Use of GPR119 agonists for the treatment of weight related disorders

Abstract

The present invention relates to the use of GPR119 agonists for the treatment and / or prevention of weight related diseases and disorders such as obesity and corpulence.

Description

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

[0002] This application claims the benefit of Indian Patent Application No. 202411061030, filed August 12, 2024, which is hereby incorporated by reference.

[0003] FIELD OF THE INVENTION

[0004] The present invention relates to the use of GPR119 agonists for the treatment and / or prevention and / or for slowing the progression of weight related diseases and disorders such as obesity and corpulence.

[0005] BACKGROUND OF THE INVENTION

[0006] Adiposity-based chronic disorders, also known as obesity-related chronic diseases, encompass a spectrum of health conditions that are closely linked to excess body fat. Adipose tissue, or body fat, is not just a passive energy storage depot but also an active endocrine organ that secretes hormones and inflammatory molecules, influencing metabolism, immune function, and inflammation. Excessive adiposity disrupts the delicate balance of these hormonal and metabolic processes, leading to insulin resistance, dyslipidemia, chronic low-grade inflammation, and endothelial dysfunction, which are the key underlying mechanisms contributing to the development of these chronic diseases. Addressing obesity and its associated metabolic abnormalities is crucial for preventing and managing adiposity-based chronic diseases, highlighting the importance of comprehensive lifestyle interventions, public health policies, and healthcare strategies aimed at promoting healthy weight management and reducing the burden of obesity-related morbidity and mortality.

[0007] Obesity is a medical condition characterized by excessive accumulation of body fat to the extent that it may have a negative effect on health. It is commonly measured using Body Mass Index (BMI), which is calculated by dividing a person's weight in kilograms by the square of their height in meters (kg / m2). A BMI of 30 or higher is typically considered obese.

[0008] 1

[0009] 160496.01601 / 154818557V.1 Obesity has reached epidemic proportions worldwide, with its prevalence increasing dramatically over the past few decades. According to the World Health Organization (WHO), global obesity rates nearly tripled between 1975 and 2016. In 2016, more than 1.9 billion adults were overweight, and of these, over 650 million were obese.

[0010] The worldwide prevalence of obesity has more than tripled between 1975 and 2022. Obesity is a chronic complex disease defined by excessive fat deposits that can impair health. Obesity can lead to increased risk of type 2 diabetes and heart disease, it can affect bone health and reproduction, and increases the risk of certain cancers.

[0011] Overton et al, Br J Pharmacol., 2008, 153(Suppl 1):S76-S81 describes the effects of certain GPR119 agonists in animal models of diabetes and obesity.

[0012] Saxenda® (liraglutide) and Wegovy® (semaglutide), which are currently used as therapeutic agents for obesity, are GLP-1 analogs, about 97% similar to the human hormone GLP-1 and are subcutaneously administered once per day. Clinical studies reveal that Saxenda® and Wegovy® can provide many health benefits including improvement in blood sugar levels and blood pressure, cholesterol levels, and obstructive sleep apnea syndrome by reducing the body weight of an obese person by 5 to 10 kg regardless of his or her initial body weight and when the reduced body weight is maintained. However, there are side effects such as nausea, vomiting, diarrhea, and constipation, and even for those who have succeeded in losing weight, discontinuation of administration of the drug leads to the yoyo phenomenon (a phenomenon in which the body weight returns to its original value), so obesity cannot be fundamentally treated without improvement in lifestyles.

[0013] There is therefore a need for improved medical therapies for weight management and treating disorders such as obesity and corpulence. The present invention addresses these needs.

[0014] 2

[0015] 160496.01601 / 154818557V.1 OBJECTIVES OF THE INVENTION

[0016] One objective of the present invention is to provide GPR119 agonists for the treatment and / or prevention and / or for slowing the progression of weight related diseases such as obesity and corpulence, and for weight management and conditions related thereto.

[0017] Another objective of the present invention is to provide GPR119 agonists for the treatment and / or prevention and / or for slowing the progression of weight related diseases such as obesity and corpulence, and for weight management and conditions related thereto with reduced side-effects and with improved obesity levels.

[0018] SUMMARY OF THE INVENTION

[0019] In one aspect, the present invention relates to the use of a GPR119 agonist for the treatment and / or prevention and / or for slowing the progression of weight related diseases and disorders such as obesity and corpulence (e.g., in a subject (such as a human subject) in need thereof).

[0020] 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:

[0021] Formula IB,

[0022] 3

[0023] 160496.01601 / 154818557V.1

[0024] Formula IE, for the treatment and / or prevention and / or for slowing the progression of a weight related disease or disorder, such as obesity, corpulence, overweight and stoutness, and conditions related thereto.

[0025] Another embodiment is a method of treating and / or preventing and / or slowing the progression of a weight related disease or disorder, such as obesity, corpulence, overweight and stoutness, and conditions related thereto, 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:

[0026] 4

[0027] 160496.01601 / 154818557V.1

[0028] Formula IE.

[0029] In one embodiment of any of the uses and methods described herein, the weight related disease or disorder is obesity.

[0030] 5

[0031] 160496.01601 / 154818557V.1 In one embodiment of any of the uses and methods described herein, the weight related disease or disorder is corpulence.

[0032] In one embodiment of any of the uses and methods described herein, the subject is overweight.

[0033] In one embodiment of any of the uses and methods described herein, the weight related disease or disorder is stoutness.

[0034] Yet another embodiment is the use of a GPR119 agonist, such as a compound of Formula IA, IB, IC, ID or IE, or a pharmaceutically acceptable salt thereof, for maintaining the weight of a subject, for example, a human subject in need thereof.

[0035] Yet another embodiment is a method for maintaining the weight of a subject in need thereof (such as a human subject) comprising administering an effective amount of a GPR119 agonist, such as a compound of Formula IA, IB, IC, ID or IE, or a pharmaceutically acceptable salt thereof.

[0036] In one embodiment of any of the uses and methods described herein, the compound of Formula IA, IB, IC, ID or IE, or a pharmaceutically acceptable salt thereof, is administered in combination with diet and / or exercise.

[0037] In one embodiment of any of the uses and methods described herein, the compound of Formula IA, IB, IC, ID or IE, or a pharmaceutically acceptable salt thereof, is administered in an amount from about 10 mg to about 1000 mg, such as from about 50 mg to about 800 mg.

[0038] BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 shows the percentage change in body weight and food consumption in Sprague Dawley rats following administration of the compound of Formula IA at 30, 100 and 300 mg / kg / day. (A) Change in body weight in male rats (B) Change in body weight in female rats (C) Change in food consumption in male rats (D) Change in food consumption in female rats.

[0040] 6

[0041] 160496.01601 / 154818557V.1 Figure 2 shows the percentage change in body weight and food consumption in Beagle dogs following administration of the compound of Formula IA at 0, 100 and 600 mg / kg / day. (A) Change in body weight in male dogs (B) Change in body weight in female dogs (C) Food consumption in male dogs per day (D) Food consumption in female dogs per day.

[0042] Figures 3A and 3B show the change in body weight (g) and food intake (g / animal / 24 hours), respectively, in DIO-mice following oral administration of the compound of Formula IA at 51.25 or 102.45 mg / kg / day, or of vehicle.

[0043] Figures 4A through 4D show the change in total cholesterol, LDL cholesterol, epididymal fat weight, and subcutaneous fat pad weight in DIO-mice following oral administration of the compound of Formula IA at 51.25 or 102.45 mg / kg / day, or of vehicle.

[0044] DETAILED DESCRIPTION OF THE INVENTION

[0045] 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.

[0046] GPR119 has been described as a class A (rhodopsin-type) orphan GPCR without close primary sequence relative in the human genome. The activation of GPR119 increases the intracellular accumulation of cAMP, leading to enhanced glucose-dependent insulin secretion from pancreatic P-cells and increased release of the gut peptides GLP-1 (glucagon-like peptide 1), GIP (glucose-dependent insulinotropic peptide) and PYY (polypeptide YY).

[0047] 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.

[0048] 7

[0049] 160496.01601 / 154818557V.1 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 obesity, overweight, stoutness, and other related disorders. 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 disease including obesity and overweight, in particular in improving weight control in patients. 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.

[0050] 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, ethanesulfonic acid, ethane- 1,2-disulfonic acid, 2-hydroxyethane sulfonic acid, methanesulfonic acid, (+)-camphor-10-sulfonic acid, benzene sulfonic acid, naphthalene-2-

[0051] 8

[0052] 160496.01601 / 154818557V.1 sulfonic acid, p-toluene-sulfonic acid and the like. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred.

[0053] The term “subject” or “patient” refers to mammals including horses, dogs, cats, and humans. In a preferred embodiment, the subject is a human. In one embodiment, the subject is overweight. In another embodiment, the subject is obese. In yet another embodiment, the subject is of a healthy or normal weight and seeks to maintain that weight.

[0054] It is to be understood that the embodiments described herein are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition and any other embodiment defined herein.

[0055] In another embodiment of any of the methods and uses described herein, the daily dose of the GPR119 agonist (such as compound of Formula I, IB, IC, ID or IE, or tautomer, stereoisomer, or pharmaceutically acceptable salt thereof) is about 0.001 mg to about 1000 mg, such as about 10 mg to about 800 mg, about 50 mg to about 300 mg, or about 100 mg to about 200 mg.

[0056] In another embodiment of any of the methods and uses described herein, the daily dose of the GPR119 agonist (such as compound of Formula I, IB, IC, ID or IE, or tautomer, stereoisomer, or pharmaceutically acceptable salt thereof) is presented in a single dose or as divided doses administered at appropriate intervals.

[0057] In another embodiment of any of the methods and uses described herein, the daily dose of the GPR119 agonist (such as compound of Formula I, IB, IC, ID or IE, or tautomer, stereoisomer, 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.

[0058] EXAMPLES

[0059] 9

[0060] 160496.01601 / 154818557V.1 EXAMPLE 1: Weight Reduction Test

[0061] Experiment 1:

[0062] A 7-day Repeated Dose Study of GPR119 Agonist in Sprague-Dawley Rats Following Oral (Gavage) Administration.

[0063] Protocol: The study design comprised four groups including one control group G1 (0 mg / kg / day); and three groups treated with the Compound of Formula IA (N = 6) - G5 (30 mg / kg / day), G6 (100 mg / kg / day) and G7 (300 mg / kg / day). Rats from control group (Gl) received 10 ml / kg of vehicle [0.5% Tween 80 and Na CMC (0.5% w / v in water)]. The dosing volume was kept constant at 10 mL / kg to all the rats throughout the dosing period. Parameters evaluated during the study included mortality, body weight, and feed consumption.

[0064] Results: Rats treated with the Compound of Formula IA at doses up to 300 mg / kg / day did not show any mortality. The percentage of weight reduction was observed in both sexes and a more significant effect was observed in male rats (-9% reduction) as compared to female rats (-2-4% reduction) at the 300 mg / kg / day dose at the end of the study, as shown in Figures IA and IB, respectively. Similarly, average feed intake was reduced in groups treated with the Compound of Formula IA as compared to the control group animals, in both sexes throughout the study period. A more significant reduction in food intake was observed in male rats (-20%) compared to female rats (-9%) at the 300 mg / kg / day dose, as shown in Figures 1C and ID, respectively.

[0065] Experiment 2:

[0066] A 14-Day Repeated Dose Study of GPR119 Agonist in Beagle Dog Following Oral (Gavage) Administration.

[0067] Protocol: The study design comprised three groups including one control group G2 (0 mg / kg / day); two groups treated with the Compound of Formula IA - G3 (100 mg / kg / day) and G4 (600 mg / kg / day) - having 3 dogs / sex / group. Dogs from the

[0068] 10

[0069] 160496.01601 / 154818557V.1 control group (G2) received 5 ml / kg of 5% (w / v) 2-hydroxypropyl-beta-cyclodextrin (HP-P-CD) in purified water as a vehicle. The dosing volume was kept constant at 5 mL / kg to all the dogs throughout the dosing period. Parameters evaluated during the repeated dose included mortality, bodyweight and feed consumption.

[0070] Result: Dogs treated with the compound of Formula IA at doses up to 600 mg / kg / day did not show any mortality. The percentage of body weight loss was slight to moderate in males (up to 7%) and females (up to 9%) at > 100 mg / kg / day dosed, when compared with Day 1 data as shown in Figures 2A and 2B. Similarly, the average feed intake was reduced in dogs treated with the compound of Formula IA as compared to the control group animals in both the sexes throughout the study period. A decrease in food consumption was found up to 60% in males and 64% in female dogs at > 100 mg / kg / day doses, when compared with control as shows in Figures 2C and 2D.

[0071] Experiment 3:

[0072] A 56-Day Repeated Dose Study of the Compound of Formula IA (Compound IA) in diet-induced obese C57BL / 6J mice (DIO mice) Following Oral (Gavage) Administration.

[0073] Protocol: Male DIO mice at least 17-18 weeks, (11-12 weeks fed on high fat diet) were taken in this study. The study design comprised, three groups including (N=8 animal / group), one vehicle control group G1 and two Compound IA treated groups, G2 (51.25 mg / kg / day) and G3 (102.45 mg / kg / day), for 8 weeks treatment period. Compound IA was administered in its free base form. DIO mice from the vehicle control group (Gl) received 10 ml / kg of vehicle [5% Hydroxypropyl Beta Cyclodextrin]. The dosing volume was kept constant at 10 ml / kg by oral gavage route to all the mice throughout the dosing period. Parameters evaluated during the study included mortality, body weight, feed consumption and fat pad weight (epididymis and subcutaneous) were observed.

[0074] Results: Treatment with Compound IA did not show any mortality. Daily oral administration of Compound IA at doses of 51.25 and 102.45 mg / kg produced a dosedependent, statistically significant reduction in both body weight and food intake in diet-induced obese (DIO) mice, compared to vehicle-treated controls (Fig. 3A and 3B).

[0075] 11

[0076] 160496.01601 / 154818557V.1 In line with this observed effect, Compound 1A at 51.25 and 102.45 mg / kg (daily PO) doses also showed significant reduction in lipid parameters like total cholesterol and LDL cholesterol levels, as well as fat pad as compared to vehicle treatment (Fig. 4A to 4D). It will be apparent to a person skilled in the art that the above description is for illustrative purposes only and should not be considered as limiting. Various modifications, additions, alterations, and improvements without deviating from the spirit and the scope of the invention may be made by a person skilled in the art.

[0077] 12

[0078] 160496.01601 / 154818557V.1

Claims

WHAT IS CLAIMED IS1. A method of treating and / or preventing and / or slowing the progression of a weight related disease or disorder, and conditions related thereto, 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; or13160496.01601 / 154818557V.1Formula IE. . The method of claim 1, wherein the weight related disease or disorder is obesity.

3. The method of claim 1, wherein the weight related disease or disorder is corpulence.

4. The method of claim 1, wherein the weight related disease or disorder is stoutness.

5. The method of claim 1, wherein the subject is overweight.

6. A method for maintaining the weight of 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 IB;14160496.01601 / 154818557V.1Formula IE.

6. The method of any one of claims 1-6, wherein the subject is a human.

7. The method of any one of claims 1-7, wherein the compound of Formula IA, IB, IC, ID or IE, or a pharmaceutically acceptable salt thereof, is administered in combination with diet and / or exercise.

8. The method of any one of claims 1-8, wherein the compound of FormulaIA, IB, IC, ID or IE, or a pharmaceutically acceptable salt thereof, is administered in an amount from about 10 mg to about 1000 mg9. The method of any one of claims 1-8, wherein the compound of Formula IA, IB, IC, ID or IE, or a pharmaceutically acceptable salt thereof, is administered in an amount from about 50 mg to about 800 mg.

10. Us of a therapeutically effective amount of a compound of Formula IA,IB, IC, ID or IE, or a pharmaceutically acceptable salt thereof:15160496.01601 / 154818557V.1Formula IE. for treating and / or preventing and / or slowing the progression of a weight related disease or disorder, and conditions related thereto, in a subject in need thereof.16160496.01601 / 154818557V.

111. The use of claim 10, wherein the weight related disease or disorder is obesity.

12. The use of claim 10, wherein the weight related disease or disorder is corpulence.

13. The use of claim 10, wherein the weight related disease or disorder is stoutness.

14. The use of claim 10, wherein the subject is overweight.

15. Use of a therapeutically effective amount of a compound of Formula IA, IB, IC, ID or IE, or a pharmaceutically acceptable salt thereof:160496.01601 / 154818557V.1Formula ID; orFormula IE. for maintaining the weight of a subject in need thereof.

16. The use of any one of claims 10-15, wherein the subject is a human.

17. The use of any one of claims 10-16, wherein the compound of Formula IA, IB, IC, ID or IE, or a pharmaceutically acceptable salt thereof, is administered in combination with diet and / or exercise.

18. The use of any one of claims 10-17, wherein the compound of Formula IA, IB, IC, ID or IE, or a pharmaceutically acceptable salt thereof, is administered in an amount from about 10 mg to about 1000 mg19. The use of any one of claims 10-18, wherein the compound of Formula IA, IB, IC, ID or IE, or a pharmaceutically acceptable salt thereof, is administered in an amount from about 50 mg to about 800 mg.18160496.01601 / 154818557V.1

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