Compounds for enzyme inhibition
View Patent ↗Peptide-based compounds including heteroatom-containing, three-membered rings efficiently and selectively inhibit specific activities of N-terminal nucleophile (Ntn) hydrolases. The activities of those Ntn having multiple activities can be differentially inhibited by the compounds described. For example, the chymotrypsin-like activity of the 20S proteasome may be selectively inhibited with the inventive compounds. The peptide-based compounds include an epoxide or aziridine, and functionalization at the N-terminus. Among other therapeutic utilities, the peptide-based compounds are expected to display anti-inflammatory properties and inhibition of cell proliferation.
1. A compound having a structure of formula I or a pharmaceutically acceptable salt thereof,
wherein
X is O, NH, or N-alkyl;
Y is NH, N-alkyl, O, or C(R 9 ) 2 ;
Z is O or C(R 9 ) 2 ;
R 1 , R 2 , R 3 , and R 4 are all hydrogen;
each R 5 , R 6 , R 7 , R 8 , and R 9 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, aryl, and C 1-6 aralkyl, each of which is optionally substituted with a group selected from alkyl, amide, amine, carboxylic acid or a pharmaceutically acceptable salt thereof, carboxyl ester, thiol, and thioether;
m is an integer from 0 to 2; and
n is an integer from 0 to 2.
2. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X is O.
3. A compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein R 5 , R 6 , R 7 , and R 8 are independently selected from C 1-6 alkyl, C 1-6 hydroxyalkyl, and C 1-6 aralkyl; and R 9 is hydrogen.
4. A compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein R 5 and R 7 are independently C 1-6 aralkyl and R 6 and R 8 are independently C 1-6 alkyl.
5. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Y is selected from N-alkyl, O, and CH 2 .
6. A compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein Z is CH 2 , and m and n are both 0.
7. A compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein Z is CH 2 , m is 0, and n is 2.
8. A compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein Z is O, m is 1, and n is 2.
9. A compound of claim 1 or a pharmaceutically acceptable salt thereof, having the following structure
10. A compound of claim 1 or a pharmaceutically acceptable salt thereof, having the following structure
11. A compound of claim 1 or a pharmaceutically acceptable salt thereof, having the structure
12. A compound of claim 1 or a pharmaceutically acceptable salt thereof, having the structure
13. A compound of claim 1 or a pharmaceutically acceptable salt thereof, having the structure
14. A compound of claim 1 or a pharmaceutically acceptable salt thereof, having the structure
15. A compound of claim 1 , having a structure of formula III or a pharmaceutically acceptable salt thereof,
wherein
X is selected from O, NH, and N-alkyl;
R 1 , R 2 , R 3 , and R 4 are all hydrogen; and
R 5 , R 6 , R 7 , and R 8 are independently selected from hydrogen, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, aryl, and C 1-6 aralkyl, each of which is optionally substituted with a group selected from amide, amine, carboxylic acid or a pharmaceutically acceptable salt thereof, carboxyl ester, thiol, and thioether.
16. A compound of claim 14 or a pharmaceutically acceptable salt thereof, wherein X is O.
17. A compound of claim 16 or a pharmaceutically acceptable salt thereof, wherein R 5 , R 6 , R 7 and R 8 are independently selected from C 1-6 alkyl, C 1-6 hydroxyalkyl, and C 1-6 aralkyl.
18. A compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein R 5 and R 7 are independently C 1-6 aralkyl and R 6 and R 8 are independently C 1-6 alkyl.
19. A compound of claim 1 , having a structure of formula IV or a pharmaceutically acceptable salt thereof,
wherein
X is O, NH, or N-alkyl;
R 1 , R 2 , R 3 , and R 4 are all hydrogen; and
R 6 and R 8 are independently selected from hydrogen, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, aryl, and C 1-6 aralkyl, each of which is optionally substituted with a group selected from amide, amine, carboxylic acid or a pharmaceutically acceptable salt thereof, carboxyl ester, thiol, and thioether.
20. A compound of claim 19 or a pharmaceutically acceptable salt thereof, wherein X is O.
21. A compound of claim 20 or a pharmaceutically acceptable salt thereof, wherein R 6 and R 8 are independently selected from C 1-6 alkyl, C 1-6 hydroxyalkyl, and C 1-6 aralkyl.
22. A compound of claim 21 or a pharmaceutically acceptable salt thereof, wherein R 6 and R 8 are independently C 1-6 alkyl.
23. A compound of claim 22 or a pharmaceutically acceptable salt thereof, wherein R 6 and R 8 are both isobutyl.
24. A compound of claim 19 or a pharmaceutically acceptable salt thereof, having the following structure
25. A compound of claim 1 , having a structure of formula V or a pharmaceutically acceptable salt thereof,
where X is O, NH, or N-alkyl;
R 1 , R 2 , R 3 , and R 4 are all hydrogen;
R 5 , R 6 , R 7 , and R 8 are independently selected from hydrogen, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, aryl, and C 1-6 aralkyl, each of which is optionally substituted with a group selected from amide, amine, carboxylic acid or a pharmaceutically acceptable salt thereof, carboxyl ester, thiol, and thioether; and
q is an integer from 0 to 3.
26. A compound of claim 25 or a pharmaceutically acceptable salt thereof, wherein X is O.
27. A compound of claim 26 or a pharmaceutically acceptable salt thereof, wherein R 5 , R 6 , R 7 , and R 8 are independently selected from C 1-6 alkyl, C 1-6 hydroxyalkyl, and C 1-6 aralkyl.
28. A compound of claim 27 or a pharmaceutically acceptable salt thereof, wherein R 5 and R 7 are independently C 1-6 aralkyl and R 6 and R 8 are independently C 1-6 alkyl.
29. A compound of claim 1 , having a structure of formula VI or a pharmaceutically acceptable salt thereof,
wherein
X is O, NH, or N-alkyl;
R 1 , R 2 , R 3 , and R 4 are all hydrogen;
R 6 and R 8 are independently selected from hydrogen, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, aryl, and C 1-6 aralkyl, each of which is optionally substituted with a group selected from amide, amine, carboxylic acid or a pharmaceutically acceptable salt thereof, carboxyl ester, thiol, and thioether; and
q is an integer from 0 to 3.
30. A compound of claim 29 or a pharmaceutically acceptable salt thereof, wherein X is O.
31. A compound of claim 30 or a pharmaceutically acceptable salt thereof, wherein R 6 and R 8 are independently selected from C 1-6 alkyl, C 1-6 hydroxyalkyl, and C 1-6 aralkyl.
32. A compound of claim 31 or a pharmaceutically acceptable salt thereof, wherein R 6 and R 8 are independently C 1-6 alkyl.
33. A compound of claim 32 or a pharmaceutically acceptable salt thereof, wherein R 6 and R 8 are both isobutyl.
34. A compound of claim 29 or a pharmaceutically acceptable salt thereof, having the structure
35. A compound of claim 29 or a pharmaceutically acceptable salt thereof, having the structure
36. A compound of claim 29 or a pharmaceutically acceptable salt thereof, having the following structure
37. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.