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US-12622948-B2 - GLP-1/GIP dual agonists

US12622948B2US 12622948 B2US12622948 B2US 12622948B2US-12622948-B2

Abstract

The present invention relates to long acting glucagon-like peptide-1 and human glucose-dependent insulinotropic polypeptide (GIP) dual agonist polypeptide which may be useful for treating type 2 diabetes mellitus (T2D), diabetes with obesity, obesity and hyperlipidemia.

Inventors

  • Rajamannar Thennati
  • Vinod Sampatrao Burade
  • Muthukumaran Natarajan
  • Dhiren Rameshchandra Joshi
  • Manish Harendraprasad GANDHI
  • Chandulal Thakarshibhai JIVANI
  • Abhishek Tiwari
  • Krunal Harishbhai Soni

Assignees

  • SUN PHARMACEUTICAL INDUSTRIES LIMITED

Dates

Publication Date
20260512
Application Date
20240822
Priority Date
20201017

Claims (20)

  1. 1 . A polypeptide comprising the amino acid sequence: (SEQ ID NO: 3) Y-X1-E-G-T-F-T-S-D-Y-S-I-X2-L-D-K-I-A-Q-X3-A-F-V- Q-W-L-X4-A-G-G-P-S-S-G-A-P-P-P-S, or a pharmaceutically acceptable salt thereof, wherein: X1 is Aib or (L)-norvaline; X2 is Leu or (L)-norvaline; X3 is Lys, wherein the side chain amino (ε-amino) group of the Lys is acylated with a moiety having the formula: wherein: U is —C(O)—CH 2 —O—(CH 2 ) 2 —O—(CH 2 ) 2 —NH—}, wherein} is point of attachment to W; W is —C(O)—C(CH 3 ) 2 —NH—], wherein] is point of attachment to Y; Y is —C(O)—(CH 2 ) 2 —CH(COOH)NH—, wherein — is point of attachment to Z; and Z is —C(O)—(CH 2 ) n —COOH or —C(O)—(CH 2 ) n —CH 3 , wherein n is an integer from 14 to 20; X4 is Ile; and the acid group of the C-terminal amino acid is a free carboxylic acid group or is amidated as a C-terminal primary amide.
  2. 2 . The polypeptide according to claim 1 , wherein X1 is Aib.
  3. 3 . The polypeptide according to claim 2 , wherein Z is —C(O)—(CH 2 ) n —COOH and n is 16 or 18.
  4. 4 . The polypeptide according to claim 1 , wherein X1 is (L)-norvaline.
  5. 5 . The polypeptide according to claim 4 , wherein Z is —C(O)—(CH 2 ) n —COOH and n is 16 or 18.
  6. 6 . The polypeptide according to claim 1 , wherein X2 is Leu.
  7. 7 . The polypeptide according to claim 6 , wherein Z is —C(O)—(CH 2 )n-COOH and n is 16 or 18.
  8. 8 . The polypeptide according to claim 1 , wherein X2 is (L)-norvaline.
  9. 9 . The polypeptide according to claim 8 , wherein Z is —C(O)—(CH 2 ) n —COOH and n is 16 or 18.
  10. 10 . The polypeptide according to claim 1 , wherein X1 is Aib and X2 is Leu.
  11. 11 . The polypeptide according to claim 10 , wherein Z is —C(O)—(CH 2 ) n —COOH and n is 16 or 18.
  12. 12 . The polypeptide according to claim 1 , wherein X1 is Aib and X2 is (L)-norvaline.
  13. 13 . The polypeptide according to claim 12 , wherein Z is —C(O)—(CH 2 ) n —COOH and n is 16 or 18.
  14. 14 . The polypeptide according to claim 1 , wherein X1 is (L)-norvaline and X2 is Leu.
  15. 15 . The polypeptide according to claim 14 , wherein Z is —C(O)—(CH 2 ) n —COOH and n is 16 or 18.
  16. 16 . The polypeptide according to claim 1 , wherein X1 is (L)-norvaline and X2 is (L)-norvaline.
  17. 17 . The polypeptide according to claim 16 , wherein Z is —C(O)—(CH 2 ) n —COOH and n is 16 or 18.
  18. 18 . The polypeptide according to claim 1 , wherein Z is —C(O)—(CH 2 ) n —COOH and n is 16 or 18.
  19. 19 . The polypeptide according to claim 1 , wherein the polypeptide comprises the amino acid sequence selected from the group consisting of: (SEQ ID NO: 4) i.) Tyr Aib Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile L-norvaline Leu Asp Lys Ile Ala Gln Lys Ala Phe Val Gln Trp Leu Ile Ala Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser-NH 2 ; (SEQ ID NO: 6) ii.) Tyr Aib Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Leu Leu Asp Lys Ile Ala Gln Lys Ala Phe Val Gln Trp Leu Ile Ala Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser-NH 2 ; and (SEQ ID NO: 7) iii.) Tyr L-norvaline Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile L-norvaline Leu Asp Lys Ile Ala Gln Lys Ala Phe Val Gln Trp Leu Ile Ala Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser-NH 2 .
  20. 20 . The polypeptide according to claim 1 , wherein {—U—W—Y—Z represents Moiety A or Moiety B, and wherein Moiety A and Moiety B have the following structures, respectively:

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. patent application Ser. No. 18/249,055, filed Apr. 13, 2023, which is a U.S. National Stage Entry of International Patent Application No. PCT/IB2021/059420, filed Oct. 13, 2021, which claims the benefit of priority of Indian Patent Application No. 202021045240, filed Oct. 17, 2020, and Indian Patent Application No. 202121002837, filed Jan. 20, 2021, each of which is hereby incorporated herein by reference in its entirety. REFERENCE TO AN ELECTRONIC SEQUENCE LISTING This application contains a Sequence Listing which has been submitted electronically and is hereby incorporated by reference in its entirety. The Sequence Listing was created on Aug. 22, 2024, is named “23-0315-WO-US-CON_SequenceListing_ST26” and is 44,662 bytes in size. FIELD OF THE INVENTION The present invention relates to long acting glucagon-like peptide-1 (GLP-1) and human glucose-dependent insulinotropic polypeptide/Gastro Intestinal Peptide (GIP) dual agonist polypeptides which may be useful for treating type 2 diabetes mellitus (T2D), diabetes with obesity, obesity and hyperlipidemia. BACKGROUND OF THE INVENTION Treatment of type 2 diabetes mellitus (T2DM) with glucagon-like peptide-1 receptor agonists (GLP-1RAs) leads to improved glycaemic control, reduced body weight, and improvement in several cardiovascular risk factors. These benefits are mediated by the glucagon-like peptide-1 receptor (GLP-1R), a member of the class B family of G protein-coupled receptors, that is expressed in pancreatic beta-cells, various cell types of the gastrointestinal tract and neurons throughout both the central (CNS) and the peripheral nervous systems. Activation of GLP-1R signaling by GLP-1RAs improves glucose homeostasis by enhancing glucose-stimulated insulin secretion, delaying gastric emptying and decreasing plasma glucagon levels, and reduces body weight by activating anorexigenic pathways in the brain. Due to the glucose-dependence of beta-cell activation, GLP-1RAs are not associated with increased risk of hypoglycaemia. While the broad metabolic benefits of GLP-1RAs have established this class in the T2DM treatment paradigm, many patients do not reach their HbA1c/glycaemic targets and weight loss achieved with these agents, thus, requiring a higher dose, which also increases GI adverse events, and remains well below what can be attained with bariatric surgery, the most potent clinical intervention for obesity. Thus, there are significant opportunities to improve upon the existing GLP-1RA class. One emerging approach is to combine foundational GLP-1RA therapy with pharmacological strategies targeting additional pathways implicated in nutrient and energy metabolism, such as the glucose-dependent insulinotropic polypeptide (GIP) pathway. GIP is an incretin that is secreted from K cells in the upper small intestine, duodenum, in response to food. Postprandial GIP levels are approximately 4-fold higher compared to GLP-1 under normal physiological conditions. GIP is responsible for the majority of the insulinotropic incretin effect in man, and has important additional functions that are distinct from GLP-1. Unlike GLP-1, GIP is both glucagonotropic and insulinotropic in a glycaemic-dependent manner, dose-dependently stimulating glucagon secretion under hypoglycaemic conditions and insulin under hyperglycaemic conditions, glucagon released does facilitate insulin secretion. Although both GIP-receptor (GIPR) and GLP-1R are present in beta-cells, GIPR expression is distributed differently in extra-pancreatic tissues as GIPR is abundant in adipose tissue and is found in many non-overlapping areas of the CNS. GIP is implicated in adipose tissue carbohydrate and lipid metabolism by its actions to regulate glucose uptake, lipolysis and lipoprotein lipase activity. The findings suggest that pharmacological activation of GIPR may have a therapeutic benefit on peripheral energy metabolism. Recently, uni-molecular, multi-functional peptides that combine GLP-1RA activity with GIP activity have been suggested as new therapeutic agents for glycaemic and weight control. U.S. Pat. No. 9,474,780 discloses dual GLP-1 and GIP receptor agonists including tirzepatide. Tirzepatide is under Phase-III clinical studies for T2DM and obesity. WIPO publication numbers WO2017/74714A1, WO2020/23386A1, WO2020/023388A1, WO2015/067715A2, WO2016/111971A1 and WO2013/164483A1 disclose GLP-1 R and GIP R dual agonist compounds. SUMMARY OF THE INVENTION The present invention provides a polypeptide or a pharmaceutically acceptable salt thereof, comprising an amino acid sequence: (Seq. ID 1)Y-X1-E-G-T-F-T-S-D-Y-S-I-X2-L-Xaa15-K-I-A-Xaa19- X3-Xaa21-F-V-Xaa24-W-L-X4-A-G-G-P-S-S-G-A-P-P-P- S-X5-X6-X7-X8-X9-X10-X11wherein X1 is Aib, (L)-norvaline or (D)-norvaline;X2 is selected from Aib, Leu, (D)-Leu, Val, (D)-Val, Ile, (D)-Ile, and L or D isomer of an amino acid of Formula wherein “” represents the point of attachm