation further comprising: a buffer having a pKa of about 3.0 to about 6.0 at 25 °C.

112. The subcutaneous formulation according to claim 110 or 111, wherein the buffer is selected from the group consisting of: acetate, citrate, succinate, and phosphate.

113. The subcutaneous formulation according to claims 98 - 112, the subcutaneous formulation having a pH sufficient to inhibit a protease (e.g., trypsin) (e.g., inactivate or deactivate it), such as in the subcutaneous layer of an individual to whom the formulation is administered subcutaneously.

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

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

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

117. 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.

118. The system according to claim 117, wherein the system comprises an adhesive body for (e.g., reversibly) securing the (subcutaneous infusion) device to the skin surface of the individual.

119. The system according to claim 117 or 118, wherein the system comprises a cavity and a hollow tube body, and the composition is configured within the cavity.

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

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

122. The system according to any one of claims 117 - 121, wherein after the subcutaneous infusion device is fixed to the skin of the individual, the second opening is configured subcutaneously within the individual.

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

124. The system according to any one of claims 117 - 123, wherein the system is configured to provide the composition to the individual continuously over a period of about 24 hours or longer.

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

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

127. The system according to any one of claims 117 - 126, wherein the composition is the composition or formulation according to any one of the preceding claims.

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