Patent EA-003922-B1 (EA)
Title: Long lasting insulinotropic peptides
Inventor: BRIDON DOMINIQUE
IPC: C07K14/16
Filed: 2000-05-17
Abstract: 1. A modified insulinotropic peptide or derivative thereof comprising a maleimido group, which reacts with thiol groups on blood components to form a stable covalent bond. 2. A peptide according to claim 2, wherein the derivative is reactive with a thiol group of albumin on human serum albumin. 3. A peptide according to claim 1, wherein the peptide is selected from the group consisting of SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:14 and SEQ ID NO:15. 4. A peptide according to claim 1 wherein the peptide is selected from the group consisting of SEQ ID:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21 and SEQ ID NO:22. 5. A composition for treating diabetes in a human, comprising a derivative of insulinotropic peptide or analog thereof, said derivative comprising a maleimido group which reacts with thiol groups on blood components to form stable covalent. 6. The composition of claim 5, wherein said peptide is selected from the group consisting of SEQ ID NO:2 SEQ ID NO:3, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:14 and SEQ ID NO:15. 7. The composition of claim 5 wherein said peptide is selected from the group consisting of SEQ ID:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21 and SEQ ID NO:22. 8. A derivative of an insulinotropic peptide, said derivative comprising a maleimido group, which reacts with a thiol group on human serum albumin to form a covalent bond. 9. The derivative of claim 8 wherein said peptide is selected from the group consisting of SEQ ID NO:2 SEQ ID NO:3, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:14 and SEQ ID NO:15. 10. The derivative of claim 8 wherein said peptide is selected from the group consisting of SEQ ID:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21 and SEQ ID NO:22. 11. A composition for treating diabetes in a human, comprising a derivative of an insulinotropic peptide, said derivative comprising a maleimido group, which reacts with a thiol group on human serum albumin to form a covalent bond. 12. The composition of claim 11, wherein the peptide is selected from the group consisting of SEQ ID NO:2 SEQ ID NO:3, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:14 and SEQ ID NO:15. 13. The compositions of claim 11, wherein the peptide is selected from the group consisting of SEQ ID:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21 and SEQ ID NO:22. 14. Use of a composition for the manufacturer of a medicament extending the in vivo half-life of an insulinotropic peptide in a diabetes patient the composition comprising a derivative of an insulinotropic peptide or analog thereof, said derivative comprising a maleimido group, which reacts with thiol groups on blood components to form stable covalent bonds. 15. Use of a composition according to claim 14, wherein the derivative is reacted with thiol group on human serum albumin. 16. Use of the composition of claim 14, wherein said peptide is selected from the group consisting of SEQ ID NO:2 SEQ ID NO:3, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:14 and SEQ ID NO:15. 17. An insulinotropic peptide selected from the group consisting of GLP-1(1-36)-Lys<37>(e-MPA)-NH<2>, GLP-1(1-36)-Lys<37>(e-AEEA-AEEA-MPA)-NH<2>, GLP-1(7-36)-Lys<37>(e-MPA)-NH2, GLP-1(7-36)-Lys<37>(e-AEEA-AEEA-MPA)-NH<2>, D-Ala<2> GLP-1(7-36)-Lys<37>-(e-MPA)-NH<2>, D-Ala<8> GLP-1(7-36)-Lys<37>(e-AEEA-AEEA-MPA)-NH<2>,exendin-4 (1-39)-Lys<40> (e-MPA)-NH<2>, exendin-4(1-39)-Lys<40> (.epsilon.-AEEA-AEEA-MPA)-NH<2>, exendin 3(1-39)-Lys<40> (e-MPA)-NH<2> and exendin-3(1-39)-Lys<40> (e-AEEA-AEEA- MPA). 18. Compound selected from group D-Ala<8> GLP-1(7-36)-Lys<37>(e-(AEEA)n-MPA)-NH<2>, wherein N is an integer from 0 to 2. 19. Compound of claim 18, representing D-Ala<8> GLP-1(7-36)-Lys<37>(e -MPA)-NH<2>. 20. Compound of claim 18, representing D-Ala<8> GLP-1(7-36)-Lys<37>(e-AEEA-MPA)-NH<2>. 21. Compound of claim 18, representing D-Ala<8> GLP-1(7-36)-Lys<37>(e-AEEA-AEEA-MPA)-NH<2>. 22. Composition, comprising a compound of claim 19, and pharmaceutically acceptable carrier. 23. Composition, comprising a compound of claim 20, and pharmaceutically acceptable carrier. 24. Composition, comprising a compound of claim 21, and pharmaceutically acceptable carrier. 25. Use of compound of claim 19, for treating diabetes and enhancing the expression of insulin in a patient. 26. Use of compound of claim 20, for treating diabetes and enhancing the expression of insulin in a patient. 27. Use of compound of claim 21, for treating diabetes and enhancing the expression of insulin in a patient. 28. Conjugate, comprising a compound of claim 19, covalently bonded with blood protein. 29. Conjugate of claim 28, characterized in that a blood protein is albumin. 30. Conjugate, comprising a compound of claim 20, covalently bonded with blood protein. 31. Conjugate of claim 30, characterized in that a blood protein is albumin. 32. Conjugate, comprising a compound of claim 21, covalently bonded with blood protein. 33. Conjugate of claim 32, characterized in that a blood protein is albumin.