Use of GPR119 agonists for the treatment of metabolic-related disorders

Abstract

This disclosure relates to the use of GPR119 agonists for the treatment and / or prevention of metabolic-related diseases and disorders, such as non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

Description

[0001] USE OF GPR119 AGONISTS FOR THE TREATMENT OF METABOLIC-RELATED DISORDERS

[0002] This application claims the benefit of Indian Provisional Application No. 202411061620, filed August 14, 2024, which is hereby incorporated by reference.

[0003] FIELD OF INVENTION

[0004] The present invention relates to the use of GPR119 agonists for the treatment and / or prevention of metabolic-related diseases and disorders, such as non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

[0005] BACKGROUND OF THE INVENTION

[0006] Non-alcoholic steatohepatitis (NASH) is a specific form of non-alcoholic fatty liver disease (NAFLD), characterized by over 5% hepatic steatosis, that is linked to a higher risk of overall mortality, cirrhosis, end-stage liver disease, cardiovascular disease, and both liver and non-liver related cancers. NAFLD is the most prevalent cause of chronic liver disease in the western world and represents the liver component of metabolic syndrome. It encompasses a range of liver conditions from simple steatosis to NASH, fibrosis, cirrhosis, end-stage liver disease, and ultimately hepatocellular carcinoma. NAFLD and NASH are the principal fatty liver diseases, accounting for the majority of cases with elevated liver lipids. The severity of NAFLD / NASH is assessed based on factors such as lipid accumulation, inflammatory cell infiltration, hepatocyte ballooning, and fibrosis extent. While not everyone with steatosis progresses to NASH, a significant number do. Currently, treatment primarily focuses on lifestyle changes, including exercise and diet.

[0007] Non-alcoholic steatohepatitis (NASH) or metabolic dysfunction-associated steatohepatitis (MASH) is a chronic liver condition characterized by the accumulation of fat in hepatocytes, accompanied by hepatocyte ballooning, inflammation, and varying degrees of fibrosis, typically without symptoms. Lipotoxic stress in the liver triggers the recruitment of immune cells through the release of pro-inflammatory cytokines and chemokines. Resdiffra® (resmetirom, a thyroid hormone receptor beta (NR1A2) agonist) is currently used as a therapeutic agent for the treatment ofNASH / MASH. There is therefore a need for improved medical therapies for the treatment and / or prevention of metabolic-related diseases and disorders, such as NAFLD and NASH. The present invention addresses these needs, thereby reducing the risk of severe liver-related complications and enhancing the quality of life for affected individuals.

[0008] OBJECTIVES OF THE INVENTION

[0009] One objective of the present invention is to provide GPR119 agonists for the treatment and / or prevention of metabolic-related diseases and disorders, such as NAFLD and NASH.

[0010] Another objective of the present invention is to provide GPR119 agonists for the treatment and / or prevention of metabolic-related diseases and disorders, such as NAFLD and NASH with enhanced safety, reduced side effects and / or an enhanced tolerability profde.

[0011] SUMMARY OF THE INVENTION

[0012] In one aspect, the present invention relates to the use of a GPR119 agonist for the treatment and / or prevention of a metabolic-related disease or disorder, such as non-alcoholic fatty liver disease and non-alcoholic steatohepatitis (e.g., in a subject (such as a human subject) in need thereof).

[0013] One embodiment is the use of a therapeutically effective amount of a compound of Formula IA, IB, IC, ID or IE, or a pharmaceutically acceptable salt thereof:

[0014] Formula IE; for the treatment and / or prevention of a metabolic-related disease or disorder, such as nonalcoholic fatty liver disease and non-alcoholic steatohepatitis (e.g., in a subject (such as a human subject) in need thereof).

[0015] Another embodiment is a method of treating and / or preventing a metabolic-related disease or disorder, such as non-alcoholic fatty liver disease and non-alcoholic steatohepatitis, in a subject in need thereof (such as a human subject). The method comprises administering to the subject a therapeutically effective amount of a compound of Formula IA, IB, IC, ID or IE, or a pharmaceutically acceptable salt thereof:

[0016] Formula IE.

[0017] In one embodiment of any of the uses and methods described herein, the non-alcoholic steatohepatitis is non-alcoholic steatohepatitis with liver fibrosis, non-alcoholic steatohepatitis with cirrhosis, non-alcoholic steatohepatitis with cirrhosis and with hepatocellular carcinoma.

[0018] In one embodiment of any of the uses and methods described herein, the non-alcoholic steatohepatitis is non-alcoholic steatohepatitis with liver fibrosis.

[0019] In one embodiment of any of the uses and methods described herein, the non-alcoholic steatohepatitis is non-alcoholic steatohepatitis with cirrhosis.

[0020] In one embodiment of any of the uses and methods described herein, the non-alcoholic steatohepatitis is non-alcoholic steatohepatitis with cirrhosis and with hepatocellular carcinoma. In one embodiment of any of the uses and methods described herein, the subject (e.g., a subject with NASH or NAFLD) has type 2 diabetes.

[0021] In one embodiment of any of the uses and methods described herein, the subject (e.g., a subject with NASH or NAFLD) is obese (e.g., has a body mass index (BMI) > 23 kg / m2).

[0022] In one embodiment of any of the uses and methods described herein, the subject (e.g., a subject with NASH or NAFLD) further has type 2 diabetes and is obese (e.g., has a body mass index (BMI) > 23 kg / m2).

[0023] BRIEF DESCRIPTION OF DRAWINGS

[0024] FIG. 1 shows the effect of the compound of Formula IA (30 mg / kg) on the plasma glucose levels (FIG. 1A), plasma alanine aminotransferase (ALT) levels (FIG IB), plasma cholesterol levels (FIG. 1C) and non-alcoholic fatty liver disease activity score (NAS) (FIG. ID) in a high fat diet (HFD) induced non-alcoholic fatty liver disease (NAFLD) mouse model.

[0025] DETAILED DESCRIPTION OF THE INVENTION

[0026] The compounds of Formulas IA, IB, IC, ID, and IE may be prepared as described in U.S. Patent No. 10,208,030, the entire contents of which are hereby incorporated by reference. The compound of Formula IA is also known as 2-((S)-l-(l-(5-ethyl-pyrimidin-2-yl)piperidin- 4-yl)ethoxy)-6-(2-fluoro-4-(methylsulfonyl)phenyl)imidazo[2,l-b][l,3,4]thiadiazole.

[0027] Throughout this specification, the use of the word "comprise" and variations such as "comprises" and "comprising" may imply the inclusion of an element or elements not specifically recited.

[0028] The term "therapeutically effective amount" as used herein means an amount of the GPR119 agonist effective in producing the desired therapeutic response in a particular patient (subject) suffering from a disease such as NASH or NAFLD. Particularly, the term "therapeutically effective amount" includes the amount of the therapeutic agent, which when administered will achieve the desired therapeutic effects. In the context of the present invention, the desired therapeutic effects include partial or total inhibition, delay, or prevention of the progression of a disease including NASH or NAFLD. In respect of the therapeutic amount of the active agents i.e., the GPR119 agonists, consideration is also given that the amount of each of the active agents used for the treatment of a subject is low enough to avoid undesired or severe side effects. The therapeutically effective amount of each of the GPR119 agonists when used in a composition will vary with the age and physical condition of the end user, the severity of the disease, the duration of the treatment, the nature of any other concurrent therapy, the specific type of therapeutic agent employed for the treatment, the particular pharmaceutically acceptable carrier utilized in the pharmaceutical compositions containing the therapeutic agents.

[0029] The terms “pharmaceutically acceptable salt” and “salt” may be used interchangeably. “Pharmaceutically acceptable salts” or “salts” as used herein refers to salts of inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid salt, carbonate salts, and the like; and salts of organic acids such as, for example, succinic acid, formic acids, acetic acid, diphenyl acetic acid, palmoic acid, triphenylacetic acid, caprylic acid, dichloroacetic acid, trifluoro acetic acid, propionic acid, butyric acid, lactic acid, citric acid, gluconic acid, mandelic acid, tartaric acid, malic acid, adipic acid, aspartic acid, fumaric acid, glutamic acid, maleic acid, malonic acid, benzoic acid, -chlorobenzoic acid, dibenzoyl tartaric acid, oxalic acid, nicotinic acid, o-hydroxybenzoic acid, -hydroxybenzoic acid, 1-hydroxy- naphthalene-2-carboxylic acid, hydroxynaphthalene-2-carboxylic acid, ethane-sulfonic acid, ethane- 1,2-disulfonic acid, 2-hydroxyethane sulfonic acid, methane-sulfonic acid, (+)- camphor- 10-sulfonic acid, benzene sulfonic acid, naphthalene-2-sulfonic acid, p-toluene- sulfonic acid and the like. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred.

[0030] The term “subject” or “patient” refers to mammals including horses, dogs, cats, and humans. In a preferred embodiment, the patient or subject is a human.

[0031] The terms “treatment”, “treating”, and the like, as used herein include amelioration or elimination of a disease or condition once it has been established or alleviation of the characteristic symptoms of such disease or condition. A method as disclosed herein may also be used to, depending on the condition of the patient, prevent the onset of a disease or condition or of symptoms associated with a disease or condition, including reducing the severity of a disease or condition or symptoms associated therewith prior to affliction with said disease or condition. Such prevention or reduction prior to affliction refers to administration of the compound or composition as described herein to a patient that is not at the time of administration afflicted with the disease or condition, “preventing” also encompasses preventing the recurrence or relapse-prevention of a disease or condition or of symptoms associated therewith, for instance after a period of improvement. For example, as used herein, in one embodiment, the term “treatment” means any type of treatment that provides benefit to a subject suffering from NASH or NAFLD.

[0032] In one embodiment of any of the methods and uses described herein, the dose (e.g., daily dose) of the GPR119 agonist (such as compound of Formula IA, IB, IC, ID or IE, or pharmaceutically acceptable salt thereof) is about 0.001 mg to about 1000 mg, such as about 50 mg to about 1000 mg, about 10 mg to about 800 mg, about 100 mg to about 500 mg, about 200 mg to about 500 mg, or about 300 mg to about 500 mg.

[0033] In one embodiment of any of the methods and uses described herein, the dose (e.g., daily dose) of the GPR119 agonist (such as compound of Formula IA, IB, IC, ID or IE, or pharmaceutically acceptable salt thereof) is about 200 mg.

[0034] In one embodiment of any of the methods and uses described herein, the dose (e.g., daily dose) of the GPR119 agonist (such as compound of Formula IA, IB, IC, ID or IE, or pharmaceutically acceptable salt thereof) is about 300 mg.

[0035] In another embodiment of any of the methods and uses described herein, the dose (e.g., daily dose) of the GPR119 agonist (such as compound of Formula IA, IB, IC, ID or IE, or pharmaceutically acceptable salt thereof) is about 500 mg.

[0036] In another embodiment of any of the methods and uses described herein, the daily dose of the GPR119 agonist (such as compound of Formula IA, IB, IC, ID or IE, or pharmaceutically acceptable salt thereof) is presented in a single dose or as divided doses administered at appropriate intervals.

[0037] In another embodiment of any of the methods and uses described herein, the daily dose of the GPR119 agonist (such as compound of Formula IA, IB, IC, ID or IE, or pharmaceutically acceptable salt thereof) is administered once daily, twice daily, three time daily, or more, depending upon the dosing requirement for providing a therapeutic effect.

[0038] In another embodiment of any of the methods and uses described herein, the GPR119 agonist (such as compound of Formula IA, IB, IC, ID or IE, or pharmaceutically acceptable salt thereof) is administered by any conventional route, such as orally (e.g., in the form of a tablet, a capsule or a drinking solution), rectally (e.g., in the form of a suppository), intramuscularly or intravenously (e.g., in the form of an injection solution or suspension), or transdermally (e.g., in the form of a patch).

[0039] In another embodiment of any of the methods and uses described herein, the GPR119 agonist (such as compound of Formula IA, IB, IC, ID or IE, or pharmaceutically acceptable salt thereof) is administered in the form of a composition (e.g., a pharmaceutical composition) that comprises one or more pharmaceutically acceptable excipients, such as, but not limited to, one or more diluents, disintegrants, binders, lubricants, glidants, pH modifiers, surfactants, solubilizers, anti-oxidants, and any combination of any of the foregoing.

[0040] In one embodiment, any of the methods and uses described herein produce one or more of the following effects in a subject:

[0041] (i) reduce at least one point in severity of a non-alcoholic fatty liver disease or nonalcoholic steatohepatitis grading scoring system;

[0042] (ii) reduce the levels of serum markers of non-alcoholic steatohepatitis activity;

[0043] (iii) reduce non-alcoholic disease activity; or

[0044] (iv) reduce the medical consequences of non-alcoholic steatohepatitis.

[0045] Accordingly, in another aspect, the present invention relates to the use of a therapeutically effective amount of a compound of Formula IA, IB, IC, ID or IE, or a pharmaceutically acceptable salt thereof:

[0046] Formula IE; for (i) reducing at least one point in severity of a non-alcoholic fatty liver disease or nonalcoholic steatohepatitis grading scoring system, (ii) reducing the level of serum markers of non-alcoholic steatohepatitis activity, (iii) reducing non-alcoholic disease activity, (iv) reducing the medical consequences of non-alcoholic steatohepatitis, or (v) any combination of any of the foregoing, in a subject with a metabolic disorder, such as NASH or NAFLD.

[0047] EXAMPLES

[0048] Example 1 - A 27 Week Study in a Diet-Induced NASH Mouse Model.

[0049] This study investigated the effect of the compound of Formula IA in ameliorating high fat diet (HFD) induced non-alcoholic fatty liver disease (NAFLD) in C57BL / 6J mice.

[0050] Biochemical analysis of plasma parameter and histological analyses of liver parameters in compound of formula 1 -treated mice revealed significant decrease in plasma markers (Glucose and ALT, Cholesterol) as well as hepatic fibrosis with decreased hepatic inflammatory cell infiltration.

[0051] Protocol Male mice (C57BL / 6J) were fed with a standard diet or a HFD. The mice were divided into three groups as described below.

[0052] Group 1 : Control (standard diet)

[0053] Group 2: HFD

[0054] Group 3 : HFD + compound of Formula 1A (30 mg / kg)

[0055] The total duration of the study was 27 weeks (11 weeks for induction of disease with HFD followed by 16 weeks of treatment with the compound of Formula IA along with the HFD). Blood glucose levels were determined after 11 weeks of HFD and mice with higher blood sugar levels (> 130 mg / dl) were used for the further experiments.

[0056] The compound of Formula IA was given by oral dosing, and its examined at week 27 (after 16 weeks of treatment) by determining the changes in key markers: fasting blood glucose, cholesterol (CHO) and alanine aminotransferase (ALT). Histological analysis of the mice livers (treated and non-treated groups) was also performed at week 27 to measure steatosis, inflammation and fibrosis using hematoxylin and eosin (H&E) staining. The NAFLD activity score (NAS) was calculated using steatosis, inflammation and fibrosis scores (H&E staining). Massons ’s trichrome (MT) staining of liver sections was also performed to observe fibrosis.

[0057] Results

[0058] After 16 weeks of treatment with the compound of Formula IA, fasting blood glucose levels and ALT was reduced compared to the disease control group (Figs. IA & IB). Among lipid parameters, a decreased level of cholesterol was observed in the mice of Group 3 (treated with the compound of formula IA (Fig. 1C). These findings are consistent with a notable reduction in liver tissue fibrosis and inflammatory cell infiltration and ultimately resulted in a decreased NAS score (Fig. ID).

Claims

WHAT IS CLAIMED IS:

1. Use of a therapeutically effective amount of a compound of Formula IA, IB, IC,ID or IE, or a pharmaceutically acceptable salt thereof:Formula ID;for the treatment and / or prevention of non-alcoholic fatty liver disease or non-alcoholic steatohepatitis in a subject in need thereof.

2. The use of claim 1, wherein the non-alcoholic steatohepatitis is non-alcoholic steatohepatitis with liver fibrosis, non-alcoholic steatohepatitis with cirrhosis, non-alcoholic steatohepatitis with hepatocellular carcinoma, or non-alcoholic steatohepatitis with cirrhosis and with hepatocellular carcinoma.

3. The use of any one of claims 1-2, wherein the non-alcoholic steatohepatitis is non-alcoholic steatohepatitis with liver fibrosis.

4. The use of any one of claims 1-2, wherein the non-alcoholic steatohepatitis is non-alcoholic steatohepatitis with cirrhosis.

5. The use of any one of claims 1-2, wherein is non-alcoholic steatohepatitis with cirrhosis and with hepatocellular carcinoma.

6. The use of any one of claims 1-5, wherein the subject has type 2 diabetes.

7. The use of any one of claims 1-5, wherein the subject has type 2 diabetes. is obese.

8. The use of any one of claims 1-5, wherein the subject has type 2 diabetes and is obese.

9. The use of any one of claims 1-5, wherein the compound of Formula IA, IB, IC, ID or IE, or a pharmaceutically acceptable salt thereof, is administered in an amount from about 300 mg to about 500 mg.

10. The use of any one of claims 1-9, wherein the use:(i) reduces at least one point in severity of a non-alcoholic fatty liver disease or nonalcoholic steatohepatitis grading scoring system in the subject;(ii) reduces the levels of serum markers of non-alcoholic steatohepatitis activity in the subject;(iii) reduces non-alcoholic disease activity in the subject;(iv) reduces the medical consequences of non-alcoholic steatohepatitis in the subject; or(v) any combination of the above.

11. A method of treating and / or preventing non-alcoholic fatty liver disease or non- alcoholic steatohepatitis in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula IA, IB, IC, ID or IE, or a pharmaceutically acceptable salt thereof:Formula ID; orFormula IE.

12. The method of claim 12, wherein the non-alcoholic steatohepatitis is nonalcoholic steatohepatitis with liver fibrosis, non-alcoholic steatohepatitis with cirrhosis, nonalcoholic steatohepatitis with hepatocellular carcinoma, or non-alcoholic steatohepatitis with cirrhosis and with hepatocellular carcinoma.

13. The method of any one of claims 11-12, wherein the non-alcoholic steatohepatitis is non-alcoholic steatohepatitis with liver fibrosis.

14. The method of any one of claims 11-12, wherein the non-alcoholic steatohepatitis is non-alcoholic steatohepatitis with cirrhosis.

15. The method of any one of claims 11-12, wherein is non-alcoholic steatohepatitis with cirrhosis and with hepatocellular carcinoma.

16. The method of any one of claims 11-15, wherein the subject has type 2 diabetes.

17. The method of any one of claims 11-15, wherein the subject has type 2 diabetes. is obese.

18. The method of any one of claims 11-15, wherein the subject has type 2 diabetes and is obese.

19. The method of any one of claims 11-15, wherein the compound of Formula IA, IB, IC, ID or IE, or a pharmaceutically acceptable salt thereof, is administered in an amount from about 300 mg to about 500 mg.

20. The method of any one of claims 11-19, wherein the method:(i) reduces at least one point in severity of a non-alcoholic fatty liver disease or nonalcoholic steatohepatitis grading scoring system in the subject;(ii) reduces the levels of serum markers of non-alcoholic steatohepatitis activity in the subject;(iii) reduces non-alcoholic disease activity in the subject;(iv) reduces the medical consequences of non-alcoholic steatohepatitis in the subject; or(v) any combination of the above.

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