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 method of inhibiting an N-terminal nucleophile hydrolase or of treating inflammation or fever, comprising administering to a subject a compound having a structure of formula (I) 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 occurrence 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 0, NH, N—C 1-6 alkyl, S, SO, SO 2 , CHOR 10 , and CHCO 2 R 10 ;
each Z is independently selected from 0, S, NH, and N—C 1-6 alkyl; or
Z is optionally a covalent bond when adjacent to an occurrence of A;
R 1 and R 3 are each independently C 1-6 aralkyl, optionally substituted with one or more of amide, amine, carboxylic acid (or a salt thereof), ester, thiol, or thioether substituents;
R 2 and R 4 are each independently C 1-6 alkyl, 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 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 1-8 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;
each R 10 is independently selected from hydrogen and C 1-6 alkyl, preferably 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), benzoyl (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. The method of claim 1 , wherein R 1 and R 3 are both C 1-6 aralkyl and both R 2 and R 4 are C 1-6 alkyl.
3. The method of claim 2 , wherein X is O, R 1 is 2-phenylethyl, R 2 is isobutyl, R 3 is phenylmethyl, and R 4 is isobutyl.
4. The method of claim 3 , wherein L and Q are absent and R 6 is C 1-6 alkyl.
5. The method of claim 4 , wherein 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.
6. The method of claim 5 , wherein R 7 is C 1-6 alkyl.
7. The method of claim 6 , wherein R 7 is butyl.
8. The method of claim 5 , wherein R 7 is C 1-6 alkenyl.
9. The method of claim 8 , wherein R 7 is allyl.
10. The method of claim 5 , wherein R 7 is C 1-6 alkynyl.
11. The method of claim 10 , wherein R 7 is propargyl.
12. The method of claim 5 , wherein R 7 is C 1-6 aralkyl.
13. The method of claim 12 , wherein R 7 is phenylmethyl.
14. The method of claim 5 , wherein R 7 is C 1-6 heteroaralkyl.
15. The method of claim 14 , wherein R 7 is selected from 2-pyridyl, 3-pyridyl, and 4-pyridyl.
16. The method of claim 3 , wherein Q is absent and L is SO 2 .
17. The method of claim 16 , wherein R 7 is selected from C 1-6 alkyl and C 1-6 aralkyl.
18. The method of claim 17 , wherein R 7 is C 1-6 alkyl.
19. The method of claim 18 , wherein R 7 is methyl.
20. The method of claim 17 , wherein R 7 is C 1-6 aralkyl.
21. The method of claim 20 , wherein R 7 is phenyl.
22. The method of claim 3 , wherein L is C═O.
23. The method of claim 22 , 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 heteroaralkyl, 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 1-8 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-, 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 alkyl-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 forming a ring;
and each occurrence of Z and A is independently other than a covalent bond.
24. The method of claim 23 , wherein Q is absent.
25. The method of claim 24 , wherein R 6 and R 7 are C 1-6 alkyl.
26. The method of claim 25 , wherein R 7 is selected from ethyl, isopropyl, 2,2,2-trifluoroethyl, and 2-(methylsulfonyl)ethyl.
27. The method of claim 24 , wherein R 7 is C 1-6 aralkyl.
28. The method of claim 27 , wherein R 7 is selected from 2-phenylethyl, phenylmethyl, (4-methoxyphenyl)methyl, (4-chlorophenyl)methyl, and (4-fluorophenyl)methyl.
29. The method of claim 24 , wherein R 6 is C 1-6 alkyl and R 7 is aryl.
30. The method of claim 29 , wherein R 7 is substituted or unsubstituted phenyl.
31. The method of claim 23 , wherein Q is absent or O and R 7 is carbocyclylM-.
32. The method of claim 31 , wherein carbocyclyl is cyclopropyl or cyclohexyl.
33. The method of claim 24 , wherein R 7 is selected from
(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-, heterocyclylMZAZ—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.
34. The method of claim 33 , wherein Z is O.
35. The method of claim 34 , 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 are C 1-6 alkyl-Y—C 1-6 alkyl, thereby forming a ring.
36. The method of claim 35 , 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.
37. The method of claim 24 , wherein R 7 is heterocyclylM- and heterocyclyl is selected from morpholino, piperidino, piperazino, and pyrrolidino.
38. The method of claim 23 , wherein Q is O or NH.
39. The method of claim 38 , 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.
40. The method of claim 39 , wherein R 7 is selected from methyl, ethyl, isopropyl, phenylmethyl, and (4-pyridyl)methyl.
41. The method of claim 23 , 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.
42. The method of claim 41 , 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.
43. The method of claim 41 , wherein L and Q are absent, and R 6 and R 7 together are C 1-3 alkyl-Y—C 1-3 alkyl.
44. The method of claim 41 , 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.
45. The method of claim 41 , wherein L is C═O, Y is absent and R 6 and R 7 together are C 1-3 alkyl-Y—C 1-3 alkyl.
46. The method of claim 41 , wherein L and A are C═O and R 6 and R 7 together are C 1-2 alkyl-ZA-C 1-2 alkyl.
47. The method of claim 42 , wherein L and A are C═O and R 6 and R 7 together are C 2-3 alkyl-A.
48. A method of inhibiting an N-terminal nucleophile hydrolase or of treating inflammation or fever, comprising administering to a subject 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 occurrence 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 0, NH, and N—C 1-6 alkyl;
X is selected from 0, NH, and N—C 1-6 alkyl;
Y is absent or is selected from 0, NH, N—C 1-6 alkyl, S, SO, SO 2 , CHOR 10 , and CHCO 2 R 10 ;
each Z is independently selected from 0, S, NH, and N—C 1-6 alkyl; or
Z is optionally a covalent bond when adjacent to an occurrence of A;
R 2 and R 4 are each independently C 1-6 alkyl 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 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 1-8 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;
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;
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), benzoyl (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.
49. A method of inhibiting an N-terminal nucleophile hydrolase, comprising administering a therapeutically effective amount of a compound of formula I of claim 1 or a pharmaceutically acceptable salt thereof or of formula II of claim 48 or a pharmaceutically acceptable salt thereof.
50. A method for the treatment of inflammation, comprising administering a therapeutically effective amount of a compound of formula I of claim 1 or a pharmaceutically acceptable salt thereof or of formula II of claim 48 or a pharmaceutically acceptable salt thereof.
51. A method for the treatment of fever, comprising administering a therapeutically effective amount of a compound of formula I of claim 1 or a pharmaceutically acceptable salt thereof or of formula II of claim 48 or a pharmaceutically acceptable salt thereof.
52. The method of claim 48 , wherein X is O.
53. The method of claim 48 , wherein:
X is O;
R 5 is N(R 6 )LQR 7 , wherein Q is absent;
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-ZAZC 1-8 alkyl-, R8ZAZ-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-, heterocyclyIM, carbocyclyIM-, R 11 SOzC 1-8 alkyl-, and R 11 SOzNH;
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;
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, and Q is absent, LR 7 is not hydrogen, unsubstituted C 1-6 alkyIC=O, a further chain of amino acids, t-butoxycarbonyl (Boc), benzoyl (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.
54. The method of claim 53 , wherein L is C=O.
55. The method of claim 54 , wherein R 7 is heterocyclylM- and hetercyclyl is selected from morpholino, piperidino, piperazino, and pyrrolidino.
56. The method of claim 55 , wherein R 6 is H and R 7 is heterocyclylM-, wherein heterocyclyl is morpholino and M is CH 2 -.
57. The method of claim 56 , wherein R 2 and R 4 are isobutyl.
58. A method of inhibiting an N-terminal nucleophile hydrolase or of treating inflammation or fever, comprising administering to a subject a compound having a structure of formula II or a pharmaceutically acceptable salt thereof,
wherein L is C=O,
M is CH 2 -;
Q is absent;
X is O;
R 2 and R 4 are both isobutyl;
R 5 is N(R 6 )LQR 7 ;
R 6 is hydrogen; and
R 7 is heterocyclylM-, and hetercyclyl is selected from morpholino, piperidino, piperazino, and pyrrolidino.
59. The method of claim 58 , wherein heterocyclyl is morpholino, or a pharmaceutically acceptable salt of said compound of Formula II.
60. A method of inhibiting an N-terminal nucleophile hydrolase,
comprising administering a therapeutically effective amount of a compound of formula II of claim 58 or 59 , or a pharmaceutically acceptable salt thereof.
61. A method for the treatment of inflammation, comprising
administering a therapeutically effective amount of a compound of formula II of claim 58 or 59 , or a pharmaceutically acceptable salt thereof.
62. A method for the treatment of fever, comprising administering a therapeutically effective amount of a compound of formula II of claim 58 or 59 , or a pharmaceutically acceptable salt thereof.