Stable GLP-1 based GLP-1/glucagon receptor co-agonists

Patent metadata

Field	Value
Publication number	US-9988430-B2
Application number	US-201514879428-A
Country	US
Kind code	B2
Filing date	Oct 9, 2015
Priority date	Oct 10, 2014
Publication date	Jun 5, 2018
Grant date	Jun 5, 2018

Abstract

New GLP-1 derivatives, compositions thereof and their use in medicine.

First claim

The invention claimed is:

1. A GLP-1 derivative comprising:
(i) a polypeptide consisting of the amino acid sequence of SEQ ID NO:5; and
(ii) a substituent comprising a lipophilic moiety and at least two negatively charged moieties, wherein one of the negatively charged moieties is distal of the lipophilic moiety;
wherein the polypeptide optionally comprises a C-terminal amide;
or a pharmaceutically acceptable salt and/or ester thereof.

2. The GLP-1 derivative according to claim 1 , wherein the substituent is covalently attached to the polypeptide via an amino acid residue in the polypeptide at position.

3. The GLP-1 derivative according to claim 1 , wherein the substituent comprises at least three negatively charged moieties.

4. The GLP-1 derivative according to claim 1 , wherein the lipophilic moiety comprises an alkyl group of at least 12 carbon atoms.

5. The GLP-1 derivative according to claim 4 , wherein the lipophilic moiety comprises an alkyl group has 12-20 carbon atoms.

6. The GLP-1 derivative according to claim 5 , wherein the lipophilic moiety comprises an alkyl group has 14-18 carbon atoms.

7. The GLP-1 derivative according to claim 6 , wherein the lipophilic moiety comprises an alkyl group has 16 carbon atoms.

8. The GLP-1 derivative according to claim 1 , wherein the substituent is covalently attached to the side chain of an amino acid.

9. The GLP-1 derivative according to claim 8 , wherein the substituent is covalently attached to the nitrogen atom of the side chain of a lysine.

10. The GLP-1 derivative according to claim 1 , wherein the structure of the substituent is Z 1 —Z 2 —Z 3 —Z 4 —Z 5 —Z 6 —Z 7 —Z 8 —Z 9 —Z 10 —,
wherein the lipophilic moiety is Z 1 and consists of:

wherein n is 6-20 and the symbol * represents the attachment point to the nitrogen of a neighbouring group;
wherein Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , Z 8 , Z 9 , and Z 10 individually are absent or are amino acids selected from the group consisting of Glu, γGlu, Gly, Ser, Ala, Thr, and Ado; and
wherein Z 1 —Z 2 —Z 3 —Z 4 —Z 5 —Z 6 —Z 7 —Z 8 —Z 9 —Z 10 together comprise at least two negatively charged moieties.

11. The GLP-1 derivative according to claim 10 , wherein Z 2 —Z 3 —Z 4 —Z 5 —Z 6 —Z 7 —Z 8 —Z 9 —Z 10 is selected from the group consisting of:
γGlu-γGlu-Ado-Ado-;
γGlu-γGlu-Ado-Ado-γGlu-;
γGlu-γGlu-Ado-γGlu-γGlu-;
γGlu-γGlu-Ado-γGlu-Ado-γGlu-Ado-γGlu-;
γGlu-γGlu-Ser-Gly-;
γGlu-γGlu-Ser-Gly-Glu-Ser-Gly-;
γGlu-γGlu-γGlu-Ado-Ado-;
γGlu-γGlu-γGlu-γGlu-;
γGlu-Ado-Ado-;
γGlu-Ado-Ado-γGlu-γGlu-; and
Gly-Ser-Glu-Gly-Ser-γGlu-γGlu-.

12. The GLP-1 derivative according to claim 11 , wherein n is 12-20.

13. The GLP-1 derivative according to claim 12 , wherein n is 14-18.

14. The GLP-1 derivative according to claim 13 , wherein n is 16.

15. A pharmaceutical composition comprising the GLP-1 derivative according to claim 1 and one or more pharmaceutically acceptable excipients.

16. A method for treating a disease, comprising administering the GLP-1 derivative according to claim 1 to a subject in need thereof, wherein the disease is selected from the group consisting of obesity, hyperglycaemia, type 2 diabetes, impaired glucose tolerance, and type 1 diabetes.

17. The GLP-1 derivative according to claim 1 , wherein the GLP-1 derivative is N ε34 -[2-[[(2S)-2-[[(2S)-4-carboxy-2-[[2-[[(2S)-2-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]-3-hydroxypropanoyl]amino]acetyl]amino]butanoyl]amino]-3-hydroxypropanoyl]amino]acetyl]-[Imp7,Aib8,His9,Lys18,Glu22,Arg26,Leu33,Thr35]-GLP-1-(7-35)-peptide amide (SEQ ID NO: 5)

18. The GLP-1 derivative according to claim 1 , wherein the GLP-1 derivative is N ε34 -[2-[[(2S)-2-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]-3-hydroxypropanoyl]amino]acetyl]-[Imp7,Aib8,His9,Lys18,Glu22,Arg26,Leu33,Thr35]-GLP-1-(7-35)-peptide amide (SEQ ID NO: 5)

19. The GLP-1 derivative according to claim 1 , wherein the GLP-1 derivative is N ε34 -[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]-[Imp7,Aib8,His9,Lys18,Glu22,Arg26,Leu33,Thr35]-GLP-1-(7-35)-peptide amide (SEQ ID NO: 5)

20. The GLP-1 derivative according to claim 1 , wherein the GLP-1 derivative is N ε34 -[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]butanoyl]-[Imp7,Aib8,His9,Lys18,Glu22,Arg26,Leu33,Thr35]-GLP-1-(7-35)-peptide amide (SEQ ID NO: 5)

21. The GLP-1 derivative according to claim 1 , wherein the GLP-1 derivative is N ε34 -[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-[Imp7,Aib8,His9,Lys18,Glu22,Arg26,Leu33,Thr35]-GLP-1-(7-35)-peptide amide (SEQ ID NO: 5)

22. The GLP-1 derivative according to claim 1 , wherein the GLP-1 derivative is N ε34 -[2-[[(2S)-2-[[(2S)-4-carboxy-2-[[2-[[(2S)-2-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]-3-hydroxypropanoyl]amino]acetyl]amino]butanoyl]amino]-3-hydroxypropanoyl]amino]acetyl]-[Imp7,Aib8,His9,Lys18,Glu22,Arg26,Leu33,Thr35]-GLP-1-(7-35)-peptide (SEQ ID NO: 5)

23. The GLP-1 derivative according to claim 1 , wherein the GLP-1 derivative is N ε34 -[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(2S)-2-[[2-[[(2S)-4-carboxy-2-[[(2S)-2-[[2-(17-carboxyheptadecanoylamino)acetyl]amino]-3-hydroxypropanoyl]amino]butanoyl]amino]acetyl]amino]-3-hydroxypropanoyl]amino]butanoyl]amino]butanoyl]-[Imp7,Aib8,His9,Lys18,Glu22,Arg26,Leu33,Thr35]-GLP-1-(7-35)-peptide (SEQ ID NO: 5)

24. The GLP-1 derivative according to claim 1 , wherein the GLP-1 derivative is N ε34 -[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butanoyl]amino]butanoyl]amino]butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-[Imp7,Aib8,His9,Lys18,Glu22,Arg26,Leu33,Thr35]-GLP-1-(7-35)-peptide (SEQ ID NO: 5)

25. The GLP-1 derivative according to claim 1 , wherein the GLP-1 derivative is N ε34 -[2-[[(2S)-2-[[(2S)-4-carboxy-2-[[2-[[(2S)-2-[[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl]amino]butanoyl]amino]-3-hydroxypropanoyl]amino]acetyl]amino]butanoyl]amino]-3-hydroxypropanoyl]amino]acetyl]-[Imp7,Aib8,His9,Lys18,Glu22,Arg26,Leu33,Thr35]-GLP-1-(7-35)-peptide amide (SEQ ID N

Assignees

• Novo Nordisk As

Inventors

• Reedtz-Runge Steffen
• Sensfuss Ulrich
• Kruse Thomas
• Spetzler Jane
• Thoegersen Henning
• Tornoee Christian W
• Lau Jesper F

Classifications

• A61P43/00

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

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• C07K14/605 Primary

  Glucagons · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title