Exendin-4 derivatives as peptidic dual GLP-1/glucagon receptor agonists

Patent metadata

Field	Value
Publication number	US-9775904-B2
Application number	US-201514679743-A
Country	US
Kind code	B2
Filing date	Apr 6, 2015
Priority date	Apr 7, 2014
Publication date	Oct 3, 2017
Grant date	Oct 3, 2017

Abstract

The present invention relates to dual GLP-1/glucagon receptor agonists and their medical use, for example in the treatment of disorders of the metabolic syndrome, including diabetes and obesity, as well as for reduction of excess food intake.

First claim

The invention claimed is:

1. A peptidic compound of formula (I):

or a salt or solvate thereof,
wherein:
X14 is an amino acid residue with a functionalized —NH 2 side chain group selected from the group consisting of Lys, Orn, Dab, and Dap, wherein the —NH 2 side chain group is functionalized by —Z—C(O)—R 5 , wherein
Z is a linker comprising 1-5 amino acid linker groups selected from the group consisting of γ-glutamate (γE) and AEEAc and combinations thereof in all stereoisomeric forms,
R 5 is a moiety comprising up to 50 carbon atoms and heteroatoms selected from the group consisting of N and O,
X28 is an amino acid residue selected from the group consisting of Ala, Lys, and Ser,
X29 is an amino acid residue selected from the group consisting of D-Ala and Gly, and
R 1 is NH 2 or OH.

2. The compound or salt or solvate thereof of claim 1 , wherein R 1 is NH 2 .

3. The compound or salt or solvate thereof according to claim 1 , wherein the peptidic compound has a relative activity of at least 0.09% compared to that of natural glucagon at the glucagon receptor.

4. The compound or salt or solvate thereof according to claim 1 , wherein the peptidic compound exhibits a relative activity of at least 0.1% compared to that of a glucagon-like peptide (GLP-1)(7-36)-amide at the GLP-1 receptor.

5. The compound or salt or solvate thereof according to claim 1 , wherein
X14 is Lys, wherein the —NH 2 side chain group is functionalized with a group —Z—C(O)R 5 , wherein Z is a group selected from the group consisting of γE, γE-γE, AEEAc-AEEAc-γE, and AEEAc-AEEAc-AEEAc, and
R 5 is a group selected from the group consisting of pentadecanyl, heptadecanyl, and 16-carboxy hexadecanyl.

6. The compound or salt or solvate thereof according to claim 1 , wherein X14 is Lys, wherein the —NH 2 side chain group is functionalized with a group —Z—C(O)R 5 , wherein Z is a group selected from the group consisting of γE, γE-γE, AEEAc-AEEAc-γE, and AEEAc-AEEAc-AEEAc, and
R 5 is a group selected from the group consisting of pentadecanyl and heptadecanyl.

7. The compound or salt or solvate thereof according to claim 1 , wherein
X14 is Lys, wherein the —NH 2 side chain group is functionalized by a group selected from the group consisting of (S)-4-Carboxy-4-hexadecanoylamino-butyryl-, (S)-4-Carboxy-4-octadecanoylamino-butyryl-, (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-, (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-hexadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl, and (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-octadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl, [2-(2-{2-[2-(2-{2-[2-(2-Octadecanoylamino-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetyl-,
X28 is Ala,
X29 is an amino acid residue selected from the group consisting of D-Ala and Gly, and
R 1 is NH 2 .

8. The compound or salt or solvate thereof according to claim 1 , wherein
X14 is Lys, wherein the —NH 2 side chain group is functionalized by (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-,
X28 is Ser,
X29 is an amino acid residue selected from the group consisting of D-Ala and Gly, and
R 1 is NH 2 .

9. The compound or salt or solvate thereof according to claim 1 , wherein
X14 is Lys, wherein the —NH 2 side chain group is functionalized by (S)-4-carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-,
X28 is Lys,
X29 is an amino acid residue selected from the group consisting of D-Ala and Gly, and
R 1 is NH 2 .

10. The compound or salt or solvate thereof according to claim 1 , wherein
X14 is Lys, wherein the —NH 2 side chain group is functionalized by a group selected from the group consisting of (S)-4-Carboxy-4-hexadecanoylamino-butyryl-, (S)-4-Carboxy-4-octadecanoylamino-butyryl-, and (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-,
X28 is an amino acid residue selected from the group consisting of Ala, Lys, and Ser,
X29 is D-Ala, and
R 1 is NH 2 .

11. The compound or salt or solvate thereof of claim 1 , wherein
X14 is Lys, wherein the —NH 2 side chain group is functionalized by a group selected from the group consisting of (S)-4-Carboxy-4-hexadecanoylamino-butyryl-, (S)-4-Carboxy-4-octadecanoylamino-butyryl-, (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-, (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-hexadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl, and (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-octadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl, [2-(2-{2-[2-(2-{2-[2-(2-Octadecanoylamino-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetyl-,
X28 is an amino acid residue selected from the group consisting of Ala, Lys, and Ser,
X29 is Gly, and
R 1 is NH 2 .

12. The compound or salt or solvate thereof of claim 1 , wherein
X14 is Lys, wherein the —NH 2 side chain group is functionalized by (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-,
X28 is Ala,
X29 is an amino acid residue selected from the group consisting of Gly and D-Ala, and
R 1 is NH 2 .

13. The compound or salt or solvate thereof of claim 1 , selected from the compounds of SEQ ID NOs: 6-19, or a salt or solvate thereof.

14. The compound or salt or solvate thereof of claim 13 , selected from the compounds of SEQ ID NOs: 6-18, or a salt or solvate thereof.

15. The compound, salt or solvate according to claim 1 , wherein the compound is the amino acid sequence of SEQ ID NO: 7.

16. The compound, salt or solvate according to claim 1 , wherein the compound is the amino acid sequence of SEQ ID NO: 8.

17. A solvate of a compound of claim 1 .

18. A hydrate of a compound of claim 1 .

19. A pharmaceutical composition comprising one or more compounds of claim 1 , or a salt or solvate thereof as an active ingredient and at least one pharmaceutically acceptable carrier.

20. The pharmaceutical composition according to claim 19 , further comprising at least one additional therapeutically active agent, wherein the additional therapeutically active agent is selected from the group consisting of:
insulin and insulin derivatives selected from the group consisting of insulin glargine, insulin glusiline, insulin detemir, insulin lispro, insulin degludec, insulin aspart, basal insulin and analogues thereof, pegylated insulin, recombinant human insulin, polysialated insulins, long-acting insulin, NN1045, insulin in combination with pramlintide, PE0139, fast-acting and short-acting insulins, insulin hydrogel, oral insulin, inhalable insulin, transdermal insulin and sublingual insulin, and insulin derivatives which are bonded to albumin or another protein by a bifunctional linker;
GLP-1; GLP-1 analogues; GLP-1 receptor agonists selected from the group consisting of lixisenatide, exenatide, ITCA 650, AC-2993, liraglutide, semaglutide, taspoglutide, albiglutide, dulaglutide, rExendin-4, CJC-1134-PC, PB-1023, TTP-054, Langlenatide, HM-11260C, CM-3, ORMD-0901, NN-9924, NN-9926, NN-9927, CVX-096, ZYOG-1, ZYD-1, GSK-2374697, DA-3091, MAR-701, MAR709, ZP-2929, ZP-3022, TT-401, BHM-034, MOD-6030, CAM-2036, DA-15864, ARI-2651, ARI-2255, xtenylated exenatide, xtenylated glucagon, and polymer bound derivatives thereof;
dual GLP-1/GIP recepto

Assignees

• Sanofi Sa

Inventors

• Bossart Martin
• Elvert Ralf
• Evers Andreas
• Haack Torsten
• Stengelin Siegfried
• Wagner Michael

Classifications

• 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

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P5/50

  for increasing or potentiating the activity of insulin · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P3/08

  for glucose homeostasis (pancreatic hormones A61P5/48) · CPC title