Exendin-4 derivatives as selective glucagon receptor agonists

1. A peptidic compound having the formula (I):

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-R 1   (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

R 1 represents OH or NH 2 ;

or a salt or solvate thereof.

2. The peptidic compound of claim 1 , wherein R 1 represents OH.

3. The peptidic compound of claim 1 , wherein,

X10 represents Leu;

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

R 1 represents OH;

or a salt or solvate thereof.

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

R 1 represents OH;

or a salt or solvate thereof.

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

R 1 represents OH;

or a salt or solvate thereof.

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

R 1 represents OH;

or a salt or solvate thereof.

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

R 1 represents OH;

or a salt or solvate thereof.

8. The peptidic compound of claim 1 , wherein,

X10 represents an amino acid residue selected from Tyr, Leu, Ile, Phe, 1-Naphthylalanine, Cyclohexylglycine and tert-Leucine;

X14 represents Nle;

X21 represents an amino acid residue selected from Asp and Glu;

X29 represents Thr; and

R 1 represents OH;

or a salt or solvate thereof.

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

R 1 represents OH;

or a salt or solvate thereof.

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

R 1 represents OH;

or a salt or solvate thereof.

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

R 1 represents OH;

or a salt or solvate thereof.

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

R 1 represents OH;

or a salt or solvate thereof.

13. The peptidic compound of claim 1 , wherein the peptidic compound is selected from the compounds of SEQ ID NO: 3-25 or a salt or solvate thereof.

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 or a salt or solvate thereof.

15. A pharmaceutical composition comprising the peptidic compound of claim 1 and at least one pharmaceutically acceptable carrier.

16. A method for treating hypoglycemia or type 2 diabetes mellitus in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of at least one peptidic compound of claim 1 .

17. A pharmaceutical composition comprising at least one peptidic compound of claim 1 or a physiologically acceptable salt or solvent thereof.

18. A method for treating hypoglycemia in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of at least one peptidic compound of claim 1 .

19. The method of claim 18 , wherein the at least one peptidic compound and the at least one other compound are administered simultaneously, separately, or sequentially.

20. The method of claim 18 , wherein the at least one peptidic compound is administered parenterally.

21. A method for treating hypoglycemia in a patient in need thereof, 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.