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 associated with the proteasome. 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. Oral administration of these peptide-based proteasome inhibitors is possible due to their bioavailability profiles.
1. A compound having a structure of formula (I) or a pharmaceutically acceptable salt thereof:
wherein
L is selected from C═O and C═S;
X is selected from O, S, NH, and N—C 1-6 alkyl;
Z is absent, C 1-6 alkyl, or C 1-6 alkoxy;
R 1 , R 2 , and R 3 are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, aryl, C 1-6 aralkyl, heteroaryl, heterocyclyl, C 1-6 heterocycloalkyl, C 1-6 heteroaralkyl, carbocyclyl, and C 1-6 carbocyclolalkyl;
R 4 is selected from hydrogen, C 1-6 aralkyl, and C 1-6 alkyl;
R 5 is heteroaryl; and
R 6 and R 7 are independently selected from hydrogen, C 1-6 alkyl, and C 1-6 aralkyl.
2. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Z is absent.
3. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 , R 6 , and R 7 are independently selected from hydrogen and methyl.
4. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein L is C═O.
5. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , and R 3 are independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, C 1-6 aralkyl, C 1-6 heterocycloalkyl, C 1-6 heteroaralkyl, and C 1-6 carbocyclolalkyl.
6. A compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein any of R 1 , R 2 , and R 3 are independently C 1-6 alkyl.
7. A compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein any of R 1 , R 2 , and R 3 are independently selected from methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and isobutyl.
8. A compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein any of R 1 , R 2 , and R 3 are independently propargyl.
9. A compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein any of R 1 , R 2 , and R 3 are independently C 1-6 hydroxyalkyl.
10. A compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein any of R 1 , R 2 , and R 3 are independently selected from hydroxymethyl and hydroxyethyl.
11. A compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein any of R 1 , R 2 , and R 3 are independently C 1-6 alkoxyalkyl.
12. A compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein any of R 1 , R 2 , and R 3 are independently selected from methoxymethyl and methoxyethyl.
13. A compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein any of R 1 , R 2 , and R 3 are independently C 1-6 heteroaralkyl.
14. A compound of claim 13 or a pharmaceutically acceptable salt thereof, wherein any of R 1 , R 2 , and R 3 are independently selected from imidazolylmethyl, pyrazolylmethyl, and thiazolylmethyl, and pyridylmethyl.
15. A compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein any of R 1 , R 2 , and R 3 are independently cyclohexylmethyl.
16. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , and R 3 are all different.
17. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein at least one of R 1 and R 2 is selected from C 1-6 hydroxyalkyl and C 1-6 alkoxyalkyl.
18. A compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein at least one of R 1 and R 2 is C 1-6 alkoxyalkyl.
19. A compound of claim 18 or a pharmaceutically acceptable salt thereof, wherein at least one of R 1 and R 2 is selected from methoxymethyl and methoxyethyl.
20. A compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from C 1-6 alkyl and C 1-6 aralkyl.
21. A compound of claim 20 or a pharmaceutically acceptable salt thereof, wherein R 3 is C 1-6 alkyl.
22. A compound of claim 21 or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from methyl, ethyl, isopropyl, sec-butyl, and isobutyl.
23. A compound of claim 22 or a pharmaceutically acceptable salt thereof, wherein R 3 is isobutyl.
24. A compound of claim 20 or a pharmaceutically acceptable salt thereof, wherein R 3 is C 1-6 aralkyl.
25. A compound of claim 24 or a pharmaceutically acceptable salt thereof, wherein R 3 is phenylmethyl.
26. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 5 is 5- or 6-membered heteroaryl.
27. A compound of claim 26 or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from isoxazole, isothiazole, furan, thiophene, oxazole, thiazole, pyrazole, or imidazole.
28. A compound of claim 27 or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from isoxazole, furan, or thiophene.
29. A compound of claim 28 or a pharmaceutically acceptable salt thereof, wherein R 5 is furan or thiophene.
30. A compound of claim 29 or a pharmaceutically acceptable salt thereof, wherein R 5 is unsubstituted furan-3-yl or thien-2-yl.
31. A compound of claim 28 or a pharmaceutically acceptable salt thereof, wherein R 5 is isoxazol-3-yl or isoxazol-5-yl.
32. A compound of claim 31 or a pharmaceutically acceptable salt thereof, wherein R 5 is isoxazol-3-yl that has a substituent at the 5-position.
33. A compound of claim 31 or a pharmaceutically acceptable salt thereof, wherein R 5 is isoxazol-5-yl that has a substituent at the 3-position.
34. A compound of claim 32 or 33 or a pharmaceutically acceptable salt thereof, wherein the substituent is selected from C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyalkyl, C 1-6 hydroxyalkyl, carboxylic acid, aminocarboxylate, C 1-6 alkylaminocarboxylate, (C 1-6 alkyl) 2 aminocarboxylate, C 1-6 alkylcarboxylate, C 1-6 heteroaralkyl, C 1-6 aralkyl, C 1-6 heterocycloalkyl, and C 1-6 carbocycloalkyl.
35. A compound of claim 34 or a pharmaceutically acceptable salt thereof, wherein the substituent is selected from methyl, ethyl, isopropyl, and cyclopropylmethyl.
36. A compound of claim 34 or a pharmaceutically acceptable salt thereof, wherein the substituent is selected from C 1-6 heteroaralkyl and C 1-6 heterocycloalkyl.
37. A compound of claim 36 or a pharmaceutically acceptable salt thereof, wherein the substituent is 1,2,4-triazol-5-ylmethyl.
38. A compound of claim 36 or a pharmaceutically acceptable salt thereof, wherein the substituent is azetidin-1-ylmethyl.
39. A compound of claim 36 or a pharmaceutically acceptable salt thereof, wherein the substituent is
wherein W is O, NR, or CH 2 , and R is H or C 1-6 alkyl.
40. A compound of claim 39 or a pharmaceutically acceptable salt thereof, wherein W is O.
41. A compound of claim 36 or a pharmaceutically acceptable salt thereof, wherein the substituent is selected from C 1-6 alkoxy and C 1-6 alkoxyalkyl.
42. A compound of claim 41 or a pharmaceutically acceptable salt thereof, wherein the substituent is selected from methoxy, ethoxy, methoxymethy, and methoxyethyl.
43. A compound of claim 36 or a pharmaceutically acceptable salt thereof, wherein the substituent is selected from carboxylic acid, aminocarboxylate, C 1-6 alkylaminocarboxylate, (C 1-6 alkyl) 2 aminocarboxylate, or C 1-6 alkylcarboxylate.
44. A compound of claim 43 or a pharmaceutically acceptable salt thereof, wherein the substituent is methyl carboxylate.
45. A compound selected from
or a pharmaceutically acceptable salt thereof.
46. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
47. A pharmaceutical composition of claim 46 , which is orally bioavailable.
48. A method for the treatment of inflammation, comprising administering a therapeutically effective amount of a pharmaceutical composition of claim 47 .
49. A compound of claim 45 which is
or a pharmaceutically acceptable salt thereof.