KR20220098168A - treatment of liver disorders - Google Patents

Abstract

Provided herein are methods and compositions for treating liver disorders, including, but not limited to, non-alcoholic steatohepatitis, and symptoms and signs thereof in a patient.

Description

treatment of liver disorders

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No. 62/933,277, filed on November 8, 2019, and U.S. Provisional Application No. 63/004,403, filed April 2, 2020, the contents of each of which are incorporated herein by reference in their entirety included as

Field

The present invention relates to methods and compositions for treating liver disorders in a patient.

Fatty liver disease (FLD) encompasses a wide range of disease states characterized by excessive fat accumulation in the liver, often accompanied by inflammation. FLD can lead to non-alcoholic fatty liver disease (NAFLD), which can be characterized by insulin resistance. If untreated, NAFLD can progress to a persistent inflammatory response or non-alcoholic steatohepatitis (NASH), progressive liver fibrosis, which eventually leads to cirrhosis. In Europe and the United States, NAFLD is the second most common cause of liver transplantation. Thus, although treatment is urgently needed, since the patient has no apparent symptoms, the patient is burdened with a treatment regimen, particularly injection medications, medications administered multiple times a day, or anything that produces dangerous or irritating side effects. may not have the motivation to maintain There is currently no approved treatment for NASH.

A method of treating a liver disorder in a patient in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the liver disorder is liver inflammation, liver fibrosis. , alcohol induced fibrosis, steatosis, alcoholic steatosis, primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), non-alcoholic fatty liver disease (NAFLD), and non-alcoholic steatohepatitis (NASH). Provided herein is a method wherein:

Also, a method of treating a liver disorder with a farnesoid X receptor (FXR) agonist in a patient in need thereof, comprising administering a therapeutically effective amount of an FXR agonist, wherein the FXR agonist is of formula ( A compound of I) or a pharmaceutically acceptable salt thereof, wherein the patient has discontinued at least one prior therapy with another FXR agonist other than the compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein Liver disorders include liver inflammation, liver fibrosis, alcohol-induced fibrosis, steatosis, alcoholic steatosis, primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), non-alcoholic fatty liver disease (NAFLD), and non-alcoholic fatty acids. Provided herein is a method selected from hepatitis (NASH):

In some embodiments, the patient suffered from pruritus during one or more prior therapies.

In addition, non-alcoholic steatohepatitis of non-alcoholic fatty liver disease (NAFLD) in a patient in need of inhibition or delay of progression of non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH). Provided herein is a method of inhibiting or delaying progression to (NASH) comprising administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof:

Also, a method of inhibiting or delaying the progression of NASH in a patient in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. This is provided herein:

Also provided is a method of treating a liver disorder in a patient in need thereof with a farnesoid X receptor (FXR) agonist that preferentially concentrates in liver tissue over one or more of kidney, lung, heart, and skin tissues, the method comprising: A method comprising administering a therapeutically effective amount of an FXR agonist, wherein the FXR agonist is a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the liver disorder is liver inflammation, liver fibrosis, alcohol-induced fibrosis, steatosis, alcohol Provided herein is a method selected from sexual steatosis, primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), non-alcoholic fatty liver disease (NAFLD), and non-alcoholic steatohepatitis (NASH):

In some embodiments, administering does not result in pruritus of greater than grade 2 severity in the patient. In some embodiments, administering does not result in pruritus that is greater than grade 1 in severity in the patient. In some embodiments, administering does not cause pruritus in the patient.

Also, a method of treating a liver disorder with an FXR agonist that does not cause detectable pruritus in a patient in need thereof, comprising administering a therapeutically effective amount of the FXR agonist, wherein the FXR agonist comprises: I) or a pharmaceutically acceptable salt thereof, wherein the liver disorder is liver inflammation, liver fibrosis, alcohol-induced fibrosis, steatosis, alcoholic steatosis, primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), non- Provided herein is a method selected from alcoholic fatty liver disease (NAFLD), and non-alcoholic steatohepatitis (NASH):

In some embodiments, the liver disorder is NAFLD. In some embodiments, the liver disorder is NASH. In some embodiments, the liver disorder is PSC. In some embodiments, the liver disorder is PBC.

In some embodiments, administering results in a liver concentration to plasma concentration ratio of the compound of formula (I) of at least 10.

In some embodiments, the therapeutically effective amount is 0.5 μg/day - 600 mg/day. In some embodiments, a therapeutically effective amount is 0.5 μg/day - 20 mg/day. In some embodiments, a therapeutically effective amount is 0.5 μg/day - 4 mg/day.

In some embodiments, administering comprises administering the compound of formula (I), or a pharmaceutically acceptable salt thereof, daily for a treatment period of at least one week. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered once daily or twice daily. In some embodiments, the amount of compound of formula (I), or a pharmaceutically acceptable salt thereof, administered on the first day of the treatment period is greater than or equal to the amount administered on all subsequent days of the treatment period. In some embodiments, the amount of compound of formula (I), or a pharmaceutically acceptable salt thereof, administered on the first day of the treatment period is the same as the amount administered on all subsequent days of the treatment period. In some embodiments, the treatment period is at least 1 month. In some embodiments, the duration of treatment is the remaining lifespan of the patient.

In some embodiments, the patient is obese. In some embodiments, the patient is not obese. In some embodiments, the patient also has diabetes and/or a cardiovascular disorder. In some embodiments, the patient is at risk of developing an adverse effect affecting one or more of the kidneys, lungs, heart, and skin. In some embodiments, the patient is 2-17 years old. In some embodiments, the patient is between 18-54 years of age. In some embodiments, the patient is 65 years of age or older. In some embodiments, the patient has undergone a liver transplant. In some embodiments, the patient has elevated levels of alkaline phosphatase, gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT), and/or aspartate aminotransferase (AST).

In some embodiments, the method does not comprise administering an antihistamine, an immunosuppressant, a steroid, rifampicin, an opioid antagonist, or a selective serotonin reuptake inhibitor (SSRI).

In some embodiments, the patient's NAS score decreases upon administration. In some embodiments, TGR5 signaling is not activated upon administration.

In some embodiments, administering results in a reduced expression level of a marker of fibrosis. In some embodiments, Ccr2, Col1a1, Col1a2, Col1a3, Cxcr3, Dcn, Hgf, Il1a, Inhbe, Lox, Loxl1, Loxl2, Loxl3, Mmp2, Pdgfb, Plau, Serpine1, Perpinh1, Snai, Tgfb3, Thbs1, Tgf2 , Timp2, and/or the expression level of Timp3 is reduced.

In some embodiments, administering results in reduced expression levels of markers of liver inflammation. In some embodiments, the level of Adgre1, Ccr2, Ccr5, Il1A, and/or Tlr4 is decreased.

1A shows plasma concentrations of Compound I at various time points following intravenous (IV) administration to rats (1 mg/kg), dogs (1 mg/kg) and monkeys (0.3 mg/kg).
1B shows the plasma concentrations of compound I at various time points following oral administration to mice (10 mg/kg), rats (10 mg/kg), dogs (3 mg/kg) and monkeys (5 mg/kg) .
2A shows the liver to plasma concentration ratios of Compound I, obeticholic acid (OCA), silofexor, or tropexor after IV administration of 2 mg/kg to Sprague-Dawley (SD) rats.
2B shows the tissue to plasma ratio of concentrations of Compound I in kidney, lung, and liver following IV administration of 2 mg/kg of Compound I with or without co-administration of rifampicin to SD rats.
3 shows the tissue distribution of radiolabeled Compound I in plasma, liver, small intestine, cecum, kidney, lung, heart, and skin following oral administration of 5 mg/kg of Compound I to Long-Evans rats.
4 is measured by 7-alpha-hydroxy-4-cholesten-3-one (7α-C4) after administration of oral doses of 0.3 mg/kg, 1 mg/kg or 5 mg/kg to cynomolgus monkeys. The pharmacokinetics of compound I administration are presented.
Figure 5a presents the pharmacokinetics of compound I administration following administration of an oral dose of 1 mg/kg to cynomolgus monkeys at a daily dose of 1 day or 7 consecutive days.
Figure 5b shows cynomolgus monkeys by 7-alpha-hydroxy-4-cholesten-3-one (7α-C4) after administration of an oral dose of 1 mg/kg at a daily dose of 1 day or 7 consecutive days. The measured pharmacodynamics of compound I administration are presented.
6 is RT-qPCR measuring liver SHP1, hepatic OSTb, ileal SHP1, and ileal FGF15 RNA expression after administration of 10 mg/kg of Compound I, 30 mg/kg of OCA, or vehicle control to C5BL/6 mice. present the results.
7A shows differentially expressed genes modulated by administering 10 mg/kg of Compound I (a total of 500 genes modulated) or 30 mg/kg of OCA (a total of 44 genes modulated) to C5BL/6 mice. Numbers (vs. vehicle-treatment: fold-change >1.5-fold;p<0.05), as well as the number of differentially expressed genes adjusted in common by both compounds (37 genes in total) are shown.
7B shows the mean expression levels of select FXR-related genes (presented by CPM values) in C5BL/6 mice treated with 10 mg/kg of Compound I or 30 mg/kg of OCA or vehicle control.
Figure 7c shows the number of routes (p<0.05), as well as both compounds, enhanced by administration of 10 mg/kg Compound I (32 routes) or 30 mg/kg OCA (6 routes) to C5BL/6 mice. presents the number of pathways (two pathways) reinforced by .
7D shows the 25 routes that are statistically most potent upon administration of 10 mg/kg of Compound I to C57BL/6 mice, and compares the enrichment of these pathways with that of administration of 30 mg/kg of OCA.
8 presents the design of a study testing the efficacy of Compound I in a mouse model of NASH.
9 presents the NAFLD activity scores (NAS) of control mice and mice treated with Compound I at 10, 30, and 100 mg/kg.
10A shows the steatosis scores of control mice and NASH mice treated with 10, 30, and 100 mg/kg of Compound I.
10B presents the inflammation scores of control mice and NASH mice treated with 10, 30, and 100 mg/kg of Compound I.
10C shows the ballooning scores of control mice and NASH mice treated with Compound I at 10, 30, and 100 mg/kg.
11A shows histological sections of fibrosis of control mice and NASH mice treated with 100 mg/kg of compound I.
11B shows the amount of fibrosis in control mice and NASH mice treated with Compound I at 10, 30, and 100 mg/kg.
12A shows the serum alanine aminotransferase (ALT) levels of control mice and NASH mice treated with 10, 30, and 100 mg/kg of Compound I.
12B shows the aspartate amino transferase (AST) of control mice and NASH mice treated with Compound I at 10, 30, and 100 mg/kg.
12C shows the serum triglyceride levels of control mice and NASH mice treated with 10, 30, and 100 mg/kg of Compound I.
12D shows the serum total cholesterol levels of control mice and NASH mice treated with 10, 30, and 100 mg/kg of Compound I.
13A shows liver triglyceride levels of control mice and NASH mice treated with Compound I at 10, 30, and 100 mg/kg.
13B shows representative histology of steatosis assessment for control mice and NASH mice treated with 100 mg/kg of Compound I.
14A shows COL1A expression in the liver of control mice and NASH mice treated with 10, 30, and 100 mg/kg of Compound I.
14B shows the expression levels of inflammatory genes in control mice and NASH mice treated with 30 mg/kg of compound I.
14C shows the expression of fibrosis genes in control mice and NASH mice treated with 30 mg/kg of compound I.
15A and 15B show the mean serum concentrations of Compound I in different dosing groups on days 1 and 7 after administration of Compound I, respectively.
16A and 16B show the change in mean serum levels of 7α-C4 from baseline predose in different dosing groups on days 1 and 7 after administration of Compound I or placebo, respectively.
17A and 17B show the change in mean serum levels of FGF-19 from predose baseline in different dosing groups on days 1 and 7 after administration of Compound I or placebo, respectively.
18 shows the change in mean serum levels of low density lipoprotein (LDL) from baseline before dosing in different dosing groups after administration of Compound I or placebo.

Fatty liver disease (FLD) encompasses a wide range of disease states characterized by excessive fat accumulation in the liver, often accompanied by inflammation. FLD can lead to non-alcoholic fatty liver disease (NAFLD), which can be characterized by insulin resistance. If untreated, NAFLD can progress to a persistent inflammatory response or non-alcoholic steatohepatitis (NASH), progressive liver fibrosis, which eventually leads to cirrhosis.

Fatty liver diseases such as NAFLD and NASH are often asymptomatic or their symptoms are vague and difficult to define for the patient. However, in Europe and the United States, NAFLD is the second most common cause of liver transplantation. Thus, although treatment is urgently needed, since the patient has no apparent symptoms, the patient is burdened with a treatment regimen, particularly injection medications, medications administered multiple times a day, or anything that produces dangerous or irritating side effects. may not have the motivation to maintain

The farnesoid X receptor (FXR) is a nuclear hormone receptor that controls the conversion of cholesterol to bile acids and maintains the homeostasis of multiple metabolic pathways, and is therefore considered an important clinical target for NASH. However, FXR agonists such as cilofexor, tropexor, obeticholic acid (OCALIVA®), and ED-305 (Enanta) have all reported pruritus as a side effect. Pruritus can be problematic, particularly for conditions requiring chronic drug administration, as it causes patient discomfort, reduces the patient's quality of life, and can affect adherence to treatment regimens.

Provided herein are methods and compositions for treating a liver disorder in a patient in need thereof. In some embodiments, the treatment does not cause pruritus. In some embodiments, the treatment results in less pruritus associated with corresponding treatment with an FXR agonist selected from the group consisting of obeticholic acid (OCA), silofexor, or tropexor. In some embodiments, the method comprises administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or enantiomer thereof:

In some embodiments, the method comprises administering to the patient a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or enantiomer thereof, in combination with a therapeutically effective amount of another agent. Compounds of formula (I) are described in their entirety, in particular in US 2010/0152166, which is incorporated by reference in its entirety, particularly with respect to the compounds of formula (I) or pharmaceutically acceptable salts or enantiomers thereof, as well as methods for their preparation and use. has been disclosed.

In certain embodiments, the liver disorder is liver inflammation, fibrosis, or steatohepatitis. In certain embodiments, the liver disorder is selected from liver fibrosis, alcohol-induced fibrosis, steatosis, alcoholic steatosis, primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), NAFLD, and NASH. In some embodiments, the liver disorder is NASH. In some embodiments, the liver disorder is liver inflammation. In some embodiments, the liver disorder is liver fibrosis. In some embodiments, the liver disorder is alcohol-induced fibrosis. In some embodiments, the liver disorder is steatosis. In some embodiments, the liver disorder is alcoholic steatosis. In some embodiments, the liver disorder is NAFLD. In some embodiments, the liver disorder is primary sclerosing cholangitis (PSC). In some embodiments, the liver disorder is primary biliary cirrhosis (PBC).

Also provided herein are methods of inhibiting or delaying the progression of NAFLD to NASH. In some embodiments, provided herein are methods of inhibiting or delaying the progression of NASH. NASH may progress to, for example, one or more of liver cirrhosis, liver cancer, and the like.

Justice

Unless otherwise indicated, as used herein, the following definitions shall apply. Additionally, if any term or symbol used herein is not defined as set forth below, it shall have its ordinary meaning in the art.

"Comprising" is intended to mean that the compositions and methods include the recited elements, but do not exclude other elements. "Consisting essentially of" when used to define compositions and methods shall mean excluding other elements of any essential significance to the combination. For example, a composition consisting essentially of elements as defined herein will not exclude other elements that do not materially affect the basic and novel feature(s) of the claimed invention. "Consisting of" shall mean excluding, for example, more than trace ingredients and substantial method steps other than those recited. Embodiments defined by each of these conjunctions are included within the scope of the present invention.

“Combination therapy” or “combination therapy” refers to the use of two or more drugs or agents for treatment, for example, administering a compound of formula (I) to liver disorders such as NAFLD, NASH, and their respective symptoms and Combination therapy is used with a second agent useful for treating the indication. "Combination" administration refers to the administration of two agents (eg, a compound of Formula (I), and a second agent) in any manner in which the pharmacological effects of both agents appear in the patient at the same time. Thus, combination administration does not require that a single pharmaceutical composition, the same dosage form, or even the same route of administration be used for administration of both agents, or that the two agents be administered exactly simultaneously. Both agents may also be formulated into a single pharmaceutically acceptable composition. Non-limiting examples of such single compositions are oral compositions or oral dosage forms. For example, and without limitation, it is contemplated that a compound of Formula (I) may be administered in combination therapy with a second agent in accordance with the present disclosure.

As used herein, “second agent” refers to an agent other than a compound of formula (I) and useful in the methods described herein. The term second is intended as a term to distinguish an agent from a compound of formula (I) or a pharmaceutically acceptable salt or enantiomer thereof, and is not intended to imply the order of administration.

As used herein, the term “excipient” refers to an inert or inert substance that can be used in the manufacture of a drug or pharmaceutical, such as a tablet containing a compound of the present invention as an active ingredient. Any used as a binder, disintegrant, coating agent, compression/encapsulation aid, cream or lotion, lubricant, parenteral solution, chewable tablet, sweetening or flavoring agent, suspending/gelling agent, or wet granulating agent Various substances, including but not limited to substances, may be encompassed by the term excipient. Binders include, for example, carbomer, povidone, xanthan gum, and the like; Coatings include, for example, cellulose acetate phthalate, ethylcellulose, gellan gum, maltodextrin, enteric coatings, and the like; Compression/encapsulation aids include, for example, calcium carbonate, dextrose, fructose dc (dc = “directly compressible”), honey dc, lactose (anhydrous or monohydrate; optionally aspartame, cellulose, or microcrystalline combined with cellulose), starch dc, sucrose, and the like; Disintegrants include, for example, croscarmellose sodium, gellan gum, sodium starch glycolate, and the like; Creams or lotions include, for example, maltodextrin, carrageenan, and the like; Lubricants include, for example, magnesium stearate, stearic acid, sodium stearyl fumarate, and the like; Materials for chewing tablets include, for example, dextrose, fructose dc, lactose (monohydrate, optionally in combination with aspartame or cellulose) and the like; Suspending/gelling agents include, for example, carrageenan, sodium starch glycolate, xanthan gum, and the like; Sweetening agents include, for example, aspartame, dextrose, fructose dc, sorbitol, sucrose dc, and the like; Wet granulating agents include, for example, calcium carbonate, maltodextrin, microcrystalline cellulose, and the like.

“Patient” refers to a mammal and includes humans and non-human mammals. Examples of patients include, but are not limited to, mice, rats, hamsters, guinea pigs, pigs, rabbits, cats, dogs, goats, sheep, cattle, and humans. In some embodiments, a patient refers to a human.

"Pharmaceutically acceptable" refers to one that is safe and non-toxic for administration, preferably in vivo, and more preferably in humans.

"Pharmaceutically acceptable salt" refers to a pharmaceutically acceptable salt. The compounds described herein can be administered as a pharmaceutically acceptable salt.

"Salt" refers to an ionic compound formed between an acid and a base. When the compounds provided herein contain acidic functional groups, such salts include, but are not limited to, alkali metal, alkaline earth metal, and ammonium salts. Ammonium salts as used herein include salts containing protonated nitrogen bases and alkylated nitrogen bases. Exemplary, but non-limiting, cations useful for pharmaceutically acceptable salts include Na, K, Rb, Cs, NH ₄ , Ca, Ba, imidazolium, and ammonium cations based on naturally occurring amino acids. When a compound as used herein contains a basic functional group, such salts include, but are not limited to, salts of organic acids such as carboxylic acids and sulfonic acids, and inorganic acids such as hydrogen halide, sulfuric acid, phosphoric acid, and the like. Exemplary, but non-limiting, anions useful in pharmaceutically acceptable salts are oxalate, maleate, acetate, propionate, succinate, tartrate, chloride, sulfate, bisulfate, monobasic, dibasic, and tribasic phosphates. , mesylate, tosylate, and the like.

A “therapeutically effective amount” or dose of a compound or composition refers to an amount of the compound or composition that results in reduction or inhibition of symptoms, or prolongation of survival in a patient. Such results may require multiple doses of the compound or composition.

“Treatment” or “treatment” of a disease in a patient includes: 1) preventing the disease from developing in a patient predisposed to the disease or not yet showing symptoms of the disease; 2) inhibiting the disease or arresting its development; or 3) ameliorating the disease or causing its regression.

As used throughout this specification, the term "optional" or "optionally" means that the event or circumstance described thereafter may, but does not necessarily, occur, and such recitation includes instances where the event or circumstance occurs and instances where it does not. means to do For example, "a nitrogen atom is optionally oxidized to provide an N-oxide (N→O) moiety" may, but is not necessarily the case, a nitrogen atom being oxidized, and this is not necessarily the case, as such a description suggests that the situation in which the nitrogen atom is not oxidized and that the nitrogen atom is It is meant to include an oxidized situation.

How to use and what to use

A method of treating a liver disorder in a patient (eg, a human patient) in need thereof, comprising administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Liver disorders include liver inflammation, liver fibrosis, alcohol-induced fibrosis, steatosis, alcoholic steatosis, primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), non-alcoholic fatty liver disease (NAFLD), and non-alcoholic fatty acids. Provided herein is a method selected from hepatitis (NASH). Also, a method of treating a hepatic disorder with an FXR agonist in a patient (eg, a human patient) in need thereof, comprising administering a therapeutically effective amount of the FXR agonist, wherein the FXR agonist comprises the formula Provided herein is a method which is a compound of (I), or a pharmaceutically acceptable salt thereof.

In some embodiments, the liver disorder is NAFLD or NASH. In some embodiments, the liver disorder is NAFLD. In some embodiments, the liver disorder is NASH. In some embodiments, the patient has undergone a liver biopsy. In some embodiments, the method further comprises obtaining a result of a liver biopsy.

In addition, non-alcoholic fatty liver disease (NAFLD) in patients (eg, human patients) in need of inhibition or delay of progression of non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH). Provided herein is a method of inhibiting or delaying the progression of ) to non-alcoholic steatohepatitis (NASH) comprising administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof do. Further, there is provided a method of inhibiting or delaying the progression of NASH in a patient (eg, a human patient) in need thereof, wherein a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable Provided herein are methods comprising administering a salt.

The compound of formula (I) is preferentially distributed to the liver, as demonstrated in the examples described herein, and although not wishing to be bound by theory, it is the FXR target in the liver that the compound has less off-target adverse effects. will allow you to reach For example, the examples herein show that compounds of formula (I) have approximately 20-fold higher concentrations in the liver than in plasma, kidney, lung, heart, and skin. These traits may be particularly beneficial to vulnerable groups such as children, the elderly, and people with comorbidities.

Additionally, pruritus is a well-documented adverse effect of several FXR agonists and can lead to patient discomfort, reduced quality of life, and increased likelihood of treatment discontinuation. Pruritus is particularly burdensome for indications such as those described herein, including NASH with the potential for chronic drug administration. The tissue specificity of the compound of formula (I), in particular the preference of the liver over skin tissue, is a surprising and unexpected observation that makes it more likely that the compound will not cause pruritus in the skin, and this theory has been proven by human trials to date. has been

Thus, in a patient (eg, a human patient) in need of treatment for a liver disorder, with a farnesoid X receptor (FXR) agonist that is preferentially distributed in liver tissue over one or more of kidney, lung, heart, and skin tissues. Provided herein is a method of treating a liver disorder comprising administering a therapeutically effective amount of an FXR agonist, wherein the FXR agonist is a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

In some embodiments, a method of treating a liver disorder with a farnesoid X receptor (FXR) agonist (such as a compound of Formula (I) or a pharmaceutically acceptable salt thereof) in a patient in need thereof, comprising: Provided herein is a method wherein the FXR agonist does not activate TGR5 signaling. In some embodiments, the level of the FXR-regulated gene is increased. In some embodiments, the level of small heterodimer partner (SHP), bile salt efflux pump (BSEP) and fibroblast growth factor 19 (FGF-19) is increased. In some embodiments, the liver disorder is NASH.

In some embodiments, there is provided a method of reducing liver damage comprising administering to an individual in need thereof an FXR agonist (such as a compound of Formula (I) or a pharmaceutically acceptable salt thereof) to an individual in need thereof. provided herein. In some embodiments, fibrosis is reduced. In some embodiments, the expression level of one or more markers for fibrosis is reduced. In some embodiments, Ccr2, Col1a1, Col1a2, Col1a3, Cxcr3, Dcn, Hgf, Il1a, Inhbe, Lox, Loxl1, Loxl2, Loxl3, Mmp2, pdgfb, Plau, Serpine1, Perpinh1, Snai, Tgfb3, Thbs1, Tgf , the level of Timp2, and/or Timp3 expression is reduced. In some embodiments, the level of collagen is reduced. In some embodiments, the level of collagen fragments is reduced. In some embodiments, the expression level of the fibrosis marker is reduced by at least 2, at least 3, at least 4, or at least 5-fold. In some embodiments, the expression level of the fibrosis marker is reduced by about 2-fold, about 3-fold, about 4-fold, or about 5-fold.

In some embodiments, there is provided a method of reducing liver damage comprising administering to an individual in need thereof an FXR agonist (such as a compound of Formula (I) or a pharmaceutically acceptable salt thereof) to an individual in need thereof. provided herein. In some embodiments, inflammation is reduced. In some embodiments, one or more markers of inflammation are reduced. In some embodiments, the expression level of Adgre1, Ccr2, Ccr5, Il1A, and/or Tlr4 is decreased. In some embodiments, the expression level of the inflammatory marker is reduced by at least 2-, at least 3-, at least 4-, or at least 5-fold. In some embodiments, the expression level of the fibrosis marker is reduced by about 2-fold, about 3-fold, about 4-fold, or about 5-fold.

In some embodiments, administering results in a liver concentration to plasma concentration ratio of a compound of formula (I) of 10 or more, such as 11 or more, 12 or more, 13 or more, 14 or more, or 15 or more.

In some embodiments, administering does not result in pruritus of greater than grade 2 severity in the patient. In some embodiments, administering does not result in pruritus that is greater than grade 1 in severity in the patient. In some embodiments, administering does not cause pruritus in the patient. The classification of adverse effects is known. According to version 5 of the Common Terminology Criteria for Adverse Events (published November 27, 2017), grade 1 pruritus is characterized as “mild or local; local intervention recommendation”. Grade 2 pruritus is characterized as "widespread and intermittent; skin changes due to scratching (e.g., edema, papules, abrasions, lichenification, exudation/scabies); oral intervention recommendations; limited instrumental ADL". Grade 3 pruritus is characterized as "widespread and persistent; limited self-management ADL or sleep; systemic corticosteroid or immunosuppressive therapy recommendations". Activities of daily living (ADL) are divided into two categories: "instrumental ADL, meaning preparing meals, shopping for groceries or clothing, using the phone, managing finances, etc." and "bathing, putting on and taking off clothing, eating by oneself, toileting, etc." Self-Managed ADL, meaning Use, Medication, and Non-Cedential Dependence.

Accordingly, a method of treating a liver disorder in a patient (eg, a human patient) in need thereof with an FXR agonist that does not cause detectable pruritus in the patient in need thereof, comprising: a therapeutically effective amount Also provided herein is a method comprising administering to a patient in need thereof an FXR agonist of

In some embodiments, the patient is a human. Although obesity is strongly correlated with NAFLD and NASH, lean people can also develop NAFLD and NASH. Thus, in some embodiments, the patient is obese. In some embodiments, the patient is not obese. Obesity can also be correlated with or cause other diseases such as diabetes or cardiovascular disorders. Accordingly, in some embodiments, the patient also has diabetes and/or a cardiovascular disorder. Without being bound by theory, it is thought that comorbidities such as obesity, diabetes, and cardiovascular disorders may make NAFLD and NASH more difficult to treat. Conversely, the only currently accepted way to address NAFLD and NASH is weight loss, which will probably have little to no effect on lean patients.

Although the risk of NAFLD and NASH increases with age, children can also suffer from NAFLD and NASH, and children as young as 2 years of age have been reported in the literature (Schwimmer, et al., Pediatrics, 2006, 118:1388-1393). . In some embodiments, the patient is 2-17 years old, such as 2-10, 2-6, 2-4, 4-15, 4-8, 6-15, 6-10, 8-17, 8-15, 8 -12, 10-17, or 13-17 years old. In some embodiments, the patient is 18-64 years of age, such as 18-55, 18-40, 18-30, 18-26, 18-21, 21-64, 21-55, 21-40, 21-30, 21 -26, 26-64, 26-55, 26-40, 26-30, 30-64, 30-55, 30-40, 40-64, 40-55, or 55-64 years of age. In some embodiments, the patient is 65 years of age or older, such as 70 years old or older, 80 years old or older, 90 years old or older.

Although NAFLD and NASH are common causes of liver transplantation, patients who have already had one liver transplant often develop NAFLD and/or NASH again. Accordingly, in some embodiments, the patient has undergone a liver transplant.

In some embodiments, the patient has elevated levels of alkaline phosphatase, gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT), and/or aspartate aminotransferase (AST). In some embodiments, GGT, ALT, and/or AST levels are elevated prior to treatment with a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the patient's ALT level is about 2-4-fold higher than the upper limit of normal level. In some embodiments, the patient's AST level is about 2-4-fold higher than the upper limit of normal level. In some embodiments, the patient's GGT level is about 1.5-3-fold higher than the upper limit of normal level. In some embodiments, the patient's alkaline phosphatase level is about 1.5-3-fold higher than the upper limit of normal level. Methods for determining the levels of these molecules are well known. Normal levels of ALT in the blood range from about 7-56 units/liter. Normal levels of AST in the blood range from about 10-40 units/liter. Normal levels of GGT in the blood range from about 9-48 units/liter. Normal levels of alkaline phosphatase in the blood range from about 53-128 units/liter for 20- to 50-year-old males and about 42-98 units/liter for 20- to 50-year-old females.

Thus, in some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, reduces the level of AST, ALT, and/or GGT in an individual having elevated AST, ALT, and/or GGT levels. In some embodiments, the level of ALT is reduced by at least 2-, at least 3-, at least 4-, or at least 5-fold. In some embodiments, the level of ALT is reduced by about 2- to about 5-fold. In some embodiments, the level of AST is reduced by at least 2-, at least 3-, at least 4-, or at least 5-fold. In some embodiments, the level of AST is decreased by about 1.5 to about 3-fold. In some embodiments, the level of GGT is reduced by at least 2, at least 3, at least 4, or at least 5-fold. In some embodiments, the level of GGT is reduced by about 1.5 to about 3-fold.

In some embodiments, administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt thereof, does not substantially change the level of low density lipoprotein (LDL) (eg, serum level of LDL) in the subject. .

In some embodiments, administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt thereof, results in a decreased NAFLD activity score (NAS). For example, in some embodiments, steatosis, inflammation, and/or ballooning is reduced upon treatment. In some embodiments, a compound disclosed herein reduces liver fibrosis. In some embodiments, the compound reduces serum triglycerides. In some embodiments, the compound reduces liver triglycerides.

In some embodiments, the patient is at risk of developing an adverse effect prior to administering the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the adverse effect is an adverse effect that affects the kidneys, lungs, heart, and/or skin. In some embodiments, the adverse effect is pruritus.

In some embodiments, the patient has received one or more prior therapies. In some embodiments, the liver disorder progressed during therapy. In some embodiments, the patient has received at least one prior therapy with another FXR agonist other than a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the patient has suffered from pruritus during at least one of the one or more prior therapies.

In some embodiments, the therapeutically effective amount is less than a level that induces an adverse effect in the patient, such as less than a level that induces pruritus, such as grade 2 or grade 3 pruritus.

In some embodiments, the therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is 500 μg/day - 600 mg/day. In some embodiments, the therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is 500 μg/day - 300 mg/day. In some embodiments, the therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is 500 μg/day - 150 mg/day. In some embodiments, the therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is 500 μg/day - 100 mg/day. In some embodiments, the therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is between 500 μg/day - 20 mg/day. In some embodiments, the therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is 1 mg/day - 600 mg/day. In some embodiments, the therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is 1 mg/day - 300 mg/day. In some embodiments, the therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is 1 mg/day - 150 mg/day. In some embodiments, the therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is 1 mg/day - 100 mg/day. In some embodiments, the therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is 1 mg/day - 20 mg/day. In some embodiments, the therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is 5 mg/day - 300 mg/day. In some embodiments, the therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is 5 mg/day - 150 mg/day. In some embodiments, the therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is 5 mg/day - 100 mg/day. In some embodiments, the therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is 5 mg/day - 20 mg/day. In some embodiments, the therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is 5 mg/day - 15 mg/day. In some embodiments, the therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is 25 mg/day - 300 mg/day. In some embodiments, the therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is 25 mg/day - 150 mg/day. In some embodiments, the therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is 25 mg/day - 100 mg/day. In some embodiments, the therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is 500 μg/day - 5 mg/day. In some embodiments, the therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is 500 μg/day - 4 mg/day. In some embodiments, the therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is 5 mg/day - 600 mg/day. In another embodiment, the therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, is 75 mg/day - 600 mg/day.

In another embodiment, the therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, is about 1 mg/day. In another embodiment, the therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, is about 2 mg/day. In another embodiment, the therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, is about 5 mg/day. In another embodiment, the therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, is about 10 mg/day. In another embodiment, the therapeutically effective amount is about 15 mg/day. In another embodiment, the therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, is about 25 mg/day. In another embodiment, the therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, is about 75 mg/day. In another embodiment, the therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, is about 200 mg/day. In another embodiment, the therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, is about 400 mg/day. In another embodiment, the therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, is about 600 mg/day.

In some embodiments, administering comprises administering the compound of formula (I), or a pharmaceutically acceptable salt thereof, daily for a treatment period of at least one week. In some embodiments, administering comprises administering the compound of formula (I), or a pharmaceutically acceptable salt thereof, twice daily for a treatment period of at least one week. In some embodiments, administering comprises administering the compound of formula (I), or a pharmaceutically acceptable salt thereof, every other day for a treatment period of at least one week.

In some embodiments, the amount of compound of formula (I), or a pharmaceutically acceptable salt thereof, administered on the first day of the treatment period is greater than or equal to the amount administered on all subsequent days of the treatment period. In some embodiments, the amount of compound of formula (I), or a pharmaceutically acceptable salt thereof, administered on the first day of the treatment period is the same as the amount administered on all subsequent days of the treatment period.

In some embodiments, the duration of treatment is at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months. , 10 months, 11 months, 12 months, 1 year, 2 years, 3 years, 4 years, or more. In some embodiments, the treatment period is from about 1 week to about 1 month, from about 1 month to about 1 year, from about 1 year to about several years. In some embodiments, the duration of treatment is about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months. , 10 months, 11 months, 12 months, 1 year, 2 years, 3 years, 4 years, or more. In some embodiments, the duration of treatment is the remaining lifespan of the patient.

In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered in combination with rifampicin. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered as a monotherapy, i.e. useful in treating or substantially treating a liver disorder in a patient in need thereof, or is non-alcoholic It is administered without another agent that inhibits or delays the progression of sexual fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH), or inhibits or delays the progression of NASH. In some embodiments, the method does not comprise treating pruritus in the patient. In some embodiments, the method does not comprise administering an antihistamine, an immunosuppressant, a steroid (such as a corticosteroid), rifampicin, an opioid antagonist, or a selective serotonin reuptake inhibitor (SSRI).

In some embodiments, a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered once daily. In some embodiments, a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered twice daily. In some embodiments, the therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is 75 mg - 200 mg twice daily per patient. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered as a pharmaceutically acceptable composition comprising at least one pharmaceutically acceptable excipient, carrier, or diluent.

In some embodiments, administration modulates one or more of the following: metabolic pathways, bile secretion, retinol metabolism, drug metabolism-cytochrome P450, fat digestion and absorption, glycerolipid metabolism, chemical carcinogenesis, glycerophospholipid metabolism, nicotine Addiction, linoleic acid metabolism, ABC transporter, xenobiotic metabolism by cytochrome P450, sphingolipid metabolism, glutathione metabolism, folate biosynthesis, morphine poisoning, glycosphingolipid biosynthesis-lacto and neolacto series, arachidonic acid metabolism, tyrosine Metabolism, maturation-onset diabetes in young adults, DNA replication, cholesterol metabolism, drug metabolism-other enzymes, and ether lipid metabolism. In some embodiments, administration modulates one or more of the following: metabolic pathways, retinol metabolism, fat digestion and absorption, glycerolipid metabolism, chemical carcinogenesis, glycerophospholipid metabolism, ABC transporter, xenobiotic by cytochrome P450 Metabolism, sphingolipid metabolism, glutathione metabolism, folate biosynthesis, and morphine addiction. In some embodiments, administering modulates expression of one or more of the following: Abcb4, Apoa5, Cyp7a1, Cyp8b1, Nr0b2, and Sic51b.

compound

In some embodiments, a compound as used herein is a compound of Formula (I), or a tautomer thereof, or each isoisomer thereof, or an enantiomer or diastereomer thereof, or a pharmaceutically acceptable salt of each of the foregoing. to be:

In some embodiments, the compound used herein is a compound of Formula (I). In some embodiments, a compound as used herein is a pharmaceutically acceptable salt of a compound of Formula (I).

The compounds used herein can be prepared by a combination of various stepwise procedures known in the art, such as, for example, US 2010/0152166 (incorporated herein by reference).

In some embodiments, the compound of Formula (I) is 6-{4-[5-cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazol-4-ylmethoxy]-piperidine-1- yl}-1-methyl-1H-indole-3-carboxylic acid, or a pharmaceutically acceptable salt or enantiomer thereof:

composition

In some aspects a compound as detailed herein may be in purified form, and compositions comprising the compound in purified form are detailed herein. A composition comprising a compound as detailed herein or a salt thereof, such as a composition of a substantially pure compound, is provided. In some embodiments, a composition containing a compound as detailed herein or a salt thereof is in substantially pure form. In one variant, "substantially pure" refers to a composition containing no more than 35% impurities, wherein the impurities refer to compounds other than the compound or salt thereof that make up the majority of the composition. For example, a composition of a substantially pure compound is intended to contain no more than 35% of an impurity, wherein the impurity refers to a compound other than said compound or a salt thereof. In one variant, there is provided a composition of substantially pure compound or salt thereof, the composition containing no more than 25% impurities. In yet another variation, a composition of substantially pure compound or salt thereof, wherein the composition contains no more than 20% impurities is provided. In yet another variation, a composition of substantially pure compound or salt thereof, wherein the composition contains no more than 10% impurities is provided. In a further variant, there is provided a composition of substantially pure compound or salt thereof, the composition containing no more than 5% impurities. In yet another variation, a composition of substantially pure compound or salt thereof, the composition containing no more than 3% impurities is provided. In yet another variation, a composition of substantially pure compound or salt thereof, wherein the composition contains no more than 1% impurities is provided. In a further variant, there is provided a composition of substantially pure compound or salt thereof, the composition containing up to 0.5% impurities. In another variation, a composition of a compound that is substantially pure means that the composition contains no more than 15%, such as no more than 10%, no more than 5%, no more than 3%, or no more than 1% of impurities, wherein the impurities are in different stereochemical forms. It means that it may be a compound of For example, and not by way of limitation, a composition of compound (S) that is substantially pure means that the composition contains no more than 15% or no more than 10% or no more than 5% or no more than 3% or no more than 1% of the compound of the form (R). it means.

In one variation, the compound herein is a synthetic compound prepared for administration to a subject, such as a human. In another variation, a composition containing the compound in substantially pure form is provided. In another variation, the present disclosure encompasses pharmaceutical compositions comprising a compound detailed herein and a pharmaceutically acceptable carrier or excipient. In another variation, provided herein is a composition or pharmaceutical composition for use in any of the methods provided herein. Purified forms, pharmaceutical compositions, and methods of administering the compounds are suitable for any compound or any form thereof detailed herein.

Pharmaceutical compositions of any of the compounds detailed herein are encompassed by this disclosure. Accordingly, the present disclosure includes pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. In one aspect, a pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with an inorganic or organic acid. The pharmaceutical composition according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration or a form suitable for administration by inhalation.

The compound or pharmaceutical composition may be administered in any form, including oral, mucosal (eg, nasal, sublingual, vaginal, buccal or rectal), parenteral (eg, intramuscular, subcutaneous or intravenous), topical or transdermal delivery forms. can be formulated for available routes of delivery. The compound or pharmaceutical composition may be formulated as a tablet, caplet, capsule (such as a hard gelatin capsule or soft elastic gelatin capsule), cachet, troche, lozenge, gum, dispersion, suppository, ointment, poultice, paste, powder, dressing , creams, solutions, patches, aerosols (e.g., nasal sprays or inhalers), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), solutions and elixirs It may be formulated with suitable carriers to provide a form of delivery, including but not limited to.

The compounds described herein can be used in the preparation of compositions, such as pharmaceutical compositions, by combining the compound as an active ingredient with a pharmaceutically acceptable carrier such as those mentioned above. Depending on the therapeutic form of the system (eg, transdermal patch vs. oral tablet), the carrier can take a variety of forms. Additionally, the pharmaceutical compositions may contain preservatives, solubilizers, stabilizers, rewetners, emulsifiers, sweeteners, dyes, adjusting agents for the adjustment of osmotic pressure and salts, buffers, coating agents or antioxidants.

Compositions comprising the compounds may also contain other substances with valuable therapeutic properties. Pharmaceutical compositions may be prepared by known pharmaceutical methods. Suitable formulations are described, for example, in Remington: The Science and Practice of Pharmacy , Lippincott Williams & Wilkins, 21 ^st ed. (2005), which is incorporated herein by reference.

The compounds as described herein can be administered to a subject (eg, a human) in the form of generally acceptable oral compositions, such as tablets, coated tablets, and hard or soft shell gel capsules, emulsions or suspensions. Examples of carriers that can be used in the preparation of such compositions are lactose, corn starch or derivatives thereof, talc, stearate or salts thereof, and the like. Acceptable carriers for gel capsules having a soft shell are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Additionally, the pharmaceutical preparations may contain preservatives, solubilizers, stabilizers, rewetners, emulsifiers, sweeteners, dyes, adjusting agents for the adjustment of osmotic pressure and salts, buffers, coating agents or antioxidants.

Any of the compounds described herein may be formulated as tablets in any of the dosage forms described.

Compositions comprising a compound provided herein are also described. In one variation, the composition comprises a compound and a pharmaceutically acceptable carrier or excipient. In another variation, a composition of substantially pure compound is provided.

In some embodiments, the treatment of liver disorders; inhibiting or delaying the progression of non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH); or treating a liver disorder in a patient in need thereof; inhibiting or delaying the progression of non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH); or for inhibiting or delaying the progression of NASH, a compound of formula (I), or a tautomer thereof, or each isoisomer thereof, or an enantiomer or diastereomer thereof, or each of said pharmaceutically acceptable A pharmaceutically acceptable composition comprising a salt and at least one pharmaceutically acceptable excipient, carrier, or diluent, wherein the liver disorder is liver inflammation, liver fibrosis, alcohol-induced fibrosis, steatosis, alcoholic steatosis, primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), NAFLD, and NASH.

In some embodiments, provided herein is a unit dosage form of a pharmaceutically acceptable agent provided herein. In some embodiments, the unit dosage form comprises a therapeutically effective amount of a compound of Formula (I). In some embodiments, the unit dosage form comprises a therapeutically effective amount of a compound of Formula (I) and a therapeutically effective amount of another agent. In some embodiments, the unit dosage form is for the treatment of liver disorders; inhibiting or delaying the progression of non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH); or treating a liver disorder in a patient in need thereof; inhibiting or delaying the progression of non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH); or to inhibit or delay the progression of NASH, wherein the liver disorder is liver inflammation, liver fibrosis, alcohol-induced fibrosis, steatosis, alcoholic steatosis, primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), NAFLD, and NASH.

Also provided herein is the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament. In some embodiments, the manufacture of the medicament comprises liver inflammation, liver fibrosis, alcohol-induced fibrosis, steatosis, alcoholic steatosis, primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), non-alcoholic fatty liver disease (NAFLD), and non-alcoholic steatohepatitis (NASH). In some embodiments, the manufacture of the medicament is for the treatment of non-alcoholic steatohepatitis (NASH).

Exemplary embodiments

Provided embodiments are in particular:

1. A method of treating a liver disorder in a patient in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the liver disorder is liver inflammation, liver fibrosis, alcohol-induced fibrosis, steatosis, alcoholic steatosis, primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), non-alcoholic fatty liver disease (NAFLD), and non-alcoholic steatohepatitis (NASH) How to be.

2. A method of treating a hepatic disorder with a farnesoid X receptor (FXR) agonist in a patient in need thereof, comprising administering a therapeutically effective amount of an FXR agonist, wherein the FXR agonist is of formula ( A compound of I) or a pharmaceutically acceptable salt thereof, wherein the patient has discontinued at least one prior therapy with another FXR agonist other than the compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein Liver disorders include liver inflammation, liver fibrosis, alcohol-induced fibrosis, steatosis, alcoholic steatosis, primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), non-alcoholic fatty liver disease (NAFLD), and non-alcoholic fatty acids. Hepatitis (NASH).

3. The method of embodiment 2, wherein the patient has suffered from pruritus during at least one prior therapy.

4. Non-alcoholic steatohepatitis of non-alcoholic fatty liver disease (NAFLD) in a patient in need of inhibition or delay of progression of non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH) A method of inhibiting or delaying progression to (NASH) comprising administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

5. A method of inhibiting or delaying the progression of NASH in a patient in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. .

6. A method of treating a liver disorder in a patient in need thereof with a farnesoid X receptor (FXR) agonist that preferentially concentrates in liver tissue over one or more of kidney, lung, heart, and skin tissues, the method comprising: A method comprising administering a therapeutically effective amount of an FXR agonist, wherein the FXR agonist is a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the liver disorder is liver inflammation, liver fibrosis, alcohol-induced fibrosis, steatosis, alcohol steatosis, primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), non-alcoholic fatty liver disease (NAFLD), and non-alcoholic steatohepatitis (NASH).

7. The method according to any one of embodiments 1-6, wherein the administering does not cause pruritus of greater than grade 2 severity in the patient.

8. The method of any one of embodiments 1-7, wherein the administering does not cause pruritus of greater than grade 1 severity in the patient.

9. The method of any one of embodiments 1-8, wherein the administering does not cause pruritus in the patient.

10. A method of treating a liver disorder with an FXR agonist that does not cause appreciable pruritus in a patient in need thereof, comprising administering a therapeutically effective amount of an FXR agonist, wherein the FXR agonist comprises: I) or a pharmaceutically acceptable salt thereof, wherein the liver disorder is liver inflammation, liver fibrosis, alcohol-induced fibrosis, steatosis, alcoholic steatosis, primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), non- alcoholic fatty liver disease (NAFLD), and non-alcoholic steatohepatitis (NASH).

11. The method of any one of embodiments 1-3, or 6-10, wherein the liver disorder is NAFLD.

12. The method of any one of embodiments 1-3, or 6-10, wherein the liver disorder is NASH.

13. The method of any one of embodiments 1-3, or 6-10, wherein the liver disorder is PSC.

14. The method of any one of embodiments 1-3, or 6-10, wherein the liver disorder is PBC.

15. The method according to any one of embodiments 1-14, wherein the administering results in a liver concentration to plasma concentration ratio of the compound of formula (I) of at least 10.

16. The method of any one of embodiments 1-15, wherein the therapeutically effective amount is 0.5 μg/day - 600 mg/day.

17. The method of any one of embodiments 1-16, wherein the therapeutically effective amount is 0.5 μg/day - 20 mg/day.

18. The method of any one of embodiments 1-17, wherein the therapeutically effective amount is 0.5 μg/day - 4 mg/day.

19. The method of any one of embodiments 1-18, wherein administering comprises administering the compound of formula (I), or a pharmaceutically acceptable salt thereof, daily for a treatment period of at least one week.

20. The method according to embodiment 19, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day or twice a day.

21. The method according to embodiment 19 or 20, wherein the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof administered on the first day of the treatment period is greater than or combined with the amount administered on all subsequent days of the treatment period. How the same.

22. The method according to any one of embodiments 19-21, wherein the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof administered on the first day of the treatment period is the same as the amount administered on all subsequent days of the treatment period. Way.

23. The method of any one of embodiments 1-22, wherein the treatment period is at least 1 month.

24. The method of any one of embodiments 1-23, wherein the duration of treatment is the remaining lifespan of the patient.

25. The method of any one of embodiments 1-24, wherein the patient is obese.

26. The method of any one of embodiments 1-24, wherein the patient is not obese.

27. The method according to any one of embodiments 1-26, wherein the patient also has diabetes and/or a cardiovascular disorder.

28. The method of any one of embodiments 1-27, wherein the patient is at risk of developing an adverse effect affecting one or more of the kidneys, lungs, heart, and skin.

29. The method of any one of embodiments 1-28, wherein the patient is 2-17 years of age.

30. The method of any one of embodiments 1-28, wherein the patient is 18-54 years of age.

31. The method of any one of embodiments 1-28, wherein the patient is at least 65 years of age.

32. The method of any one of embodiments 1-31, wherein the patient has undergone a liver transplant.

33. The patient of any one of embodiments 1-32, wherein the patient has elevated levels of alkaline phosphatase, gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST). How it is made.

34. The method of any one of embodiments 1-33, wherein the method does not comprise administering an antihistamine, an immunosuppressant, a steroid, rifampicin, an opioid antagonist, or a selective serotonin reuptake inhibitor (SSRI).

Example

The present application may be better understood by reference to the following non-limiting examples provided as illustrative embodiments of the present application. The following examples are presented to illustrate the embodiments in more detail and should not be construed as limiting the scope of the present application in any way. While specific embodiments of the present application have been shown and described herein, it will be apparent that such embodiments are provided by way of example only. Numerous modifications, changes, and substitutions can be found by those skilled in the art without departing from the spirit and scope of the present invention. It should be understood that various alternatives to the embodiments described herein may be utilized in practicing the methods described herein.

"Compound I" as used herein refers to a compound of formula (I):

Example 1: In vitro metabolic stability

The hepatic metabolic rate of compound I was assessed in cryopreserved hepatocytes to determine the in vitro half-life of the compound. Mix 1 μM of compound I with preconditioned mouse, rat, canine, monkey, or human hepatocytes (0.5 x 10 ⁶ cells/mL) and allow to incubate at 37 °C for 2 h, with samples at multiple time points. collected and assayed for compound I. In vitro half-life values were determined and described in Obach et al., The Prediction of Human Pharmacokinetic Parameters from Preclinical and In Vitro Metabolism Data , J. of Pharmacology and Experimental Therapeutics, vol. 283, no. 1, pp. 46-58 (1997), adjusted using a fully-homogeneous liver model without correction for plasma proteins to predict liver clearance (CL _pred ) and liver extraction rates. The results are presented in Table 1, demonstrating that compound I was moderately metabolized in hepatocytes of all tested species.

Table 1. In vitro metabolic stability of compound I

Example 2: In vitro OATP transport assay

Polarized monolayers of MDCK-II cells grown on permeable supports were used to test the ability of organic-anion-transporting polypeptide (OATP) 1B1 or OATP 1B3 to transport compound I across the lipid bilayer into cells. MDCK-II cells were transfected with either: (1) a vector expressing OATP 1B1, (2) a vector expressing OATP 1B3, or (3) a control vector. After induction of expression in the cells, the cells were incubated at 37° C. under an atmosphere of 5% CO ₂ . After induction of expression, cells were treated with 1 μM, 3 μM, and 10 μM of Compound I, or 3 μM of Compound I and 100 μM of rifampin. Cellular uptake of compound I was then measured. The results from this experiment demonstrated that compound I was not an OATP 1B1 or OATP 1B3 substrate.

Example 3: Pharmacokinetic Assay

Compound I was administered intravenously at 1 mg/kg to Sprague-Dawley (SD) rats (n=3) or orally at 10 mg/kg (n=3), and to beagle dogs intravenously at 1 mg/kg (n=3). =3) or orally at 3 mg/kg (n=3), orally at 0.3 mg/kg to cynomolgus monkeys (n=6) or orally at 5 mg/kg (n=6), also in mice was administered orally (n=9) at 5 mg/kg. Compound I for oral administration to SD rats was formulated in a vehicle containing 10% DMSO, 10% Cremophor-EL, and 80% aqueous solution (10% 2-hydroxypropyl-β-cyclodextrin). Compound I for oral administration to beagle dogs was formulated as an aqueous solution containing 1% carboxymethyl cellulose, 0.25% Tween-80, and 0.05% antifoam. Compound I for oral administration to cynomolgus monkeys was formulated in 10% solutol, 20% PEG400, 0.5% Tween-80 and 69.5% deionized water. Serial blood samples were collected and plasma concentrations of Compound I were determined. Results are presented in Figure 1A (IV administration) and Figure 1B (oral administration), and Table 2. The results demonstrate that compound I has low to moderate clearance in vivo. In rats and dogs, the volume of distribution (V _dss ) of compound I is greater than the total body water volume (0.70 L/kg). A smaller V _dss in monkeys correlated with higher plasma protein binding.

Table 2. Pharmacokinetic parameters of compound I

Example 5: Tissue distribution of compound I

The tissue distribution of Compound I administered to rats was determined and compared with the distribution of other farnesoid X receptor (FXR) agonists silofexor, tropexor, and obeticholic acid (OCA). Compounds to be tested were administered to SD rats (n=3 per compound) by 30 min intravenous infusion at 2 mg/kg. Blood, liver, kidney, and lung tissue samples were collected from rats to determine the tissue/plasma ratio. The liver tissue/plasma ratio for compound is presented in FIG. 2A , demonstrating that substantially more compound I is localized to liver tissue compared to other tested compounds. Co-administration of Compound I with 100 μM rifampin did not result in significant changes in the distribution of Compound I to the liver ( FIG. 2B ). Taken together, these results indicate that Compound I is preferentially distributed in the liver in rodent species and exhibits a higher liver/plasma ratio than other FXR agonists being studied for the treatment of NASH (silofexor, tropexor, and OCA). demonstrated to be approximately 3 to 20-fold higher.

Radiolabeled ( ¹⁴ C) compound I was also administered to Long-Evans rats at an oral dose of 5 mg/kg (100 μCi/kg). Plasma, liver, small intestine, cecum, kidney, lung, heart and skin tissue samples were collected up to 168 hours to determine the amount of radioactive material at various time points. The results are presented in FIG. 3 . The liver, small intestine, and cecum contained the most radioactive material.

Example 6: Metabolism of compound I

Radiolabeled ( ¹⁴ C) Compound I was administered orally at 5 mg/kg or intravenously at 2 mg/kg to SD rats with intact or bile duct intubated SD rats at a total radioactive dose of 100 μCi/kg (4 cohorts each). n=3) was administered. Blood, bile, stool, and urine samples were collected from each rat for up to 168 hours. Compound I was metabolized to an acyl glucuronide metabolite prior to biliary excretion, which was determined as the major route of elimination of the compound.

Example 7: Pharmacokinetic/Pharmacodynamic Profile

Pharmacokinetics/pharmacodynamics (PK) in cynomolgus monkeys by administering an oral dose of a suspension of Compound I at a dose of 0 (vehicle), 0.3, 1, or 5 mg/kg and collecting blood samples for up to 24 hours. /PD) profile was determined. Pharmacokinetics was determined as a function of 7-alpha-hydroxy-4-cholesten-3-one (7α-C4) reduction quantified by LC-MS/MS ( FIG. 4 ). Pharmacokinetic data are presented in Table 3, which was determined by non-compartmental analysis.

Table 3. Pharmacokinetic parameters of compound I

Compound I was also orally administered to cynomolgus monkeys (n=6) at 1 mg/kg for 7 consecutive days to determine the PK/PD profile after multiple doses. The results of this study are presented in Figure 5a (PK profile) and Figure 5b (PD profile) and Table 4, indicating that plasma exposure of Compound I was similar on days 1 and 7, and that after repeated oral dosing, approximately We demonstrate that sustained inhibition of the epidemiological biomarker 7α-C4 was achieved.

Table 4. Pharmacokinetic parameters of compound I

Example 8: Mechanism of Action

C5BL/6 mice were administered 10 mg/kg of Compound I (n=6), 30 mg/kg of OCA (n=6), or vehicle control (n=6) as a single oral dose, and tissue RNA samples were administered Collected 6 hours after dose administration. RNA was analyzed by RT-qPCR and RNAseq.

In RT-qPCR, FXR-regulated gene expression in liver and ileum was quantified via the 2-ddCT method using gene-specific primers. Results are presented in Figure 6 (data presented as mean ± SEM; **** indicates p < 0.0001 versus vehicle, * indicates p < 0.05 versus vehicle, statistics are followed by one-way ANOVA determined by Turkey). These data indicate that Compound I preferentially induces FXR-specific genes in the liver of mice.

In RNAseq analysis, mRNA was extracted from the liver and sequenced using standard Illumina library preparation and sequencing protocols. Differentially expressed genes (DEGs) were determined using RSEM and edgeR software packages and analyzed using iPathwayGuide software from Advaita Bio. The results are presented in FIGS. 7A-7D , indicating that Compound I modulates a significantly higher number of NASH-related genes and metabolic pathways compared to OCA. 7A shows that administration of Compound I modulates the expression of 500 NASH-associated genes, including 37 common NASH-associated genes modulated by both Compound I and OCA, and OCA modulates the expression of 44 NASH-associated genes. shown to modulate the expression of , compared to vehicle controls (fold change ≥ 1.5; q-value < 0.05). 7B shows the mean expression levels (presented by CPM values) of select FXR-related genes in mice treated with vehicle, OCA, and Compound I. 7C shows that administration of Compound I results in enhancement of 32 global routes and administration of OCA results in enhancement of 6 global routes, including two common global routes for both administration of Compound I and OCA. suggest that you do 7D shows the 25 routes that are statistically most potent upon administration of Compound I, and compares the potentiation of these pathways to that upon administration of OCA. Collectively, RNAseq analysis of livers of mice treated with Compound I suggested more robust modulation of FXR-related genes and non-alcoholic fatty liver disease-associated metabolic pathways compared to OCA treatment.

Example 9: Clinical Study

1st study . To healthy human volunteer subjects, Compound I is dosed orally at 5 mg (n=9), 75 mg (n=9), 200 mg, or 400 mg (n=18) on a daily basis for 14 days, or placebo ( n=12). During this study, no occurrence of pruritus was observed.

Second study . Human subjects were given an oral dose of 25 mg (n=11), 75 mg (n=10), or 150 mg (n=10) of Compound I daily for 7 days, or received a placebo (n=5) . As shown in Table 5, the patient's 7-alpha-hydroxy-4-cholesten-3-one (7α-C4) levels were measured periodically, indicating that the levels were inhibited by compound I. As reported in a separate study published by an independent group, the FXR agonist MET409 (Metacrine) was administered at doses of 20 mg, 40 mg, 50 mg, 80 mg, 100 mg, or 150 mg. Healthy human volunteers were dosed daily and 7α-C4 levels were measured as shown in Table 5. Chen et al., MET409, an Optimized Sustained FXR Agonist, Was Safe and Well-Tolerated in a 14-Day Phase 1 Study in Healthy Subjects , The International Liver Congress, Vienna, Austria, April 10-14, 2019 see While pruritus was observed in subjects receiving MET409 at doses greater than or equal to 100 mg, no pruritus was observed in subjects receiving the highest dose of Compound I. Other FXR agonists such as cilofexor, tropexor, OCA, ED-305 (Enanta) are all known to cause pruritus in long-term studies.

Table 5. Comparison of MET409 and Compound I

Example 10: Mouse model of NASH

A mouse model in which NASH was induced by a high fat diet was used to evaluate the effect of Compound I in combination with CCl ₄ administration on NASH.

Mice C57/BL6J mice were fed a high-fat diet (D12492, Research Diet, fat/protein/carbohydrate 60/20/20 Kcal%, 10w) to induce obesity (>36 g mice), followed by 4 weeks. Daily with oral Compound I and biweekly with intraperitoneal carbon tetrachloride (CCl ₄ ). Figure 8. Compound I was administered at doses of 10, 30, and 100 mg/kg.

After 28 days of dosing of compound I, serum lipids, serum transaminase and hepatic lipids were analyzed. Hematoxylin & Eosin (H&E) and Sirius Red histological staining of liver tissue was used to quantify NAFLD activity score (NAS), steatosis, ballooning, inflammation and fibrosis. Plasma 7-alpha-hydroxy-4-cholesten-3-one (7α-C4) was determined as a biomarker of FXR activation. The gene expression of RNA was analyzed by RT-qPCR and RNAseq.

The Nonalcoholic Fatty Liver Disease Activity Score (NAS) is a composite score used to evaluate NASH. NAS is calculated according to hepatic steatosis, inflammation, and ballooning, and is determined by histological analysis of liver tissue using H&E staining. Specifically, inflammation scores are calculated based on H&E staining: score 0, none; 1, <2 lesions/200X field of view; 2, 2-4 lesions/200X field of view; 3, >4 lesions/200X field of view. The steatosis score is calculated by H&E staining as follows: score 0, <5%; 1, 5-33%; 2, >33-66%; 3, >66%. Hepatocyte ballooning is a form of hepatocyte degeneration associated with cell swelling, which is also measured by H&E stained liver sections. Ballooning scores are calculated as follows: 0-no hepatocyte ballooning; 1 - few ballooned hepatocytes; 2 - A large number of hepatocytes with pronounced ballooning.

As shown in FIG. 9 , mice treated with 10, 30, or 100 mg/kg of Compound I had significantly lower NAS scores compared to untreated NASH mice. Treatment with Compound I also significantly reduced steatosis, inflammation and ballooning compared to untreated NASH mice. 10a-c.

Liver fibrosis was quantified by histological analysis of the percentage of Sirius Red-positive liver sections. 11A shows representative histology of healthy mice, NASH mice, and NASH mice treated with 100 mg/kg of Compound I. 11B presents quantification of fibrosis area in mice treated with Compound I. Treatment with Compound I at 10, 30 or 100 mg/kg resulted in statistically significant reduced fibrosis compared to untreated NASH controls. As shown in FIG. 14A , Compound I dosed at 10, 30, or 100 mg/kg resulted in reduced expression of collagen alpha 1 in the liver compared to control NASH mice.

After treatment, serum was analyzed for alanine amino transferase (ALT), aspartate amino transferase (AST), triglycerides, and total cholesterol levels. 12A and 12B , serum ALT and AST levels were decreased in mice treated with Compound I. 12C shows a statistically significant decrease in serum triglyceride concentrations in mice treated with 100 mg/kg of Compound I. 12D shows statistically significant reductions in total cholesterol levels in mice treated with Compound I at 10, 30, and 100 mg/kg.

Liver triglycerides were measured from liver tissue using a biochemical analyzer (Hitachi-700). 13A shows the concentrations of liver triglycerides in control mice or mice treated with 10, 30, or 100 mg/kg of Compound I. Mice treated with 100 mg/kg of Compound I presented statistically significant reduced triglyceride levels. 13B shows a representative histological section.

The effect of compound I on gene expression was analyzed using RT-qPCR or RNA-seq of liver samples ( FIGS. 14a-c and Table 6). Table 6 presents the effect of compound I on FXR-regulated gene expression in the liver. The activity of compound I compared to vehicle was determined by dividing the expression level of each indicated gene (defined by the gene count per million (CPM) value) after treatment with compound I by the expression level of that gene in vehicle-treated animals. .

Table 6. Expression of FXR-targets, inflammation, and fibrosis genes

EC ₅₀ concentrations of compound I for FXR were determined by a fluorescence-based FXR co-activation assay. Half-log serial dilutions (10 μM-3 nM) of Compound I or OCA (obeticholic acid, a known FXR agonist) were mixed with human FXR ligand binding domain, labeled coactivator SRC, produced in Sf9 insect cells at 25° C. for 1 h. Incubated with -1 peptide and TR-FRET co-regulator buffer G. TGR5 activity was measured using a cell-based cAMP assay. See Kawamata et al. JBC 278 (11)935-440 (2003)]. Half-log serial dilutions (10 μM-3 nM) of Compound I or OCA were added to Chinese hamster ovary cells expressing recombinant human TGR5. After 30 min at RT, cAMP was measured using HTRF reading. EC ₅₀ values for FXR-regulated gene expression were determined using a cell-based RNA assay. Half-log serial dilutions of Compound I or OCA (3 μM-3 nM) were added to human HuH7 hepatocellular carcinoma cells. After 11 h at 37°C, RNA was isolated and RT- using primers for FXR-related genes: small heterodimer partner (SHP), bile salt efflux pump (BSEP) and fibroblast growth factor 19 (FGF-19). analyzed by qPCR.

As shown in Table 7, Compound I is a potent and selective FXR agonist.

Table 7. EC of compound I ₅₀

In summary, Compound I is a potent and selective FXR agonist. Compound I reduced the expression of genes related to inflammation and fibrosis, and significantly inhibited hepatic steatosis, inflammation, ballooning, and fibrosis in a mouse model of NASH.

Example 11: Pharmacokinetic Study

Thirty-six healthy subjects were randomized into four dosing groups, each of which received placebo, 25 mg, 75 mg, or 150 mg of Compound I QD for 7 days. Serum levels of Compound I in the subject were measured periodically. Mean serum concentrations of Compound I on days 1 and 7 are shown in FIGS. 15A and 15B , respectively.

Serum levels of 7-alpha-hydroxy-4-cholesten-3-one (7α-C4) in the subject were measured periodically. 16A and 16B show the change in mean serum levels of 7α-C4 from baseline predose in different dosing groups on days 1 and 7, respectively. Subjects in the placebo group experienced postprandial 7α-C4 spikes, which were suppressed in COMPOUND I-dose subjects. Partial inhibition of serum 7α-C4 levels was observed after a single dose on day 1 in all Compound I dosing groups. On day 7, maximal inhibition of serum 7α-C4 levels was observed 6 hours after dosing, corresponding to reductions of 74%, 82%, and 91% in the 25, 75, and 150 mg dosing groups, respectively. During each 24-hour dosing period, mean serum levels of Compound I in all Compound I dosing groups generally did not exceed the EC ₅₀ of Compound I. Without wishing to be bound by theory, it is believed that the decrease in 7α-C4 is associated with a higher concentration of compound I in the liver due to its preferential distribution in the liver.

Serum levels of FGF-19 in subjects were measured periodically. 17A and 17B show the change in mean serum levels of FGF-19 from baseline predose in different dosing groups on days 1 and 7, respectively. Maximum increases of 718%, 486%, and 454% from baseline in serum FGF 19 levels were observed 4 hours after dosing on Day 7.

Serum levels of low density lipoprotein (LDL) in the subject were measured periodically. 18 shows the change in mean serum levels of low density lipoprotein (LDL) from baseline before dosing in different dosing groups. Changes in serum LDL above baseline were minimal in the COMPOUND I dosing group and did not exceed the LDL elevations observed in placebo-treated subjects.

Safety was assessed during dosing and for 10 (±1) days post-dose. Compound I was safe at all doses with no reports of pruritus and was well tolerated in healthy volunteers.

All references throughout, such as publications, patents, patent applications, and published patent applications, are incorporated herein by reference in their entirety.

Claims (40)

A method of treating a liver disorder in a patient in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the liver disorder is liver inflammation, liver fibrosis. , alcohol induced fibrosis, steatosis, alcoholic steatosis, primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), non-alcoholic fatty liver disease (NAFLD), and non-alcoholic steatohepatitis (NASH). how to be.

A method of treating a liver disorder with a farnesoid X receptor (FXR) agonist in a patient in need thereof, the method comprising administering a therapeutically effective amount of an FXR agonist, wherein the FXR agonist comprises Formula (I) wherein the patient has discontinued at least one prior therapy with another FXR agonist other than a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the patient has a liver disorder is liver inflammation, liver fibrosis, alcohol-induced fibrosis, steatosis, alcoholic steatosis, primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), non-alcoholic fatty liver disease (NAFLD), and non-alcoholic steatohepatitis ( NASH).

3. The method of claim 2, wherein the patient has suffered from pruritus during at least one prior therapy. Non-alcoholic steatohepatitis (NASH) of non-alcoholic fatty liver disease (NAFLD) in a patient in need of inhibition or delay of progression of non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH) ), comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

A method of inhibiting or delaying the progression of NASH in a patient in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

A method of treating a liver disorder in a patient in need thereof with a farnesoid X receptor (FXR) agonist that preferentially concentrates in liver tissue over one or more of kidney, lung, heart, and skin tissues, comprising: a therapeutically effective amount wherein the FXR agonist is a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the liver disorder is liver inflammation, liver fibrosis, alcohol-induced fibrosis, steatosis, alcoholic steatosis. , primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), non-alcoholic fatty liver disease (NAFLD), and non-alcoholic steatohepatitis (NASH).

7. The method according to any one of claims 1 to 6, wherein the administration does not cause pruritus in the patient of greater than grade 2 severity. 8. The method according to any one of claims 1 to 7, wherein the administering does not cause pruritus in the patient of greater than grade 1 severity. 9. The method according to any one of claims 1 to 8, wherein the administration does not cause pruritus in the patient. A method of treating a liver disorder with an FXR agonist that does not cause appreciable pruritus in a patient in need thereof, comprising administering a therapeutically effective amount of the FXR agonist, wherein the FXR agonist comprises Formula (I) or a pharmaceutically acceptable salt thereof, wherein the liver disorder is liver inflammation, liver fibrosis, alcohol-induced fibrosis, steatosis, alcoholic steatosis, primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), non-alcoholic fatty liver disease (NAFLD), and non-alcoholic steatohepatitis (NASH).

11. The method of any one of claims 1-3 and 6-10, wherein the liver disorder is NAFLD. 11. The method according to any one of claims 1 to 3 and 6 to 10, wherein the liver disorder is NASH. 11. The method according to any one of claims 1 to 3 and 6 to 10, wherein the liver disorder is PSC. 11. The method according to any one of claims 1 to 3 and 6 to 10, wherein the liver disorder is PBC. 15. The method according to any one of claims 1 to 14, wherein the administering results in a liver concentration to plasma concentration ratio of the compound of formula (I) of at least 10. 16. The method of any one of claims 1-15, wherein the therapeutically effective amount is 0.5 μg/day - 600 mg/day. 17. The method according to any one of claims 1 to 16, wherein the therapeutically effective amount is 0.5 μg/day - 20 mg/day. 18. The method of any one of claims 1-17, wherein the therapeutically effective amount is 0.5 μg/day - 4 mg/day. 19. The method according to any one of claims 1 to 18, wherein administering comprises administering the compound of formula (I) or a pharmaceutically acceptable salt thereof daily for a treatment period of at least one week. 20. The method according to claim 19, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day or twice a day. 21. The method of claim 19 or 20, wherein the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof administered on the first day of the treatment period is greater than or combined with the amount administered on all subsequent days of the treatment period. How the same. 22. The method according to any one of claims 19 to 21, wherein the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof administered on the first day of the treatment period is the same as the amount administered on all subsequent days of the treatment period. how to be. 23. The method according to any one of claims 1-22, wherein the treatment period is at least one month. 24. The method according to any one of claims 1 to 23, wherein the duration of treatment is the remaining lifespan of the patient. 25. The method of any one of claims 1-24, wherein the patient is obese. 25. The method of any one of claims 1-24, wherein the patient is not obese. 27. The method according to any one of claims 1-26, wherein the patient also has diabetes and/or a cardiovascular disorder. 28. The method of any one of claims 1-27, wherein the patient is at risk of developing an adverse effect affecting one or more of the kidneys, lungs, heart, and skin. 29. The method of any one of claims 1-28, wherein the patient is 2-17 years old. 29. The method of any one of claims 1-28, wherein the patient is 18-54 years of age. 29. The method of any one of claims 1-28, wherein the patient is at least 65 years of age. 32. The method of any one of claims 1-31, wherein the patient has undergone a liver transplant. 33. The patient according to any one of the preceding claims, wherein the patient's alkaline phosphatase, gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) levels are The way it is elevated. 34. The method of any one of claims 1-33, wherein the method does not comprise administering an antihistamine, immunosuppressant, steroid, rifampicin, opioid antagonist, or selective serotonin reuptake inhibitor (SSRI). 35. The method of any one of claims 1-34, wherein the patient's NAS score is reduced. 36. The method of any one of claims 1-35, wherein TGR5 signaling is not activated. 37. The method of any one of claims 1-36, wherein the expression level of a marker of fibrosis is reduced. 38. The method of any one of claims 1-37, wherein Ccr2, Col1a1, Col1a2, Col1a3, Cxcr3, Dcn, Hgf, Il1a, Inhbe, Lox, Loxl1, Loxl2, Loxl3, Mmp2, Pdgfb, Plau, Serpine1, Perpinh1, wherein the expression level of Snai, Tgfb1, Tgfb3, Thbs1, Thbs2, Timp2, and/or Timp3 is reduced. 39. The method of any one of claims 1-38, wherein the expression level of a marker of liver inflammation is reduced. 40. The method of any one of claims 1-39, wherein the level of Adgre1, Ccr2, Ccr5, Il1A, and/or Tlr4 is reduced.

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