Analogs that target mitochondrial diseases
Disclosed are analogs of elamipretide (MTP-131). 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 , R 1b , R 1e , R 1x , R 2a , R 2b , R 3a , R 3b , R 3c , R 4a , and R 4b are each independently selected from the group consisting of H, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, and (C 1 -C 6 )alkyl; or R 1a and R 1x together with the N atom to which they are attached form a 4-6-membered heterocyclyl; and
R a , R b , R 1c and R 1d are each independently selected from the group consisting of H, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, (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); or R a and R b together with the N atom to which they are attached form a 4-6-membered heterocyclyl.
2. The compound of claim 1 , wherein R 1a and R 1x are independently H, methyl, ethyl, propyl, cyclopropyl, or cyclobutyl; or R 1a and R 1x together with the N atom to which they are attached form a 4-6-membered heterocyclyl.
3. The compound of claim 1 , wherein Aaa 1 is selected from the group consisting of
4. The compound of claim 1 , wherein Aaa 1 is
5. The compound of claim 1 , wherein Aaa 1 is an amino acid residue selected from the group consisting of:
6. The compound of claim 5 , wherein Aaa 1 is
7. The compound of claim 1 , wherein Aaa 2 is selected from the group consisting of:
8. The compound of claim 1 , wherein Aaa 2 is
9. The compound of claim 1 , wherein R 3b is H or methyl.
10. The compound of claim 1 , wherein Aaa 3 is selected from the group consisting of:
11. The compound of claim 1 , wherein Aaa 3 is
12. The compound of claim 1 , wherein Aaa 3 is selected from the group consisting of:
13. The compound of claim 12 , wherein Aaa 3 is
14. The compound of claim 1 , wherein R 4a and R 4b are each independently H or methyl.
15. The compound of claim 1 , wherein Aaa 4 is selected from the group consisting of:
16. The compound of claim 1 , wherein R a and R b are each independently H or methyl.
17. The compound of claim 16 , wherein R a and R b are each H.
18. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, selected from the following table:
19. A pharmaceutical composition, comprising a compound of claim 1 ; and a pharmaceutically acceptable carrier.
20. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, represented by:
21. A pharmaceutical composition, comprising a compound of claim 20 and a pharmaceutically acceptable carrier.
22. The compound of claim 1 , wherein Aaa 4 is selected from the group consisting of:
23. A pharmaceutical composition, comprising a compound of claim 22 ; and a pharmaceutically acceptable carrier.
24. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, represented by:
25. A pharmaceutical composition, comprising a compound of claim 24 ; and a pharmaceutically acceptable carrier.