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US-20260125445-A1 - GLP-1 DERIVATIVES AND USES THEREOF

US20260125445A1US 20260125445 A1US20260125445 A1US 20260125445A1US-20260125445-A1

Abstract

The present invention relates to novel GLP-1 derivatives that are activating the GLP-1 receptor in a way that favours a cAMP response and has an impaired beta-arrestin recruitment. More particular the present invention relates to such GLP-1 derivatives and their use for treatment of diseases such as diabetes and obesity.

Inventors

  • LARS LINDEROTH
  • Steffen Reedtz-Runge
  • MARIA WALDHOER
  • Jacob Kofoed

Assignees

  • NOVO NORDISK A/S

Dates

Publication Date
20260507
Application Date
20251016
Priority Date
20240705

Claims (17)

  1. 1 . A GLP-1 derivative comprising: (SEQ ID NO: 18) Imp-X 8 EGTFTSDVSSYLEEQAAREFIAWLVRGRK; wherein Imp is 3-(imidazol-4-yl)-propionyl; wherein X 8 is W or G; wherein K is chemically modified at the epsilon amino group with: and wherein a is 1-3, b is 1-2, and c is 14-18; or a pharmaceutically acceptable salt, amide, or ester thereof.
  2. 2 . The GLP-1 derivative according to claim 1 , wherein X 8 is W.
  3. 3 . The GLP-1 derivative according to claim 1 , wherein X 8 is G.
  4. 4 . The GLP-1 derivative according to claim 1 , wherein a is 2.
  5. 5 . The GLP-1 derivative according to claim 1 , wherein b is 1.
  6. 6 . The GLP-1 derivative according to claim 1 , wherein c is 16.
  7. 7 . The GLP-1 derivative according to claim 1 , wherein the substituent is HOOC—(CH 2 ) 16 —CO—(NHC(COOH)CH 2 CH 2 CO)—(NHCH 2 CH 2 OCH 2 CH 2 OCH 2 CO) 2 — (Formula IIIa).
  8. 8 . The GLP-1 derivative according to claim 1 , wherein the substituent is:
  9. 9 . A GLP-1 derivative consisting essentially of: (SEQ ID NO: 18) Imp-X 8 EGTFTSDVSSYLEEQAAREFIAWLVRGRK; wherein Imp is 3-(imidazol-4-yl)-propionyl; wherein X 8 is W or G; wherein K is chemically modified at the epsilon amino group with: and wherein a is 1-3, b is 1-2, and c is 14-18; or a pharmaceutically acceptable salt, amide, or ester thereof.
  10. 10 . The GLP-1 derivative according to claim 1 , wherein the GLP-1 derivative is: (Compound 1) or a pharmaceutically acceptable salt, amide, or ester thereof.
  11. 11 . The GLP-1 derivative according to claim 1 , wherein the GLP-1 derivative is: (Compound 2) or a pharmaceutically acceptable salt, amide, or ester thereof.
  12. 12 . A method of treating overweight, comprising administering the GLP-1 derivative according to claim 1 to a subject in need thereof.
  13. 13 . The method according to claim 12 , wherein the subject is suffering from obesity.
  14. 14 . The method according to claim 12 , wherein the GLP-1 derivative is: (Compound 1) or a pharmaceutically acceptable salt, amide, or ester thereof.
  15. 15 . The method according to claim 14 , wherein the subject is suffering from obesity.
  16. 16 . The method according to claim 12 , wherein the GLP-1 derivative is: (Compound 2), or a pharmaceutically acceptable salt, amide, or ester thereof.
  17. 17 . The method according to claim 16 , wherein the subject is suffering from obesity.

Description

TECHNICAL FIELD The present invention relates to novel GLP-1 derivatives, and their pharmaceutical use. Furthermore, the invention relates to pharmaceutical compositions comprising such GLP-1 derivatives, and the use of such compounds for the treatment of medical conditions relating to diabetes and obesity. CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of International Application PCT/EP2025/069132, filed Jul. 4, 2025, which claims priority to European Patent Application 24186705.0 filed Jul. 5, 2024, the contents of which are incorporated by reference in their entirety. INCORPORATION-BY-REFERENCE OF THE SEQUENCE LISTING The instant application contains a Sequence Listing which has been submitted in XML format via USPTO patent electronic filing system and is hereby incorporated by reference in its entirety. Said XML file, created on Oct. 1, 2025, is named “240010US01.xml”, and is 36,490 bytes in size. BACKGROUND Glucagon-like peptide 1 (GLP-1), analogues and derivatives thereof, are known for their ability to stimulate insulin secretion, induce weight loss due to reduction of appetite, slowing gastric emptying, improve cardiovascular, liver and kidney health. They have been used for the treatment of e.g. type 2 diabetes and obesity for some years with one of the most recent derivatives being semaglutide present in products Ozempic® and WeGovy® (WO2006/097537). GLP-1 acts by interacting with the GLP-1 Receptor which is a G-protein coupled receptor (GPCR) expressed in several tissues and cell types including pancreatic beta cells (resulting in insulin secretion) and neurons in the brain (resulting in food intake suppression). When stimulated GPCRs affect several signalling pathway, e.g. G's-protein pathway resulting in cAMP production and beta-arrestin leading to receptor internalization and potentially receptor mediated clearance of the ligand. Some GLP-1 analogues and derivatives thereof may activate the signalling pathways demonstrating a difference in potency/efficacy between the pathways. This concept is referred to as biased GLP-1 agonism. Thus, some GLP-1 analogues can activate both cAMP and beta-arrestin pathways with a maximum efficacy while other GLP-1 analogues would fully activate cAMP pathway without the full activation of beta-arrestin pathway. Preclinical evidence indicates that biased GLP-1 analogues or derivatives with reduced beta-arrestin signalling can provide a better weight loss and glucose regulation with a similar or better tolerability profile compared to balanced GLP-1 analogues or derivatives like semaglutide. Based on genetic evidence, low frequency loss-of-function (LoF) variants in beta-arrestin (ARRB1) are associated with improved HbA1c regulation in patients with T2D treated with GLP-1 receptor agonists (Dawed et al, Lancet Diabetes Endocrinol, 2023 January; 11(1):33-41). Therefore, it has been suggested that biased GLP-1 compounds favouring cAMP generation over beta-arrestin recruitment may lead to a higher benefit for a broader patient population mimicking the improved GLP-1 response in patients with beta-arrestin LoF variants. While weight loss can partially explain the benefit of GLP-1 in obesity related comorbidities (e.g. cardiovascular disease), biased GLP-1 action through other cells with reduced beta-arrestin signalling expressed in all tissues in the body, can hypothetically provide additional benefits for patients with cardiometabolic diseases. GLP-1 derivatives and biased GLP-1 derivatives are disclosed in e.g. WO2009/030738, WO2017/149070, WO2016/161244 and EP3783014. However, there is still a need for development of GLP-1 derivative and analogues having a biased signalling with high activation of the cAMP pathway and impaired beta-arrestin recruitment. SUMMARY The invention relates to derivatives of GLP-1 analogues that have an imidazolepropionyl at a position corresponding to position 7 of hGLP-1(7-37) (SEQ ID NO: 11) and Trp or Gly at a position corresponding to position 8 of hGLP-1(7-37). The derivatives have a substituent attached to a Lys residue of the GLP-1 analogue at a position corresponding to position 37 of hGLP-1 (7-37). The invention also relates to corresponding GLP-1 analogues that have an imidazolepropionyl at a position corresponding to position 7 of hGLP-1(7-37) (SEQ ID NO: 11) and Trp or Gly at a position corresponding to position 8 of hGLP-1(7-37). Furthermore, the invention relates to pharmaceutical compositions comprising such GLP-1 derivatives and pharmaceutically acceptable excipients, as well as the medical use of said derivatives. In a first aspect, the invention relates to derivatives of GLP-1 analogues that are capable of activating the GLP-1 receptor by inducing a cAMP response, while showing a reduced beta-arrestin signalling. In a further aspect, the GLP-1 derivatives of the invention are selectively activating the GLP-1 receptor over the GIP receptor. Also, or alternatively, in a second aspect, the inven