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EP-4740955-A2 - NOVEL GLP-1 ANALOGUES

EP4740955A2EP 4740955 A2EP4740955 A2EP 4740955A2EP-4740955-A2

Abstract

The present disclosure pertains to novel Glucagon like Peptide-1 (GLP-1) (7-37) analogs having an amino acid sequence with Leu or Ile at the C-terminal. The new analogs are potent GLP-1 agonists with reduced adverse effect and improved duration of action. The present disclosure further relates to acylated derivatives of the new analogs which have further improved potency and duration of action and are suitable for oral administration. The analogs of present disclosure may be useful in treatment of diabetes and obesity.

Inventors

  • THENNATI, RAJAMANNAR
  • JOSHI, Dhiren Rameshchandra
  • SONI, Krunal Harishbhai
  • TIWARI, ABHISHEK
  • PATEL, Vipulkumar Shankarbhai
  • CHATURVEDI, NISHITH
  • BURADE, Vinod Sampatrao
  • SHAHI, Pradeep Dinesh
  • NATARAJAN, MUTHUKUMARAN
  • NAGARAJA, Ravishankara Madavati
  • ZALAWADIA, Rishit Mansukhlal
  • PANDYA, Kunal
  • PATEL, Brijeshkumar

Assignees

  • Sun Pharmaceutical Industries Limited

Dates

Publication Date
20260513
Application Date
20190405

Claims (14)

  1. A polypeptide comprising the amino acid sequence: wherein X2 is Ser, Ser(OMe), D-Ser, D-Ser(OMe), Ala or Aib; X3 is absent or Gln; X4 is Glu; X16 is Glu; X24 is Ile; X33 is Leu, -D-Leu, D-Ile or Ile; X34 is absent; and X21 is Lys wherein the side chain amino (ε amino) group of Lys is acylated with a moiety: {-Q-T-U-W-Y-Z wherein Q and T are absent; U is absent or -C(O)-CH 2 -O-(CH 2 ) 2 -O-(CH 2 ) 2 -NH-} wherein } is point of attachment with group W; W is absent or selected from a group consisting of -C(O)-CH 2 -O-(CH 2 ) 2 -O-(CH 2 ) 2 -NH-], -C(O)-NH-(CH 2 ) 3-4 -NH-], -C(O)-C(CH 3 ) 2 -NH-] and wherein ] is point of attachment with group Y; Y is -C(O)-(CH 2 ) 2 -CH(COOH)NH-- and -- is point of attachment with the group Z; 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, for use in the treatment of diabetes or obesity.
  2. The polypeptide for use as in claim 1, wherein U is -C(O)-CH 2 -O-(CH 2 ) 2 -O-(CH 2 ) 2 -NH-} wherein } is point of attachment with group W; W is selected from a group consisting of -C(O)-NH-(CH 2 ) 3-4 -NH-], -C(O)-C(CH 3 ) 2 -NH-] and wherein ] is point of attachment with group Y.
  3. The polypeptide for use as in claim 1, wherein W is -C(O)-NH-(CH 2 ) 3-4 -NH-] or -C(O)-C(CH 3 ) 2 -NH-].
  4. The polypeptide for use as in claim 1, wherein W is -C(O)-C(CH 3 ) 2 -NH-].
  5. The polypeptide for use as in claim 1, wherein X2 is Aib; X3 is absent; X33 is Leu; U is -C(O)-CH 2 -O-(CH 2 ) 2 -O-(CH 2 ) 2 -NH-}; W is -C(O)-CH 2 -O-(CH 2 ) 2 -O-(CH 2 ) 2 -NH-] and Z is -C(O)-(CH 2 ) n -COOH wherein n is integer 16.
  6. The polypeptide for use as in claim 1, wherein X2 is Aib; X3 is absent; X33 is Leu; U is -C(O)-CH 2 -O-(CH 2 ) 2 -O-(CH 2 ) 2 -NH-}; W is -C(O)-C(CH 3 ) 2 -NH-] and Z is -C(O)-(CH 2 ) n -COOH wherein n is integer 16.
  7. The polypeptide for use as in claim 1, wherein X2 is Aib; X3 is absent; X33 is Leu; U is -C(O)-CH 2 -O-(CH 2 ) 2 -O-(CH 2 ) 2 -NH-}; W is -C(O)-NH-(CH 2 ) 4 -NH-] and Z is -C(O)-(CH 2 ) n -COOH wherein n is integer 16.
  8. The polypeptide for use as in claim 1, wherein X2 is Aib; X3 is absent; X33 is Leu; U is -C(O)-CH 2 -O-(CH 2 ) 2 -O-(CH 2 ) 2 -NH-}; W is and Z is -C(O)-(CH 2 ) n -COOH wherein n is integer 16.
  9. The polypeptide for use as in claim 1, wherein X2 is Aib; X3 is absent; X33 is Leu; U is -C(O)-CH 2 -O-(CH 2 ) 2 -O-(CH 2 ) 2 -NH-}; W is -C(O)-NH-(CH 2 ) 3 -NH-] and Z is -C(O)-(CH 2 ) n -COOH wherein n is integer 16.
  10. The polypeptide for use as in claim 1, wherein X2 is Ser, Ser(OMe), D-Ser, D-Ser(OMe); X3 is absent; X33 is Leu; U is -C(O)-CH 2 -O-(CH 2 ) 2 -O-(CH 2 ) 2 -NH-}; W is -C(O)-CH 2 -O-(CH 2 ) 2 -O-(CH 2 ) 2 -NH-], -C(O)-NH-(CH 2 ) 3-4 -NH-], -C(O)-C(CH 3 ) 2 -NH-] 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.
  11. The polypeptide for use as in claim 1, wherein W is selected from a group consisting of -C(O)-NH-(CH 2 ) 3-4 -NH-], -C(O)-C(CH 3 ) 2 -NH-] and
  12. The polypeptide for use as in claim 1, wherein X2 is Ala; X3 is absent; X33 is Leu; W is absent; Z is -C(O)-(CH 2 ) n -CH 3 wherein n is integer 14.
  13. The polypeptide for use as in claim 1, wherein X2 is Aib; X3 is absent; X33 is Leu; W is absent; Z is -C(O)-(CH 2 ) n -CH 3 wherein n is integer 14.
  14. The polypeptide for use as in claim 1, wherein diabetes is type II diabetes mellitus.

Description

RELATED APPLICATIONS This application claims the benefit of three Indian provisional applications having application nos. IN 201821013109 (filed on April 05, 2018); IN 201821040468 (filed on October 26, 2018) and IN 201821040474 (filed on October 26, 2018), which are hereby incorporated by reference. FIELD OF THE DISCLOSURE The present disclosure relates to novel Glucagon like Peptide-1 (GLP-1) (7-38) analogs having an amino acid sequence with Leu or Ile at the C-terminal. The new analogs are potent GLP-1 agonists with reduced adverse effect and improved duration of action. The present disclosure further relates to acylated derivatives of the new analogs, which have further improved potency and duration of action and are suitable for oral administration. The analogs disclosed herein are acylated with protracting moieties, which increase the duration of activity of the compounds. The analogs disclosed herein may be useful in treatment of diabetes and obesity. BACKGROUND OF THE DISCLOSURE Glucagon-like peptide-1 (GLP-1) is a hormone that is mainly produced in enteroendocrine L cells of the gut and is secreted into the blood stream when food containing fat, protein hydrolysate and/or glucose enters the duodenum. GLP-1 is derived from the cell-specific post-translational processing of the preproglucagon gene. Initially, the peptide GLP-1(1-37) was identified from this processing, but it was the two N-terminally truncated products, GLP-1(7-37) (SEQ ID NO: 1) and GLP-1(7-36) amide, that were found to recognize the pancreatic receptor and which were determined to be the active species in vivo. GLP-1 has been found to stimulate insulin secretion, thereby causing glucose uptake by cells and decreased serum glucose levels. GLP-1 agonists are available for the treatment for Type 2 Diabetes Mellitus (T2DM) as favored drugs as they are devoid of hypoglycemia and with a positive benefit of weight loss. The endogenous substance, GLP-1(7-37) and GLP-1(7-36)amide, are cleaved by peptidases and thus have a very short half-life. Efforts were made to improve the performance by developing GLP-1 analogues with improved half-life. The first drug approved in 2005 was Exenatide with twice a day dosing at dose level 10 mcg and was found to show a significant improvement in HbA1c, a marker of glucose control. Further, Novo Nordisk developed Liraglutide (United States Patent No. 6,268,343) (SEQ ID NO: 2) with once a day dosing of 1.8 mg, s.c./day and approved in 2010. Further research and development produced once a week products like, Albiglutide developed by GSK and Dulaglutide developed by Eli Lilly. Recently, Semaglutide (International Publication No. WO 2006/097537 A2), a GLP-1 analogue was approved by USFDA. Semaglutide (SEQ ID NO: 3) is marketed under the brand name Ozempic®. It is administered as a once-weekly subcutaneous injection. Many attempts to make GLP-1 analogs having improved potency and duration of action are reported in literature. United States Patent No. 7,291,594 B2 (the US '594 patent) discloses GLP-1 (7-35) derivatives having added several residues of arginine and/or lysine to the C-terminus thereof to provide high bioavailability via mucous membranes. The US '594 patent further discloses that these derivative can be conferred with resistance to dipeptidyl peptidase IV (DPP-IV) by substituting amino acid 8 in its GLP-1 amino acid sequence with Ser, or with resistance to trypsin by substituting amino acids 26 and 34 with Gln and Asn, respectively. United States Patent No. 7,893,017 B2 (the US '017 patent) discloses acylated GLP-1 analog wherein the GLP-1 analog is stabilized against DPP-IV by modification of at least one amino acid residue in positions 7 and 8 relative to the sequence GLP-1 (7-37) and wherein said acylation is a diacid attached directly to the C-terminal amino acid residue of said GLP-1 analog. United States Patent No. 8,951,959 B2 (the US '959 patent) discloses a DPP-IV resistant GLP-1 (7-37) analogue having a non-proteogenic amino acid residue containing trifluromethyl group in position 8 relative to the sequence GLP-1, and is acylated with a moiety comprising two acidic groups to the lysine residue in position 26. United States Patent No. 7,084,243 B2 (the US '243 patent) discloses GLP-1 (7-37) analogues having Val or Gly at position 8 relative to the sequence GLP-1 (7-37) as DPP-IV resistant peptides. International Publication No. WO 2017/149070 A1(the WO '070) discloses GLP-1 analogues having a Trp at a position corresponding to position 8 of GLP-1 (7-37) and these Trp8 compounds were shown to be very stable against degradation by DPP-IV. International Publication No. WO 2004/103390A2 (the WO '390) discloses that the modification at the P'1 position (corresponding to 9 position in case of GLP-1 (7-37)) can produce GLP-1 analogues with greatly reduced susceptibility to enzyme-mediated (such as DPP-IV) cleavage relative to the native substrate, yet retain the biological activity of the native