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 at least three peptide units, 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 amacuire of formula (I) or a pharmaceutically acceptable salt thereof,
wherein each A is independantly selected from C═O, C═S, and SO 2 ; or
A is optionally a covalent bond when adjacent to an occurrence of Z;
L in absent or is selected from C═O, C═S, and SO 2 ;
M is absent or is C 1-12 alkyl;
Q is absent or is selected from O, NH, and N—C 1-6 alkyl;
X is selected from O, NH, and N—C 1-6 alkyl;
Y is absent or is selected from O, NH, N—C 1-6 alkyl, S, SO, SO 2 , CHOR 10 , and CHCO 2 R 10 ;
each Z is independently selected from O, S, NH, and N—C 1-6 alkyl; or
Z is optionally a covalent bond when adjacent to an occurrence of A;
R 1 , R 2 , R 3 , and R 4 are each independently selected from C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, aryl, and C 1-6 aralkyl, any of which is optionally substituted with one or more of amide, amine, caiboxylic acid (or a salt thereof), ester, thiol, or thioether substituents;
R 5 is N(R 6 )LQR 7 ;
R 6 is selected from hydrogen, OH, and C 1-6 alkyl;
R 7 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, aryl, C 1-6 aralkyl, heteroaryl, C 1-6 heteroaralkyl, R 8 ZAZ-C 1-8 alkyl-, R 11 Z-C 1-8 alkyl-, (R 8 O)(R 9 O)P(═O)O—C 1-8 alkyl-ZAZ-C 1-6 alkyl-, R 8 ZAZ-C 1-8 alkyl-ZAZ-C 1-8 alkyl-, heterocyclylMZAZ-C 1-8 alkyl-, (R 8 O)(R 9 O)P(═O)O—C 1-8 alkyl-, (R 10 ) 2 N—C 1-12 alkyl-, (R 10 ) 3 N + -C 1-12 alkyl-, heterocyclylM-, carbocyclylM-, R 11 SO 2 C 1-8 alkyl-, and R 11 SO 2 NH; or
R 6 and R 7 together are C 1-6 alkyl-Y—C 1-6 alkyl, C 1-6 alkyl-ZAZ-C 1-6 alkyl, ZAZ-C 1-6 alkyl-ZAZ-C 1-6 alkyl, ZAZ-C 1-6 alkyl-ZAZ, or C 1-6 alkyl-A, thereby forming a ring;
R 8 and R 9 are independently selected from hydrogen, metal cation, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, aryl, heteroaryl, C 1-6 aralkyl, and C 1-6 heteroaralkyl, or R 8 and R 9 together are C 1-6 alkyl, thereby forming a ring;
each R 10 is independently selected from hydrogen and C 1-6 alkyl; and
R 11 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, C 1-6 aralkyl, and C 1-6 heteroaralkyl,
provided that when R 6 is H or CH 3 and Q is absent, LR 7 is not hydrogen, unsubstituted C 1-6 alkylC═O, a further chain of amino acids, t-butoxycarbonyl (Boc), beozoyl (Bz), fluoren-9-ylmethoxycarbonyl (Fmoc), triphenylmethyl(trityl), benzyloxycarbonyl (Cbz), trichloroethoxycarbonyl (Troc); or substituted or unsubstituted aryl or heteroaryl; and
in any occurrence of the sequence ZAZ, at least one member of the sequence must be other than a covalent bond.
2. A compound of claim 1 , wherein R 1 , R 2 R 3 , and R 4 are independently selected from C 1-6 alkyl and C 1-6 aralkyl.
3. A compound of claim 2 , wherein R 1 and R 3 are both C 1-6 aralkyl and both R 2 and R 4 are C 1-6 alkyl.
4. A compound of claim 3 , wherein X is O, R 1 is 2-phenylethyl, R 2 is isobutyl, R 3 is phenylmethyl, and R 4 is isobutyl.
5. A compound of claim 4 , wherein L and Q are absent and R 6 is C 1-6 alkyl.
6. A compound of claim 5 , wherin R 7 is selected from C 1-6 alkyl. C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 aralkyl, and C 1-6 heteroaralkyl.
7. A compound of claim 6 , wherein R 7 is C 1-6 alkyl.
8. A compound of claim 7 , wherein R 7 is butyl.
9. A compound of claim 6 , wherein R 7 is C 1-6 alkenyl.
10. A compound of claim 9 , wherein R 7 is allyl.
11. A compound of claim 6 , wherein R 7 is C 1-6 alkynyl.
12. A compound of claim 11 , wherein R 7 is propargyl.
13. A compound of claim 6 , wherein R 7 is C 1-6 aralkyl.
14. A compound of claim 13 , wherein R 7 is phenylmethyl.
15. A compound of claim 6 , wherein R 7 is C 1-6 heteroaralkyl.
16. A compound of claim 15 , wherein R 7 is selected from 2-pyridyl, 3-pyridyl, and 4-pyridyl.
17. A compound of claim 4 , wherein Q is absent and L is SO 2 .
18. A compound of claim 17 , wherein R 7 is selected from C 1-6 alkyl and C 1-6 aralkyl.
19. A compound of claim 18 , wherein R 7 is C 1-6 alkyl.
20. A compound of claim 19 , wherein R 7 is methyl.
21. A compound of claim 18 , wherein R 7 is C 1-6 aralkyl.
22. A compound of claim 21 , wherein R 7 is phenyl.
23. A compound of claim 4 , wherein L is C═O.
24. A compound of claim 23 , wherein R 7 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, aryl, C 1-6 aralkyl, heteroaryl, C 1-6 hetcroaralkyl, R 8 ZA-C 1-8 alkyl-, R 11 Z-C 1-8 alkyl (R 8 O)(R 9 O)P(═O)O—C 1-8 alkyl-ZAZ-C 1-6 alkyl-, (R 8 O)(R 9 O)P(═O)O—C 1-6 alkyl-Z-C 1-8 alkyl-, R 8 ZA-C 1-8 alkyl-ZAZ-C 1-8 alkyl, heterocyclylMZAZ-C 1-8 alkyl, (R 8 O)(R 9 O)P(═O)O—C 1-8 alkyl-, (R 10 ) 2 N—C 1-8 alkyl-, (R 10 ) 3 N ++ —C 1-8 alkyl-, heterocyclylM-, carbocyclylM-, R 11 SO 2 C 1-8 alkyl-, and R 11 SO 2 NH; or
R 6 and R 7 together are C 1-6 alky-Y—C 1-6 alkyl, C 1-6 alkyl-ZA-C 1-6 alkyl, A-C 1-6 alkyl-ZA-C 1-6 alkyl, A-C 1-6 alkyl-A or C 1-6 alkyl-A, thereby fomiing a ring;
and each occurrence of Z and A is independently other than a covalent bond.
25. A compound of claim 24 , wherein Q is absent.
26. A compound of claim 25 , wherein R 6 and R 7 are C 1-6 alkyl.
27. A compound of claim 26 , wherein R 7 is selected from ethyl, isopropyl, 2,2,2-trifluoroethyl, and 2-(methylsulfonyl)ethyl.
28. A compound of claim 25 , wherein R 7 is C 1-6 aralkyl.
29. A compound of claim 28 , wherein R 7 is selected from 2-phenylethyl, phenylmethyl, (4-methoxyphenyl)methyl, (4-chlorophenyl)methyl, and (4-fluorophenyl)methyl.
30. A compound of claim 25 , wherein R 6 is C 1-6 alkyl and R 7 is aryl.
31. A compound of claim 30 , wherein R 7 is substituted or unsubstituted phenyl.
32. A compound of claim 24 , wherein Q is absent or O and R 7 is carbocyclylM-.
33. A compound of claim 32 , wherein carbocyclyl is cyclopropyl or cyclohexyl.
34. A compound of claim 25 , wherein R 7 is selected from R 8 ZA-C 1-6 alkyl-, R 11 Z-C 1-8 alkyl-, (R 8 O)(R 9 O)P(═O)O—C 1-8 alkyl-ZAZ-C 1-8 alkyl, (R 8 O)(R 9 O)P(═O)O—C 1-8 alkyl-Z-C 1-8 alkyl-, R 8 ZA-C 1-8 alkyl-ZAZ-C 1-8 alkyl-, heteroeyclylMZAZ-C 1-8 alkyl-, (R 8 O)(R 9 O)P(═O)O—C 1-8 alkyl-, A is C═O, and Z is O or NH.
35. A compound of claim 34 , wherein Z is O.
36. A compound of claim 35 , wherein R 7 is heterocyclylMZAZ-C 1-8 alkyl- and heterocyclyl is oxodioxolenyl or N(R 12 )(R 13 ), wherein R 12 and R 13 together arc C 1-6 alkyl-Y—C 1-6 alkyl, thereby forming a ring.
37. A compound of claim 36 , wherein R 7 is selected from (R 10 ) 2 N—C 1-8 alkyl- and (R 10 ) 3 N + (CH 2 ) n —, and R 10 is C 1-6 alkyl.
38. A compound of claim 25 , wherein R 7 is heterocyclylM- and hetercyclyl is selected from morpholino, piperidino, piperazino, and pyrrolidino.
39. A compound of claim 24 , wherein Q is O or NH.
40. A compound of claim 39 , wherein R 6 is C 1-6 alkyl and R 7 is selected from C 1-6 alkyl, C 1-6 aralkyl, and C 1-6 heteroaralkyl.
41. A compound of claim 40 , wherein R 7 is selected from methyl, ethyl, isopropyl, phenylmethyl, and (4-pyridyl)methyl.
42. A compound of claim 24 , wherein R 6 and R 7 together are C 1-6 alkyl-Y—C 1-6 alkyl, C 1-6 alkyl-ZA-C 1-6 alkyl, or C 1-6 alkyl-A, thereby forming a ring.
43. A compound of claim 42 , wherein L is C═O, Q and Y are absent, and R 6 and R 7 together are C 1-3 alkyl-Y—C 1-3 alkyl.
44. A compound of claim 1 , wherein L and Q are absent, and R 6 and R 7 together are C 1-3 alkyl-Y—C 1-3 alkyl.
45. A compound of claim 42 , wherein L is C═O, Q is absent, Y is selected from NH and N—C 1-6 alkyl, and R 6 and R 7 together are C 1-3 alkyl-Y—C 1-3 alkyl.
46. A compound of claim 42 , wherein L is C═O, Y is absent and R 6 and R 7 together are C 1-2 alkyl-Y—C 1-3 alkyl.
47. A compound of claim 42 , wherein L and A are C═O and R 6 and R 7 together are C 1-2 alkyl-ZA-C 1-2 alkyl.
48. A compound of claim 42 , wherein L and A are C═O and R 6 and R 7 together are C 2-3 alkyl-A.
49. A compound having a structure of formula II or a pharmaceutically acceptable salt thereof,
wherein each A is independently selected from C═O, C═S, and SO 2 ; or
A is optionally a covalent bond when adjacent to an occulTence of Z;
L is absent or is selected from C═O, C═S, and SO 2 ;
M is absent or is C 1-12 alkyl;
Q is absent or is selected from O, NH, and N—C 1-6 alkyl;
X is selected from O, NH, and N—C 1-6 alkyl;
Y is absent or is selected from O, NH, N—C 1-6 alkyl, S, SO, SO 2 , CHOR 10 , and CHCO 2 R 10 ;
each Z is independently selected from O, S, NH, and N—C 1-6 alkyl; or
Z is optionally a covalent bond when adjacent to an occunence of A;
R 2 and R 4 are each independently selected from C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, aryl, and C 1-6 aralkyl, any of which is optionally substituted with one or more of amide, amine, carboxylic acid (or a salt thereof), ester, thiol, or thioether substituents;
R 5 is N(R 6 )LQR 7 ;
R 6 is selected from hydrogen, OH, and C 1-6 alkyl;
R 7 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, aryl, C 1-6 aralkyl, heteroaryl, C 1-6 heteroaralkyl, R 11 ZAZ-C 1-8 alkyl-, R 11 Z-C 1-8 alkyl-, (R 8 O)(R 9 O)P(═O)O—C 1-8 alkyl-ZAZ-C 1-6 alkyl-, R 8 ZAZ-C 1-8 alkyl-ZAZ-C 1-8 alkyl-, heteroeyelylMZAZ-C 1-8 alkyl-, (R 8 O)(R 9 O)P(═O)O—C 1-8 alkyl-; (R 10 ) 2 N—C 1-12 alkyl-, (R 10 ) 3 N—C 1-12 alkyl, heterocyclylM-, carbocyclylM-, R 11 SO 2 C 1-8 alkyl-, and R 11 SO 2 NH; or
R 6 and R 7 together are C 1-6 alkyl-Y—C 1-6 alkyl, C 1-6 alkyl-ZAZ-C 1-6 alkyl, ZAZ-C 1-6 alkyl-ZAZ-C 1-6 alkyl, ZAZ-C 1-6 alkyl-ZAZ, or C 1-6 alkyl-A;
R 8 and R 9 are independently selected from hydrogen, metal cation, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, aryl, heteroaryl, C 1-6 aralkyl, and C 1-6 heteroaralkyl, or R 8 and R 9 together are C 1-6 alkyl, thereby forming a ring;
each R 10 is independently selected from hydrogen and C 1-6 alkyl; and
R 11 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, carbocyclyl, hoterocyclyl, aryl, heteroaryl, C 1-6 aralkyl, and C 1-6 heteroaralkyl,
provided that when R 6 is H or CH 3 and Q is absent, LR 7 is not hydrogen, unsubstituted C 1-6 alkylC═O, a further chain of amino acids, t-butoxycarbonyl (Boc), benzoyl (Bz), fluoren-9-ylmethoxycarbonyl (Fmoc), triphenylmethyl(trityl), benayloxycarbonyl (Cbz), trichloroethoxycarbonyl (Troc); or substituted or unsubstituted aryl or heteroaryl; and
in any occurrence of the sequence ZAZ, at least one member of the sequence must be other than a covalent bond.
50. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.