Exendin-4 Derivatives as Selective Glucagon Receptor Agonists
First Claim
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1. A peptidic compound having the formula (I):
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Tza-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-X10-Ser-Lys-Gln-X14-Glu-Ser-Arg-Arg-Ala-Gln-X21 Phe-Ile-Glu-Trp-Leu-Leu-Ala-X29-Gly-Pro-Glu-Ser-Gly-Ala-Pro-Pro-Pro-Ser-R1
(I)wherein,X10 represents an amino acid residue selected from Tyr, Leu, Val, Ile, Phe, Phenylglycine, 1-Naphthylalanine, 2-Fluorophenylalanine, Cyclohexylglycine and tert-Leucine;
X14 represents an amino acid residue selected from Leu and Nle;
X21 represents an amino acid residue selected from Asp and Glu;
X29 represents an amino acid residue selected from Gly and Thr; and
R1 represents OH or NH2;
or a salt or solvate thereof.
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Abstract
The present invention relates to glucagon receptor agonists and their medical use, for example in the treatment of severe hypoglycemia.
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Citations
25 Claims
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1. A peptidic compound having the formula (I):
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Tza-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-X10-Ser-Lys-Gln-X14-Glu-Ser-Arg-Arg-Ala-Gln-X21 Phe-Ile-Glu-Trp-Leu-Leu-Ala-X29-Gly-Pro-Glu-Ser-Gly-Ala-Pro-Pro-Pro-Ser-R1
(I)wherein, X10 represents an amino acid residue selected from Tyr, Leu, Val, Ile, Phe, Phenylglycine, 1-Naphthylalanine, 2-Fluorophenylalanine, Cyclohexylglycine and tert-Leucine; X14 represents an amino acid residue selected from Leu and Nle; X21 represents an amino acid residue selected from Asp and Glu; X29 represents an amino acid residue selected from Gly and Thr; and R1 represents OH or NH2; or a salt or solvate thereof. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 20, 21, 22, 23, 24, 25)
X14 represents an amino acid residue selected from Leu and Nle; X21 represents an amino acid residue selected from Asp and Glu; X29 represents an amino acid residue selected from Gly and Thr; and R1 represents OH; or a salt or solvate thereof.
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4. The peptidic compound of claim 1, wherein,
X10 represents Tyr; -
X14 represents an amino acid residue selected from Leu and Nle; X21 represents Glu; X29 represents an amino acid residue selected from Gly and Thr; and R1 represents OH; or a salt or solvate thereof.
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5. The peptidic compound of claim 1, wherein,
X10 represents 1-Naphthylalanine; -
X14 represents an amino acid residue selected from Leu and Nle; X21 represents an amino acid residue selected from Asp and Glu; X29 represents Thr; and R1 represents OH; or a salt or solvate thereof.
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6. The peptidic compound of claim 1, wherein,
X10 represents Cyclohexylglycine; -
X14 represents an amino acid residue selected from Leu and Nle; X21 represents an amino acid residue selected from Asp and Glu; X29 represents Thr; and R1 represents OH; or a salt or solvate thereof.
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7. The peptidic compound of claim 1, wherein,
X10 represents an amino acid residue selected from Tyr, Leu, Val, Ile, Phenylglycine, 1-Naphthylalanine, 2-Fluorophenylalanine and Cyclohexylglycine; -
X14 represents Leu; X21 represents an amino acid residue selected from Asp and Glu; X29 represents an amino acid residue selected from Gly and Thr; and R1 represents OH; or a salt or solvate thereof.
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8. The peptidic compound of claim 1, wherein,
X10 represents an amino acid residue selected from Tyr, Leu, Ile, Phe, 1-aphthylalanine, Cyclohexylglycine and tert-Leucine; -
X14 represents Nle; X21 represents an amino acid residue selected from Asp and Glu; X29 represents Thr; and R1 represents OH; or a salt or solvate thereof.
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9. The peptidic compound of claim 1, wherein,
X10 represents an amino acid residue selected from Leu, Phe, 1-Naphthylalanine, 2-Fluorophenylalanine and Cyclohexylglycine; -
X14 represents an amino acid residue selected from Leu and Nle; X21 represents Asp; X29 represents Thr; and R1 represents OH; or a salt or solvate thereof.
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10. The peptidic compound of claim 1, wherein,
X10 represents an amino acid residue selected from Tyr, Leu, Val, Ile, Phenylglycine, 1-Naphthylalanine, Cyclohexylglycine and tert-Leucine; -
X14 represents an amino acid residue selected from Leu and Nle; X21 represents Glu; X29 represents an amino acid residue selected from Gly and Thr; and R1 represents OH; or a salt or solvate thereof.
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11. The peptidic compound of claim 1, wherein,
X10 represents an amino acid residue selected from Tyr, Leu, Val, Ile, Phe, Phenylglycine, 1-Naphthylalanine, 2-Fluorophenylalanine, Cyclohexylglycine and tert-Leucine; -
X14 represents an amino acid residue selected from Leu and Nle; X21 represents an amino acid residue selected from Asp and Glu; X29 represents Thr; and R1 represents OH; or a salt or solvate thereof.
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12. The peptidic compound of claim 1, wherein,
X10 represents an amino acid residue selected from Tyr, Leu and Val; -
X14 represents Leu; X21 represents Glu; X29 represents Gly; and R1 represents OH; or a salt or solvate thereof.
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13. The peptidic compound of claim 1, wherein the peptidic compound is selected from the compounds of SEQ ID NO:
- 3-25 as well as salts or solvates thereof.
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14. The peptidic compound of claim 1, wherein the peptidic compound is selected from the compounds of SEQ ID NO:
- 3, 5, 6, 9, 15, 20, 23, 24, and 25 as well as salts or solvates thereof.
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15. A method of treating hypoglycaemia or beta-blocker and calcium-channel blocker toxication, increasing blood glucose levels, reducing or maintaining body weight, providing adjunctive therapy with insulin, or inducing temporary relaxation of the gastro-intestinal system in a patient, the method comprising administering to the patient a therapeutically effective amount of at least one peptidic compound of claim 1.
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16. A pharmaceutical composition comprising the peptidic compound of claim 1 and at least one pharmaceutically acceptable carrier.
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17. The pharmaceutical composition of claim 16 comprising at least one additional therapeutically active agent, wherein the additional therapeutically active agent is selected from Insulin and Insulin derivatives, GLP-1, GLP-1 analogues and GLP-1 receptor agonists, dual GLP1/glucagon receptor agonists, dual GLP1/GIP receptor agonists, PYY3-36 or analogues thereof, pancreatic polypeptide or analogues thereof, Glucagon receptor agonists, GIP receptor agonists or antagonists, ghrelin antagonists or inverse agonists, Xenin and analogues thereof, DDP4 inhibitors, SGLT2 inhibitors, Biguanides Thiazolidinediones, dual PPAR agonists, Sulfonylureas, Meglitinides, alpha-glucosidase inhibitors, Amylin and Amylin analogues, GPR119 agonists, Cycloset, inhibitors of 11-beta-HSD, activators of glucokinase, inhibitors of 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, CCR-2 antagonists, HMG-CoA-reductase inhibitors, fibrates, nicotinic acid and the derivatives thereof, PPAR-(alpha, gamma or alpha/gamma) agonists or modulators, PPAR-delta agonists, ACAT inhibitors, cholesterol absorption inhibitors, bile acid-binding substances, IBAT inhibitors, MTP inhibitors, modulators of PCSK9, HDL-raising compounds, ABC regulators, active substances for the treatment of obesity, such as Sibutramine, Tesofensine, Orlistat, CB-1receptor antagonists, MCH-1 antagonists, MC4 receptor agonists, NPY5 or NPY2 antagonists, NPY4 agonists, beta-3-agonists, leptin or leptin mimetics, agonists of the 5HT2c receptor, or the combinations of bupropione/naltrexone (CONTRAVE), bupropione/zonisamide (EMPATIC), bupropione/phentermine or pramlintide/metreleptin, drugs for influencing high blood pressure, chronic heart failure or atherosclerosis, such as angiotensin II receptor antagonists, ACE inhibitors, ECE inhibitors, diuretics, beta-blockers, calcium antagonists, centrally acting hypertensives, antagonists of the alpha-2-adrenergic receptor, inhibitors of neutral endopeptidase, thrombocyte aggregation inhibitors.
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20. A method for treating or preventing hypoglycemia or type 2 diabetes mellitus or delaying progression from prediabetes to type 2 diabetes in a patient, the method comprising administering to the patient a therapeutically effective amount of at least one peptidic compound of claim 1.
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21. A pharmaceutical composition comprising at least one peptidic compound of claim 1 or a physiologically acceptable salt or solvent thereof.
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22. A method for treating hypoglycemia in a patient, the method comprising administering to the patient a therapeutically effective amount of at least one peptidic compound of claim 1.
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23. A method for treating hypoglycemia in a patient, the method comprising administering to the patient a therapeutically effective amount of at least one peptidic compound of claim 1 and a therapeutically effective amount of at least one other compound useful for treating hypoglycemia.
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24. The method according to claims of claim 22, wherein the at least one peptidic compound and the at least one other compound are administered simultaneously, separately, or sequentially.
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25. The method of claim 22, wherein the at least one peptidic compound is administered parenterally.
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18-19. -19. (canceled)
Specification