Mitochondria-targeting peptides
Disclosed are analogs of SBT-20. The compounds are useful for the treatment and prevention of ischemia-reperfusion injury (e.g., cardiac ischemia-reperfusion injury) or myocardial infarction.
1. A compound of formula (I), or a pharmaceutically acceptable salt thereof:
wherein:
Aaa 1 is an amino acid residue selected from the group consisting of:
Aaa 2 is an amino acid residue selected from the group consisting of:
Aaa 3 is an amino acid residue selected from the group consisting of:
Aaa 4 is an amino acid residue selected from the group consisting of:
R 1a and R 4d are each independently (C 1 -C 6 )alkyl;
R 2a , R 2b , R 2e , R 3a , R 3b , R 4a , R 4b , R 4c are each independently selected from the group consisting of H and (C 1 -C 6 )alkyl; and
R a , R b , R 2c , and R 2d are each independently selected from the group consisting of H, (C 1 -C 6 )alkyl, C(O)((C 1 -C 6 )alkyl), C(O)((C 1 -C 6 ) haloalkyl), C(O)O((C 1 -C 6 )alkyl), and C(O)O(aryl (C 1 -C 6 )alkyl).
2. The compound of claim 1 , wherein Aaa 1 is selected from the group consisting of:
3. The compound of claim 2 , wherein Aaa 1 is
4. The compound of claim 1 , wherein Aaa 1 is an amino acid residue selected from the group consisting of:
5. The compound of claim 1 , wherein Aaa 2 is selected from the group consisting of:
6. The compound of claim 1 , wherein Aaa 2 is
7. The compound of claim 1 , wherein Aaa 3 is selected from the group consisting of:
8. The compound of claim 1 , wherein Aaa 3 is selected from the group consisting of:
9. The compound of claim 1 , wherein Aaa 3 is selected from the group consisting of:
10. The compound of claim 1 , wherein Aaa 4 is selected from the group consisting of:
11. The compound of claim 1 , wherein Aaa 4 is selected from the group consisting of:
12. The compound of claim 1 , wherein Aaa 4 is selected from the group consisting of:
13. The compound of claim 1 , wherein R a and R b are each independently H or methyl.
14. The compound of claim 1 , wherein R a and R b are each H.
15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, selected from the following table:
16. A pharmaceutical composition, comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
17. The compound of claim 15 , or a pharmaceutically acceptable salt thereof, wherein the compound is:
18. The compound of claim 15 , or a pharmaceutically acceptable salt thereof, wherein the compound is:
19. A method for treating or preventing ischemia-reperfusion injury in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
20. The method of claim 19 , wherein the ischemia-reperfusion injury is cardiac ischemia-reperfusion injury.
21. A method for treating or preventing a myocardial infarction in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
22. The method of claim 19 , wherein the compound is administered orally, topically, systemically, intravenously, subcutaneously, intraperitoneally, or intramuscularly.