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US-20260125440-A1 - INCRETIN ANALOGS AND USES THEREOF

US20260125440A1US 20260125440 A1US20260125440 A1US 20260125440A1US-20260125440-A1

Abstract

Incretin analogs are provided that have activity at each of the glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1) and glucagon (GCG) receptors. The incretin analogs have structural features resulting in balanced activity and extended duration of action at each of these receptors. Methods also are provided for treating diseases such as type 2 diabetes mellitus, dyslipidemia, metabolic syndrome, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis and obesity.

Inventors

  • Milata Mary Abraham
  • Jorge Alsina-Fernandez
  • Tamer Coskun
  • Hongchang Qu
  • James Lincoln Wallis

Assignees

  • ELI LILLY AND COMPANY

Dates

Publication Date
20260507
Application Date
20250813

Claims (20)

  1. 1 . A compound comprising: YX 2 QGTX 6 TSDX 10 SIX 13 LDX 16 X 17 AQX 20 X 21 FIX 24 X 25 LLEGGPSSGEPPPX 39 , wherein X 2 is Aib, X 6 is αMeF(2F), X 10 can be Y or 4Pal, X 13 can be L or αMeL, X 16 is Orn, X 17 is selected from the group consisting of C, D, E, K and Q, X 20 can be 4Pal, Iva or αMeL, X 21 can be A or Aib, X 24 can be E or e, X 25 can be Y or αMeY, and X 39 can be E or S (SEQ ID NO:5), and wherein a carboxy-terminal (C-terminal) amino acid optionally is amidated; or a pharmaceutically acceptable salt thereof.
  2. 2 . (canceled)
  3. 3 . The compound of claim 1 , wherein X 17 is K.
  4. 4 . The compound of claim 3 , wherein the [K] at position X 17 and the is conjugated to a C 16 -C 22 fatty acid moiety by a linker between the K at position X 17 and the fatty acid moiety.
  5. 5 . The compound of claim 4 , wherein the linker comprises one to four amino acids.
  6. 6 . The compound of claim 5 , wherein the amino acids are E or γE.
  7. 7 . The compound of claim 4 , wherein the linker further comprises the following structure: H—{NH—CH 2 —CH 2 —[O—CH 2 —CH 2 ] m —O—(CH 2 ) p —CO} n —OH, wherein m is any integer from 1 to 12, n is any integer from 1 to 12, and p is 1 or 2.
  8. 8 . The compound of claim 4 , wherein the linker further comprises one to four (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) moieties.
  9. 9 . The compound of claim 1 , wherein X 17 is K chemically modified through conjugation to an epsilon-amino group of a K side-chain with the following structure: (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γE) b -CO—(CH 2 ) c —CO 2 H, wherein a is 0, 1 or 2; b is 1 or 2; and c is an integer between 16 to 20.
  10. 10 . The compound of claim 9 , wherein a is 1.
  11. 11 . The compound of claim 9 , wherein a is 2.
  12. 12 . The compound of claim 9 , wherein b is 1.
  13. 13 . The compound of claim 9 , wherein b is 2.
  14. 14 . The compound of claim 9 , wherein c is 20.
  15. 15 . The compound of claim 1 , wherein X 10 is Y.
  16. 16 . The compound of claim 1 , wherein X 10 is 4Pal.
  17. 17 . The compound of claim 1 , wherein X 13 is L.
  18. 18 . The compound of claim 1 , wherein X 13 is αMeL.
  19. 19 . The compound of claim 1 , wherein X 20 is 4Pal.
  20. 20 . The compound of claim 1 , wherein X 20 is Iva.

Description

The present application is being filed along with a Sequence Listing in ST.26 XML format. The Sequence Listing is provided as a file titled “X22622A_US_000 SequenceListing” created Aug. 13, 2025, and is 39,402 bytes in size. The Sequence Listing information in the ST.26 XML format is incorporated herein by reference in its entirety. No new matter is added herewith. The disclosure relates to incretin analogs having activity at each of a glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1) and glucagon (GCG) receptors. The incretin analogs herein have structural features that provide balanced activity at each of these receptors and that have an extended duration of action. Such incretin analogs may be useful for treating conditions, diseases and disorders including type 2 diabetes mellitus (T2DM), dyslipidemia, metabolic syndrome, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) and/or obesity, as well as cardiovascular diseases that are not considered metabolic diseases and neurodegenerative diseases. Over the past several decades, the prevalence of diabetes continues to rise. T2DM is the most common form of diabetes accounting for about 90% of all diabetes. T2DM is characterized by high blood glucose levels stemming from insulin resistance. The current standard of care for T2DM includes diet and exercise, as well as treatment with oral medications and injectable glucose-lowering drugs including incretin-based therapies, such as GLP-1 receptor agonists. GLP-1 is a 36-amino acid peptide, the major biologically active fragment of which is produced as a 30-amino acid, C-terminal amidated peptide (GLP-17-36; SEQ ID NO:2) that stimulates glucose-dependent insulin secretion and that prevents hyperglycemia in diabetics. A variety of GLP-1 analogs currently are available for treating T2DM, including dulaglutide, exenatide and liraglutide. Many currently marketed GLP-1 analogs, however, are dose-limited by gastrointestinal side effects, such as nausea and vomiting. When treatment with oral medications and incretin-based therapies is insufficient, treatment with insulin is considered. Despite the treatment options available, significant numbers of individuals receiving approved therapies are not reaching glycemic control goals (see, e.g., Casagrande et al. (2013) Diabetes Care 36:2271-2279). Uncontrolled diabetes can lead to one or more conditions that impact morbidity and mortality of such individuals. One of the main risk factors for T2DM is obesity, and many individuals with T2DM (˜90%) are overweight or obese. It is documented that a decrease in body adiposity will lead to improvement in obesity-associated co-morbidities including hyperglycemia and cardiovascular events. Therefore, therapies effective in glucose control and weight reduction are needed for better disease management. In view thereof, new therapies being studied include compounds having not only activity at a GLP-1 receptor but also activity at one or more other receptors, such as the GIP and/or GCG receptors. In fact, certain compounds already have been described as having triple receptor agonist activity (i.e., activity at each of the GIP, GLP-1 and GCG receptors). For example, Intl. Patent Application Publication No. WO 2015/067716 describes GCG analogs having triple receptor agonist activity. Similarly, Intl. Patent Application Publication No. WO 2016/198624 describes exendin-4 analogs having triple receptor agonist activity. Likewise, Intl. Patent Application Publication Nos. WO 2014/049610 and WO 2017/116204 each describe a variety of compounds having triple receptor agonist activity. Moreover, Intl. Patent Application Publication No. WO 2017/153575 describes GCG and GLP-1 co-agonists that also are stated to have GIP receptor agonist activity. Although typically used for treating T2DM, incretins and analogs thereof having activity at one or more of the GIP, GLP-1 and/or GCG receptors also have been described as having a potential for therapeutic value in a number of other conditions, diseases or disorders, including, for example, Alzheimer's disease, bone-related disorders, dyslipidemia, metabolic syndrome, NAFLD and NASH, obesity and Parkinson's disease. See, e.g., Jall et al. (2017) Mol. Metab. 6:440-446; Carbone et al. (2016) J. Gastroenterol. Hepatol. 31:23-31; Finan et al. (2016) Trends Mol. Med. 22:359-376; Choi et al. (2017) Potent body weight loss and efficacy in a NASH animal model by a novel long-acting GLP-1/Glucagon/GIP triple-agonist (HM15211), ADA Poster 1139-P; Ding (2008) J. Bone Miner. Res. 23:536-543; Tai et al. (2018) Brain Res. 1678:64-74; Müller et al. (2017) Physiol. Rev. 97:721-766; Finan et al. (2013) Sci. Transl. Med. 5:209; Hölscher (2014) Biochem. Soc. Trans. 42:593-600. Nevertheless, a need remains for treatments for such conditions, diseases and disorders, especially T2DM, that are capable of providing effective glucose control, with weight loss benefits