Dual GLP-1/glucagon receptor agonists derived from exendin-4

Patent metadata

Field	Value
Publication number	US-9758561-B2
Application number	US-201514679770-A
Country	US
Kind code	B2
Filing date	Apr 6, 2015
Priority date	Apr 7, 2014
Publication date	Sep 12, 2017
Grant date	Sep 12, 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 having the formula (I):
H 2 N-His-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-X14-X15-Glu-Glu-Ala-X19-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Aib-X28-X29-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-R 1   (I)

or a salt or solvate thereof,
wherein
X2 is an amino acid residue selected from the group consisting of D-Ser and Ser,
X3 is an amino acid residue selected from the group consisting of Gin and His,
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,
X15 is an amino acid residue selected from the group consisting of Glu and Asp,
X19 is an amino acid residue selected from the group consisting of Ala and Val,
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 Thr, 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 of claim 1 , wherein the peptidic compound has a relative activity of at least 0.1% compared to that of natural glucagon at the glucagon receptor.

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

5. 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 —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 of claim 5 , 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 of claim 1 , wherein
X2 is D-Ser,
X3 is an amino acid residue selected from the group consisting of Gln and His,
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, (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-octadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl, and [2-(2-{2-[2-(2-{2-[2-(2-Octadecanoylamino-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetyl-,
X15 is an amino acid residue selected from the group consisting of Glu and Asp,
X19 is an amino acid residue selected from the group consisting of Ala and Val,
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 Thr, D-Ala, and Gly, and
R 1 is NH 2 .

8. The compound or salt or solvate thereof of claim 1 , wherein
X2 is D-Ser,
X3 is His,
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-octadecanoylamino-butyryl- and (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-,
X15 is an amino acid residue selected from the group consisting of Glu and Asp,
X19 is Ala,
X28 is an amino acid residue selected from the group consisting of Ala and Lys,
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 of claim 1 , wherein
X2 is an amino acid residue selected from the group consisting of D-Ser and Ser,
X3 is Gln,
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, (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-octadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl, and [2-(2-{2-[2-(2-{2-[2-(2-Octadecanoylamino-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetyl-,
X15 is an amino acid residue selected from the group consisting of Glu and Asp,
X19 is an amino acid residue selected from the group consisting of Ala and Val,
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 Thr, D-Ala, and Gly, and
R 1 is NH 2 .

10. The compound or salt or solvate thereof of claim 1 , wherein
X2 is D-Ser,
X3 is an amino acid residue selected from the group consisting of Gln and His,
X14 is Lys wherein the —NH 2 side chain group is functionalized by a group selected from the groups consisting of (S)-4-Carboxy-4-octadecanoylamino-butyryl- and (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-,
X15 is Glu,
X19 is an amino acid residue selected from the group consisting of Ala and Val,
X28 is an amino acid residue selected from the group consisting of Ala and Lys,
X29 is an amino acid residue selected from the group consisting of D-Ala and Gly, and
R 1 is NH 2 .

11. The compound or salt or solvate thereof of claim 1 , wherein
X2 is an amino acid residue selected from the group consisting of D-Ser and Ser,
X3 is an amino acid residue selected from the group consisting of Gln and His,
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, (2-{2-[2-(2-{2-[(4S)-4-Carboxy-4-octadecanoylamino-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl, and [2-(2-{2-[2-(2-{2-[2-(2-Octadecanoylamino-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetyl-,
X15 is Asp,
X19 is an amino acid residue selected from the group consisting of Ala and Val,
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 Thr, D-Ala, and Gly, and
R 1 is NH 2 .

12. The compound or salt or solvate thereof of claim 1 , wherein
X2 is an amino acid residue selected from the group consisting of D-Ser and Ser,
X3 is an amino acid residue selected from the group consisting of Gln and His,
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-octadeca

Assignees

• Sanofi Sa

Inventors

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

Classifications

• A61P5/50

  for increasing or potentiating the activity of insulin · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P5/48

  of the pancreatic hormones · CPC title

• A61P43/00

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