Glucagon analogues

Patent metadata

Field	Value
Publication number	US-9486505-B2
Application number	US-201313937674-A
Country	US
Kind code	B2
Filing date	Jul 9, 2013
Priority date	Sep 23, 2011
Publication date	Nov 8, 2016
Grant date	Nov 8, 2016

Abstract

The present invention relates to novel glucagon peptides, to the use of said glucagon peptides in therapy, to methods of treatment comprising administration of said glucagon peptides to patients in need thereof, and to the use of said glucagon peptides in the manufacture of medicaments. The glucagon peptides of the present invention are of particular interest in relation to the treatment of hyperglycemia, diabetes and obesity, as well as a variety of diseases or conditions associated with hyperglycemia, diabetes and obesity.

First claim

The invention claimed is:

1. A pharmaceutical composition comprising:
(i) a glucagon peptide comprising:
(a) the amino acid sequence of SEQ ID NO: 1 modified by (i) Lys at X 24 , (ii) a substitution slected from the group consisting of His at X 3 , Glu at X 15 , and Ala, Ile, Phe, Arg, Thr, Val, Leu, Glu, Trp or Tyr, at X 16 , and (iii) up to five additional amino acid substitutions; and
(b) a substituent comprising three or more negatively charged moieties, wherein one of said negatively charged moieties is distal of a lipophilic moiety, and wherein said substituent is attached at the side chain nitrogen of Lys at X 24 ;
or a pharmaceutically acceptable salt, ester, amide, acid or prodrug thereof; and

(ii) a GLP-1 compound.

2. The composition of claim 1 , wherein said glucagon peptide is N ε24 -[(4S)-4-carboxy-4-[[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]butanoyl]-[Val 10 ,Leu 16 ,Glu 21 ,Lys 24 ,Leu 27 ,Ser 28 ]-Glucagon:

3. The composition of claim 2 , wherein said GLP-1 compound is selected from the group consisting of
N ε26 -((S)-4-Carboxy-4-hexadecanoylamino-butyryl)[Arg34]GLP-1-(7-37):

and
N ε26 -[2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-(17-carboxyheptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37):

4. The composition of claim 3 , wherein the GLP-1 compound is N ε26 -((S)-4-Carboxy-4-hexadecanoylamino-butyryl)[Arg34]GLP-1-(7-37):

5. The composition of claim 3 , wherein the GLP-1 compound is N ε26 -[2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-(17-carboxyheptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37):

6. The composition of claim 1 , wherein said glucagon peptide is N ε24 -[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]butanoyl]amino]butanoyl]-[Leu 16 ,Lys 24 ,Leu 27 ,Ser 28 ]-Glucagon:

7. The composition of claim 6 , wherein said GLP-1 compound is selected from the group consisting of
N ε26 -((S)-4-Carboxy-4-hexadecanoylamino-butyryl)[Arg34]GLP-1-(7-37):

and
N ε26 -[2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-(17-carboxyheptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37):

8. The composition of claim 7 , wherein the GLP-1 compound is N ε26 -((S)-4-Carboxy-4-hexadecanoylamino-butyryl)[Arg34]GLP-1-(7-37):

9. The composition of claim 7 , wherein the GLP-1 compound is N ε26 -[2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-(17-carboxyheptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37):

10. The composition of claim 1 , wherein said glucagon peptide is N 68 24 -[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]amino]butanoyl]amino]butanoyl]-[Arg 12 ,Ala 16 ,Lys 24 ,Leu 27 ,Ser 28 ]-Glucagon:

11. The composition of claim 10 , wherein said GLP-1 compound is selected from the group consisting of
N ε26 -((S)-4-Carboxy-4-hexadecanoylamino-butyryl)[Arg34]GLP-1-(7-37):

and
N ε26 -[2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-(17-carboxyheptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37):

12. The composition of claim 11 , wherein the GLP-1 compound is N ε26 -((S)-4-Carboxy-4-hexadecanoylamino-butyryl)[Arg34]GLP-1-(7-37):

13. The composition of claim 11 , wherein the GLP-1 compound is N ε26 -[2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-(17-carboxyheptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37):

14. The composition of claim 1 , wherein said glucagon peptide is N ε24 -[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-[Leu 16 ,Lys 24 ,Leu 27 ,Ser 28 ]-Glucagon:

15. The composition of claim 14 , wherein said GLP-1 compound is selected from the group consisting of
N ε26 -((S)-4-Carboxy-4-hexadecanoylamino-butyryl)[Arg34]GLP-1-(7-37):

and
N ε26 -[2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-(17-carboxyheptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37):

16. The composition of claim 15 , wherein the GLP-1 compound is N ε26 -((S)-4-Carboxy-4-hexadecanoylamino-butyryl)[Arg34]GLP-1-(7-37):

17. The composition of claim 15 , wherein the GLP-1 compound is N ε26 -[2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-(17-carboxyheptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37):

18. The composition of claim 1 , X 16 is selected from the group consisting of Ala and Leu.

19. The method of claim 1 , wherein X 16 is selected from the group consisting of Ile, Phe, Arg, Thr, Val, Glu, Trp, and Tyr.

20. The composition of claim 1 , wherein said up of five additional amino acid substitutions are selected from the group consisting of:
Val at X 10 ;
Arg at X 12 ;
Lys at X 17 ;
Lys at X 20 ;
Glu at X 21 ;
Leu or Glu at X 27 ;
Ser, Ile, Gly, Gin, Ala, or Thr at X 28 ; and
Val, Leu, or Ile at X 29 .

21. The composition of any one of claims 1 and 18 - 20 , wherein said substituent comprises f

Assignees

• Novo Nordisk As

Inventors

• Lau Jesper F
• Kruse Thomas
• Thoegersen Henning
• Sensfuss Ulrich
• Nielsen Peter Kresten

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P3/08

  for glucose homeostasis (pancreatic hormones A61P5/48) · 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

• A61P9/12

  Antihypertensives · CPC title