Exendin-4 derivatives as selective peptidic dual GLP-1/glucagon receptor agonists
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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.
635 Citations
34 Claims
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1. A peptidic compound having the formula (I):
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34)
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2. The compound of claim 1, wherein R1 is NH2;
- or a salt or solvate thereof.
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3. The compound of claim 1, wherein the peptidic compound or the salt or solvate thereof has a relative activity of at least 0.09% compared to that of natural glucagon at the glucagon receptor.
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4. The compound of claim 1, wherein the peptidic compound or the salt or solvate thereof exhibits a relative activity of at least 0.1% compared to that of GLP-1(7-36)-amide at the GLP-1 receptor.
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5. The compound of claim 1, wherein X14 is Lys, wherein the —
- NH2 side chain group is functionalized with a group —
Z—
C(O)R5, wherein Z is a group selected from gGlu, gGlu-gGlu, AEEAc-AEEAc-gGlu, and AEEAc-AEEAc-AEEAc; andR5 is a group selected from pentadecanyl or heptadecanyl; or a salt or solvate thereof.
- NH2 side chain group is functionalized with a group —
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6. The compound of claim 1, wherein X14 is Lys, wherein the —
- NH2 side chain group is functionalized by (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-, [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 D-Ala and Gly; and R1 is NH2; or a salt or solvate thereof.
- NH2 side chain group is functionalized by (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-, [2-(2-{2-[2-(2-{2-[2-(2-Octadecanoylamino-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetyl-;
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7. The compound of claim 1, wherein X14 is Lys, wherein the —
- NH2 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 D-Ala and Gly; and R1 is NH2; or a salt or solvate thereof.
- NH2 side chain group is functionalized by (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-;
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8. The compound of claim 1, wherein X14 is Lys, wherein the —
- NH2 side chain group is functionalized by (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-, (S)-4-Carboxy-4-octadecanoylamino-butyryl-;
X28 is Lys; X29 is an amino acid residue selected from D-Ala and Gly; and R1 is NH2; or a salt or solvate thereof.
- NH2 side chain group is functionalized by (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-, (S)-4-Carboxy-4-octadecanoylamino-butyryl-;
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9. The compound of claim 1, wherein X14 is Lys, wherein the —
- NH2 side chain group is functionalized by (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-;
X28 is an amino acid residue selected from Ala, Lys and Ser; X29 is D-Ala; R1 is NH2; and or a salt or solvate thereof.
- NH2 side chain group is functionalized by (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-;
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10. The compound of claim 1, wherein X14 is Lys, wherein the —
- NH2 side chain group is functionalized by (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-, [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 Ala, Lys and Ser; X29 is Gly; and R1 is NH2; or a salt or solvate thereof.
- NH2 side chain group is functionalized by (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-, [2-(2-{2-[2-(2-{2-[2-(2-Octadecanoylamino-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetylamino}-ethoxy)-ethoxy]-acetyl-;
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11. The compound of claim 1, wherein X14 is Lys, wherein the —
- NH2 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 Gly and D-Ala; R1 is NH2; and or a salt or solvate thereof.
- NH2 side chain group is functionalized by (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-;
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12. The compound of claim 1, wherein X14 is Lys, wherein the —
- NH2 side chain group is functionalized by (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-;
X28 is an amino acid residue selected from Ala, Ser and Lys; X29 is an amino acid residue selected from Gly and D-Ala; and R1 is NH2; or a salt or solvate thereof.
- NH2 side chain group is functionalized by (S)-4-Carboxy-4-((S)-4-carboxy-4-hexadecanoylamino-butyrylamino)-butyryl-;
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13. The compound of claim 1, selected from the compounds of SEQ ID NOs:
- 6-17, or salts or solvates thereof.
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14. The compound of claim 1, wherein the compound is the compound of SEQ ID NO:
- 6, or a salt or solvate thereof.
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15. The compound of claim 1, wherein the compound is the compound of SEQ ID NO:
- 7, or a salt or solvate thereof.
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16. The compound of claim 1, wherein the compound is the compound of SEQ ID NO:
- 8, or a salt or solvate thereof.
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17. The compound of claim 1, wherein the compound is the compound of SEQ ID NO:
- 9, or a salt or solvate thereof.
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18. The compound of claim 1, wherein the compound is the compound of SEQ ID NO:
- 10, or a salt or solvate thereof.
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19. The compound of claim 1, wherein the compound is the compound of SEQ ID NO:
- 11, or a salt or solvate thereof.
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20. The compound of claim 1, wherein the compound is the compound of SEQ ID NO:
- 15, or a salt or solvate thereof.
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21. A medicament comprising the compound of claim 1, or a salt or solvate thereof.
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22. A pharmaceutical composition comprising the compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, which is present as an active agent together with at least one pharmaceutically acceptable carrier.
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23. The pharmaceutical composition of claim 22, further comprising at least one additional therapeutically active agent.
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24. The pharmaceutical composition of claim 23, wherein the at least one additional therapeutically active agent is selected from the group consisting of:
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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, and GLP-1 receptor agonists selected from the group consisting of;
lixisenatide, exenatide, exendin-4, 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 YY3-36 (PYY3-36);
pancreatic polypeptide;
glucagon receptor agonists;
GIP receptor agonists or antagonists;
ghrelin receptor 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;
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 diacylglvcerol acyltransferase (DGAT);
inhibitors of protein tyrosine phosphatase 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 1 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; and
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 or partial agonists, neuropeptide Y5 (NPY5) or NPY2 antagonists, NPY4 agonists, beta-3-agonists, leptin or leptin mimetics, agonists of the 5HT2c receptor, combinations of bupropione/naltrexone, combinations of bupropione/zonisamide, combinations of bupropione/phentermine, combinations of pramlintide/metreleptin, and combinations of phentermine/topiramate;lipase inhibitors;
angiogenesis inhibitors;
H3 antagonists;
Agouti-related protein (AgRP) inhibitors;
triple monoamine uptake inhibitors;
methionine aminopeptidase type 2 (MetAP2) inhibitors;
nasal formulation of the calcium channel blocker diltiazem;
antisense molecules against production of fibroblast growth factor receptor 4; and
prohibitin targeting peptide-1; anddrugs for influencing high blood pressure, chronic heart failure, or atherosclerosis selected from the groups consisting of;
angiotensin II receptor antagonists, angiotensin-converting-enzyme (ACE) inhibitors, endothelin-converting-enzyme (ECE) inhibitors, diuretics, beta-blockers, calcium antagonists, centrally acting hypertensives, antagonists of the alpha-2-adrenergic receptor, inhibitors of neutral endopeptidase, and thrombocyte aggregation inhibitors.
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25. A method for the treatment of hyperglycemia, type 1 diabetes, type 2 diabetes, obesity, or any combination of these individual diseases, the method comprising administering to a subject in need thereof the compound of claim 1.
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26. A method for the treatment of obesity, the method comprising administering to a subject in need thereof the compound of claim 1.
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27. The method of claim 25 for the treatment of hyperglycemia or type 2 diabetes.
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28. The method of claim 27 for the treatment of type 2 diabetes, further comprising simultaneous treatment of obesity.
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29. The method of claim 27 for the treatment of type 2 diabetes.
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30. A method for reducing blood glucose levels and/or reducing HbA1c levels of a subject suffering from diabetes and/or obesity, the method comprising administering to the subject the compound of claim 1.
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31. A method for reducing body weight of a subject suffering from hyperglycemia, diabetes, and/or obesity, the method comprising administering to the subject the compound of claim 1.
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32. A method for treating hyperglycemia, diabetes or obesity in a patient, the method comprising administering to the patient in need thereof an effective amount of at least one compound of claim 1 and an effective amount of at least one other compound useful for treating diabetes, obesity, dyslipidemia or high blood pressure.
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33. The method of claim 32, wherein the effective amount of at least one compound of claim 1 and the one other compound are administered to the patient simultaneously.
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34. The method of claim 32, wherein the effective amount of at least one compound of claim 1 and the one other compound are administered to the patient sequentially.
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2. The compound of claim 1, wherein R1 is NH2;
Specification
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Current AssigneeSanofi
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Original AssigneeSanofi
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InventorsBossart, Martin, Evers, Andreas, Haack, Torsten, Lorenz, Katrin, Kadereit, Dieter, Wagner, Michael, Henkel, Bernd
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Primary Examiner(s)Ha, Julie
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Assistant Examiner(s)Hellman, Kristina M
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Application NumberUS15/205,689Publication NumberTime in Patent Office690 DaysField of SearchNoneUS Class CurrentCPC Class CodesA61K 38/26 GlucagonsA61K 45/06 Mixtures of active ingredie...A61P 1/16 for liver or gallbladder di...A61P 3/00 Drugs for disorders of the ...A61P 3/04 Anorexiants; Antiobesity ag...A61P 3/10 for hyperglycaemia, e.g. an...A61P 43/00 Drugs for specific purposes...A61P 9/00 Drugs for disorders of the ...A61P 9/10 for treating ischaemic or a...A61P 9/12 AntihypertensivesC07K 14/605 Glucagons