Dual GLP-1/GIP receptor agonists

Patent metadata

Field	Value
Publication number	US-9751926-B2
Application number	US-201414569260-A
Country	US
Kind code	B2
Filing date	Dec 12, 2014
Priority date	Dec 13, 2013
Publication date	Sep 5, 2017
Grant date	Sep 5, 2017

Abstract

The present invention relates to exendin-4 derivatives and their medical use, for example in the treatment of disorders of the metabolic syndrome, including diabetes and obesity, as well as reduction of excess food intake.

First claim

The invention claimed is:

1. A peptidic compound of formula (I):
R 1 —Z—R 2   (I),

or a salt or solvate thereof,
wherein Z is a peptide moiety of formula (II):
Tyr-Aib-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Ile-Gln-X14-Glu-X16-Glu-Ala-Val-X20-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Ala-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-X40   (II),

wherein:
X14 is an amino acid residue selected from Met, Leu, Nle, Met(O), and Met(O 2 ),
X16 is an amino acid residue selected from Lys and Glu,
X20 is an amino acid residue selected from Arg, Aib, (S)Me-Lys, (R)Me-Lys, and (S)Me-Orn,
X40 is absent or is Lys,
R 1 is NH 2 , and
R 2 is OH or NH 2 .

2. The compound, salt, or solvate of claim 1 , which is a glucagon-like peptide (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist.

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

4. The compound, salt or solvate of claim 1 , wherein the peptidic compound has a relative activity of at least 0.04% compared to that of natural GIP at the GIP receptor.

5. The compound, salt or solvate of claim 1 , wherein the peptidic compound exhibits a relative activity of at least 0.07% compared to that of GLP-1(7-36) at the GLP-1 receptor.

6. The compound, salt or solvate of claim 1 , wherein
X14 is an amino acid residue selected from Met, Leu, Nle, Met(O), and Met(O 2 ),
X16 is an amino acid residue selected from Lys and Glu,
X20 is an amino acid residue selected from Arg, Aib, (S)Me-Lys, (R)Me-Lys, and (S)Me-Orn, and
X40 is absent.

7. The compound, salt or solvate of claim 1 , wherein
X14 is Leu,
X16 is Lys,
X20 is an amino acid residue selected from Aib, (S)Me-Lys, (R)Me-Lys, and (S)Me-Orn, and
X40 is absent.

8. The compound, salt or solvate of claim 1 , wherein
X14 is an amino acid residue selected from Met, Leu, Nle, Met(O), and Met(O 2 ),
X16 is an amino acid residue selected from Lys and Glu,
X20 is Arg, and
X40 is absent or is Lys.

9. The compound, salt or solvate of claim 1 , wherein
X14 is an amino acid residue selected from Met, Leu, Nle, Met(O), and Met(O 2 ),
X16 is Lys,
X20 is Arg, and
X40 is absent or is Lys.

10. The compound, salt or solvate of claim 1 , wherein
X14 is an amino acid residue selected from Met and Leu,
X16 is Glu,
X20 is an amino acid residue selected from Arg, Aib, (S)Me-Lys, (R)Me-Lys, and (S)Me-Orn, and
X40 is absent or is Lys.

11. The compound, salt or solvate of claim 1 , wherein
X14 is an amino acid residue selected from Leu and Nle,
X16 is an amino acid residue selected from Lys and Glu,
X20 is an amino acid residue selected from Arg, Aib, (S)Me-Lys, (R)Me-Lys, and (S)Me-Orn, and
X40 is absent.

12. The compound, salt or solvate of claim 1 , wherein
X14 is an amino acid residue selected from Met, Met(O), and Met(O 2 ),
X16 is an amino acid residue selected from Lys and Glu,
X20 is Arg, and
X40 is absent.

13. The compound, salt or solvate of claim 1 , wherein the compound comprises any one of SEQ ID NOs: 8-20 or a salt or solvate thereof.

14. The compound, salt or solvate of claim 1 , wherein the compound is any one of SEQ ID NOs: 10-14 and 16-20 or a salt or solvate thereof.

15. A pharmaceutical composition comprising the compound of claim 1 , or a salt or solvate thereof.

16. The pharmaceutical composition of claim 15 , together with at least one pharmaceutically acceptable carrier.

17. The pharmaceutical composition of claim 15 , 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 receptor agonists; dual GLP-1/glucagon receptor agonists; protein YY 3-36 (PYY3-36); pancreatic polypeptide; glucagon receptor agonists; GIP receptor agonists or antagonists; ghrelin antagonists or inverse agonists; xenin; dipeptidyl peptidase IV (DPP-IV) inhibitors; sodium glucose cotransporter 2 (SGLT2) inhibitors; dual SGLT2/SGLT1 inhibitors; biguanides; thiazolidinediones; dual peroxisome proliferator-activated receptor (PPAR) agonists; sulfonylureas; meglitinides; alpha-glucosidase inhibitors; amylin and pramlintide; G protein-coupled receptor 119 (GPR119) agonists; GPR40 agonists; GPR120 agonists; GPR142 agonists; systemic or low-absorbable transmembrane G protein-coupled receptor 5 (TGR5) agonists; bromocriptine mesylate; inhibitors of 11-beta-hydroxysteroid dehydrogenase (HSD); activators of glucokinase; inhibitors of diacylglycerol acyltransferase (DGAT); inhibitors of protein tyrosinephosphatase 1; inhibitors of glucose-6-phosphatase; inhibitors of fructose-1,6-bisphosphatase; inhibitors of glycogen phosphorylase; inhibitors of phosphoenol pyruvate carboxykinase; inhibitors of glycogen synthase kinase; inhibitors of pyruvate dehydrogenase kinase; alpha2-antagonists; C—C motif receptor (CCR-2) antagonists; modulators of glucose transporter-4; somatostatin receptor 3 agonists; 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA)-reductase inhibitors; fibrates; nicotinic acid and derivatives thereof; nicotinic acid receptor 1 agonists; PPAR-alpha, gamma, or alpha/gamma agonists or modulators; PPAR-delta agonists; acyl-CoA cholesterol acyltransferase (ACAT) inhibitors; cholesterol absorption inhibitors; bile acid-binding substances; ileal bile acid transporter (IBAT) inhibitors; microsomal triglyceride transfer protein (MTP) inhibitors; modulators of proprotein convertase subtilisin/kinexin type 9 (PCSK9); low-density lipoprotein (LDL) receptor up-regulators by liver selective thyroid hormone receptor β agonists; high-density lipoprotein (HDL)-raising compounds; lipid metabolism modulators; phospholipase A2 (PLA2) inhibitors; apolipoprotein A1 (ApoA-1) enhancers; thyroid hormone receptor agonists; cholesterol synthesis inhibitors; omega-3 fatty acids and derivatives thereof;
substances for the treatment of obesity selected from the group consisting of sibutramine, tesofensine, tetrahydrolipstatin, cannabinoid-1 (CB-1) receptor antagonists, melanin-concentrating hormone-1 (MCH-1) antagonists, melanocortin 4 (MC4) receptor agonists and partial agonists, neuropeptide Y5 (NPY5) or NPY2 antagonists, NPY4 agonists, beta-3-agonists, leptin or leptin mimetics, agonists of the 5-hydroxy tryptophan 2c (5HT2c) receptor, combinations of bupropione/naltrexone, combinations of bupropione/zonisamide, combinations of bupropione/phentermine, combinations of pramlintide/metreleptin, and combinations of phentermine/topiramate;

Assignees

• Sanofi Sa

Inventors

• Kadereit Dieter
• Lorenz Katrin
• Evers Andreas
• Haack Torsten
• Wagner Michael
• Henkel Bernd
• Lorenz Martin
• Stengelin Siegfried

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07K14/57563

  Vasoactive intestinal peptide [VIP]; Related peptides · CPC title

• C07K14/605 Primary

  Glucagons · CPC title

• A61K38/26

  Glucagons · CPC title