Cyclic CRF antagonist peptides
Cyclic CRF antagonist peptides having improved properties of “drugability”. The peptides are 33 residues in length with a lactam bond between the residues in position 22 and 25; however, they may be N-terminally shortened by up to 3 residues.
1. A cyclic corticotropin releasing factor (CRF) antagonist peptide, or a pharmaceutically acceptable salt thereof, which peptide has the amino acid sequence:
wherein Y is an acyl group having up to 20 carbon atoms; R 17 is Glu or C α CH 3 -L-leucine (CML); R 19 is 2-aminoisobutyric acid (Aib), CML, C α CH 3 -L-phenylalanine (CMP), or C α CH 3 -L-valine (CMV); R 24 is Aib, CML, D-CML, D-Aph(Cbm) or D-Aph(Hor); R 26 is Asn or Aib, R 32 is CMP, CMV, CML, or Aib.
2. A cyclic CRF antagonist peptide having the formula:
3. A cyclic CRF antagonist peptide having the formula:
4. A cyclic CRF antagonist peptide having the formula:
5. A cyclic CRF antagonist peptide having the formula:
6. The cyclic CRF antagonist peptide of claim 1 wherein the acyl group is selected from the group consisting of acetyl, propionyl, butyroyl, valeroyl, hexanoyl, octanoyl, decanoyl, tetradecanoyl, and 21-amino-4,7,10,13,16,19-hexaoxaheneicosanoyl.
7. The cyclic CRF antagonist peptide of claim 1 , wherein R 19 is Aib, wherein R 24 is Aib, and R 32 is Aib.
8. The cyclic CRF antagonist peptide of claim 7 wherein the acyl group is selected from the group consisting of acetyl, propionyl, butyroyl, valeroyl, hexanoyl, octanoyl, decanoyl, tetradecanoyl, and 21-amino-4,7,10,13,16,19-hexaoxaheneicosanoyl.
9. A cyclic CRF antagonist peptide, or a pharmaceutically acceptable salt thereof, which peptide has the amino acid sequence:
wherein Y is H, Tyr or D-Tyr or an acyl group having about 20 or fewer carbon atoms; R 1 is Asp or des-R 1 ; R 2 is Leu or des-R 2 ; R 3 is Ser or Thr or des-R 3 ; R 20 is Ala or Aib; R 21 is Gln or Aib; R 23 is Ala or Aib; R 25 is Lys or Orn; R 26 is Asn or Aib, and; R 31 is Glu.
10. The cyclic CRF antagonist peptide of claim 9 wherein the acyl group is selected from the group consisting of acetyl, propionyl, butyroyl, valeroyl, hexanoyl, octanoyl, decanoyl, tetradecanoyl, and 21-amino-4,7,10,13,16,19-hexaoxaheneicosanoyl.
11. The cyclic CRF antagonist peptide of claim 9 wherein the acyl group is acetyl.
12. The cyclic CRF antagonist peptide of claim 9 wherein the acyl group is propionyl.
13. The cyclic CRF antagonist peptide of claim 9 wherein the acyl group is butyroyl.
14. The cyclic CRF antagonist peptide of claim 9 wherein the acyl group is valeroyl.
15. The cyclic CRF antagonist peptide of claim 9 wherein the acyl group is hexanoyl.
16. The cyclic CRF antagonist peptide of claim 9 wherein the acyl group is octanoyl.
17. The cyclic CRF antagonist peptide of claim 9 wherein the acyl group is decanoyl.
18. The cyclic CRF antagonist peptide of claim 9 wherein the acyl group is tetradecanoyl.
19. The cyclic CRF antagonist peptide of claim 9 wherein the acyl group is 21-amino-4,7,10,13,16,19-hexaoxaheneicosanoyl.
20. The cyclic CRF antagonist peptide of claim 1 , wherein Y is an acyl group having up to 12 carbon atoms.
21. The cyclic CRF antagonist peptide of claim 1 , wherein Y is an acyl group having up to 15 carbon atoms.
22. The cyclic CRF antagonist peptide of claim 1 , wherein Y is an acyl group and the carbon atoms are selected from the group consisting of Ac, For, Acr and Bz.
23. A pharmaceutical composition comprising the cyclic CRF antagonist peptide of claim 1 and a pharmaceutically acceptable carrier.
24. A cyclic CRF antagonist peptide having the formula:
25. A cyclic CRF antagonist peptide having the formula:
26. A cyclic CRF antagonist peptide having the formula:
27. A cyclic CRF antagonist peptide having the formula: