Novel GLP-1 Derivatives

Patent metadata

Field	Value
Publication number	US-2016108102-A1
Application number	US-201514750095-A
Country	US
Kind code	A1
Filing date	Jun 25, 2015
Priority date	Sep 19, 2003
Publication date	Apr 21, 2016
Grant date	—

Abstract

Novel polypeptide derivatives having protracted profile of action.

First claim

1 . A compound which has the formula (I):
A-W-B-Y-therapeutic polypeptide   (I)
wherein: the therapeutic polypeptide is a GLP-1 peptide comprising the amino acid sequence of formula (V):
Xaa 7 -Xaa 8 -Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Xaa 18 -Tyr-Leu-Glu-Xaa 22 -Xaa 23 -Ala-Ala-Xaa 26 -Glu-Phe-Ile-Xaa 30 -Trp-Leu-Val-Xaa 34 -Xaa 35 -Xaa 36 -Xaa 37 -Xaa 38   Formula (V) (SEQ ID No: 3)

wherein Xaa 7 is L-histidine or desamino-histidine; Xaa 8 is Ala, Gly or Aib; Xaa 18 is Ser or Arg; Xaa 22 is Gly, Glu or Aib; Xaa 23 is Gln or Glu; Xaa 26 is Lys or Arg; Xaa 30 is Ala or Glu; Xaa 34 is Lys or Arg; Xaa 35 is Gly or Aib; Xaa 36 is Arg or Lys; Xaa 37 is Gly, Ala or Lys; Xaa 38 is Lys, amide or is absent; A is an albumin binding residue selected from the group consisting of:

where the chiral carbon atom is either R or S,

where the chiral carbon atom is either R or S,

where the two chiral carbon atoms independently are either R or S,

where the two chiral carbon atoms independently are either R or S,
B is —(CH 2 ) l —O—[(CH 2 ) n —O] m —(CH 2 ) p —[C(O)NH—(CH 2 ) l —O—[(CH 2 ) n —O] m —(CH 2 ) p ] q —,
where l, m, n, and p independently are 1-5, and q is 0-5,
Y is a chemical group linking B and the therapeutic polypeptide, selected from the group consisting of —C(O)NH—, —NHC(O)—, —C(O)NHCH 2 —, —CH 2 NHC(O)—, —OC(O)NH—, —NHC(O)O—, —C(O)NHCH 2 —, CH 2 NHC(O)—, —C(O)CH 2 —, —CH 2 C(O)—, —C(O)CH═CH—, —CH═CHC(O)—, —(CH 2 ) s —, —C(O)—, —C(O)O—, —OC(O)—, —NHC(O)— and —C(O)NH—, wherein s is 0 or 1, and
W is a chemical group linking A and B, selected from the group consisting of —C(O)NH—, —NHC(O)—, —C(O)NHCH 2 —, —CH 2 NHC(O)—, —OC(O)NH—, —NHC(O)O—, —C(O)CH 2 —, —CH 2 C(O)—, —C(O)CH═CH—, —CH═CHC(O)—, —(CH 2 ) s —, —C(O)—, —C(O)O—, —OC(O)—, —NHC(O)— and —C(O)NH—, wherein s is 0 or 1;
and said GLP-1 peptide is attached to A-W-B-Y via the amino acid residue in positions 26, 37 or 38 in SEQ ID NO:3;
or a pharmaceutically acceptable salt or prodrug thereof.

2 . A compound according to claim 1 , wherein q is 0 or 1.

3 . A compound according to claim 2 , wherein q is 1.

4 . A compound according to claim 2 , wherein q is 0.

5 . A compound according to claim 2 , wherein l is 2.

6 . A compound according to claim 2 , wherein n is 2.

7 . compound according to claim 1 , wherein -W-B-Y- is selected from the group consisting of

8 . A compound according to claim 1 , wherein the albumin binding residue via spacer and linkers is attached to said therapeutic polypeptide via the ε-amino group of a lysine residue.

9 . A compound according to claim 8 , wherein the albumin binding residue via spacer and linkers is attached to said therapeutic polypeptide via a linker to an amino acid residue selected from cysteine, glutamate and aspartate.

10 . A compound according to claim 1 , wherein said GLP-1 peptide is selected from GLP-1(7-35), GLP-1(7-36), GLP-1(7-36)-amide, GLP-1(7-37), GLP-1(7-38), GLP-1(7-39), GLP-1(7-40), GLP-1(7-41) or an analogue thereof.

11 . A compound according to claim 1 , wherein said GLP-1 peptide comprises no more than six amino acid residues which have been exchanged, added or deleted as compared to GLP-1(7-37) (SEQ ID No. 1).

12 . A compound according to claim 11 , wherein said GLP-1 peptide comprises no more than 4 amino acid residues which are not encoded by the genetic code.

13 . A compound according to claim 1 , wherein said GLP-1 peptide comprises an Aib residue in position 8.

14 . A compound according to claim 1 , wherein said GLP-1 peptide is selected from the group consisting of Arg 34 GLP-1(7-37),
Arg 26,34 Lys 38 GLP-1(7-38), Arg 26,34 Lys 38 GLP-1(7-38)-OH, Aib 8,22,35 GLP-1(7-37), Aib 8,35 GLP-1(7-37), Aib 8,22 GLP-1(7-37), Aib 8,22,35 Arg 26,34 Lys 38 GLP-1(7-38), Aib 8,35 Arg 26,34 Lys 38 GLP-1(7-38), Aib 8,22 Arg 26,34 Lys 38 GLP-1(7-38), Aib 8,22,35 Arg 26,34 Lys 38 GLP-1(7-38), Aib 8,35 Arg 26,34 Lys 38 GLP-1(7-38), Aib 8,22,35 Arg 26 Lys 38 GLP-1(7-38), Aib 8,35 Arg 26 Lys 38 GLP-1(7-38), Aib 8,22 Arg 26 Lys 38 GLP-1(7-38), Aib 8,22,35 Arg 34 Lys 38 GLP-1(7-38), Aib 8,35 Arg 34 Lys 38 GLP-1(7-38), Aib 8,22 Arg 34 Lys 38 GLP-1(7-38), Aib 8,22,35 Ala 37 Lys 38 GLP-1(7-38), Aib 8,35 Ala 37 Lys 38 GLP-1(7-38), Aib 8,22 Ala 37 Lys 38 GLP-1(7-38), Aib 8,22,35 Lys 37 GLP-1(7-37), Aib 8,35 Lys 37 GLP-1(7-37), Aib 8,22 Lys 37 GLP-1(7-38), Gly 8 Arg 26,34 Lys 38 GLP-1(7-38), Aib 8 ,Arg 26,34 Lys 38 GLP-1(7-38), Aib 8 Lys 38 GLP-1(7-38), Ala 8 Arg 26,34 Lys 38 GLP-1(7-38), Aib 8,22,35 Lys 38 GLP-1(7-38), and Aib 8 Arg 34 GLP-1-(7-37).

15 . A compound according to claim 1 , wherein said GLP-1 peptide is attached to A-W-B-Y via the amino acid residue in position 26 of SEQ ID No:3.

16 . A compound according to claim 1 , wherein A-W-B-Y is attached via said hydrophilic spacer to the C-terminal amino acid residue of said GLP-1 peptide.

17 . A compound selected from the group consisting of:
N ε37 -{2-[2-(2-(15-carboxypentadecanoylamino)ethoxy)ethoxy]acetyl}-[Aib 8,22,35 ,Lys 37 ]GLP-1(7-37)amide

N ε37 -(2-(2-(2-(17-carboxyheptadecanoylamino)ethoxy)ethoxy)acetyl)[Aib 8,22,35 ,Lys 37 ]GLP-1(7-37)amide

N ε37 -(2-(2-(2-(19-carboxynonadecanoylamino)ethoxy)ethoxy)acetyl)[Aib 8,22,35 ,Lys 37 ]GLP-1(7-37)amide

[Aib 8,22,35 ]GLP-1(7-37)Lys(({2-[2-(2-{2-[2-(2-{2-[2-(15-carboxypentadecanoylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl amino)ethoxy]ethoxy}acetyl))amide

N ε37 -[2-(2-{3-[2,5-dioxo-3-(15-carboxypentadecylsulfanyl)-pyrrolidin-1-yl]propionylamino}ethoxy)ethoxy)acetyl]-[D-Ala 8 ,Lys 37 ]-GLP-1-[7-37]amide

[Aib 8,22,35 Ala 37 ]GLP-1(7-37)Lys((2-(2-(2-(11-(oxalylamino)undecanoylamino)ethoxy)ethoxy)acetyl-)))amide

[Aib 8,22,35 ,Ala 37 ]-GLP-1(7-37)Lys({2-[2-(2-{2-[2-(2-(15-carboxy-pentadecanoylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl)amide

[Aib 8 ,Arg 26,34 ]GLP-1(7-37)Lys{2-(2-(2-(2-[2-(2-(17-carboxyheptanoylamino)ethoxy)ethoxy]acetylamino)ethoxy)ethoxy)acetyl)}-OH

[Gly 8 ,Arg 26,34 ]GLP1-(7-37)Lys{2-(2-(2-(2-[2-(2-(17-carboxyheptadecanoylamino)ethoxy)ethoxy]acetyl)ethoxy)ethoxy)acetyl)}-OH

Assignees

• Novo Nordisk As

Inventors

• Lau Jesper
• Hansen Thomas K
• Madsen Kjeld
• Bloch Paw
• Dorwald Florencio Z
• Johansen Niels L

Classifications

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title

• A61P9/12

  Antihypertensives · CPC title