COMPOUNDS FOR PROTEASOME ENZYME INHIBITION
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;
R 10 and R 11 are independently selected from hydrogen and C 1-6 alkyl, or R 10 and R 11 together form a 3- to 6-membered carbocyclic or heterocyclic ring;
R 12 and R 13 are independently selected from hydrogen, a metal cation, C 1-6 alkyl, and C 1-6 aralkyl, or R 12 and R 13 together represent C 1-6 alkyl, thereby forming a ring;
m is an integer from 0 to 2; and
n is an integer from 0 to 2, preferably 0 or 1.
2 . A compound of claim 1 , wherein X is O.
3 . A compound of claim 2 , 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 , 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 4 , wherein R 1 , R 2 , R 3 , and R 4 are all hydrogen.
6 . A compound of claim 5 , wherein Y is selected from N-alkyl, O, and CH 2 .
7 . A compound of claim 6 , wherein Z is CH 2 , and m and n are both 0.
8 . A compound of claim 6 , wherein Z is CH 2 , m is O, and n is 2 or 3.
9 . A compound of claim 6 , wherein Z is O, m is 1, and n is 2.
10 . A compound of claim 1 , having the following structure
11 . A compound of claim 1 , having the following structure
12 . A compound of claim 1 , having the structure
13 . A compound of claim 1 , having the structure
14 . A compound of claim 1 , having the structure
15 . A compound of claim 1 , having the structure
16 . A compound 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;
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.
17 . A compound of claim 16 , wherein X is O.
18 . A compound of claim 17 , 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.
19 . A compound of claim 18 , wherein R 5 and R 7 are independently C 1-6 aralkyl and R 6 and R 8 are independently C 1-6 alkyl.
20 . A compound 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;
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.
21 . A compound of claim 20 , wherein X is O.
22 . A compound of claim 21 , wherein R 6 and R 8 are independently selected from C 1-6 alkyl, C 1-6 hydroxyalkyl, and C 1-6 aralkyl.
23 . A compound of claim 22 , wherein R 6 and R 8 are independently C 1-6 alkyl.
24 . A compound of claim 23 , wherein R 6 and R 8 are both isobutyl.
25 . A compound of claim 20 , having the following structure
26 . A compound 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 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; and
q is an integer from 0 to 3.
27 . A compound of claim 26 , wherein X is O.
28 . A compound of claim 27 , 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.
29 . A compound of claim 28 , wherein R 5 and R 7 are independently C 1-6 aralkyl and R 6 and R 8 are independently C 1-6 alkyl.
30 . A compound 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.
31 . A compound of claim 30 , wherein X is O.
32 . A compound of claim 31 , wherein R 6 and R 8 are independently selected from C 1-6 alkyl, C 1-6 hydroxyalkyl, and C 1-6 aralkyl.
33 . A compound of claim 32 , wherein R 6 and R 8 are independently C 1-6 alkyl.
34 . A compound of claim 33 , wherein R 6 and R 8 are both isobutyl.
35 . A compound of claim 30 , having the structure
36 . A compound of claim 30 , having the structure
37 . A compound of claim 30 , having the following structure
38 . A pharmaceutical composition comprising a compound of any one of claims 1 , 16 , 20 , 26 , and 30 , and a pharmaceutically acceptable carrier.
39 . A method for the treatment of inflammation, comprising administering a therapeutically effective amount of a compound of any one of claims 1 , 16 , 20 , 26 , and 30 .
40 . A method for inhibiting or reducing HIV infection, comprising administering a therapeutically effective amount of a compound of any one of claims 1 , 16 , 20 , 26 , and 30 .
41 . A method for the treatment of neurodegenerative disease, comprising administering a therapeutically effective amount of a compound of any one of claims 1 , 16 , 20 , 26 , and 30 .
42 . A method for the treatment of muscle-wasting diseases, comprising administering a therapeutically effective amount of a compound of any one of claims 1 , 16 , 20 , 26 , and 30 .
43 . A method for the treatment of cancer, comprising administering a therapeutically effective amount of a compound of any one of claims 1 , 16 , 20 , 26 , and 30 .
44 . A method for the treatment of chronic infectious diseases, comprising administering a therapeutically effective amount of a compound of any one of claims 1 , 16 , 20 , 26 , and 30 .
45 . A method for the treatment of a hyperproliferative condition, comprising administering a therapeutically effective amount of a compound of any one of claims 1 , 16 , 20 , 26 , and 30 .
46 . A method for the treatment of muscle disuse, comprising administering a therapeutically effective amount of a compound of any one of claims 1 , 16 , 20 , 26 , and 30 .
47 . A method for the treatment of immune-related conditions, comprising administering a therapeutically effective amount of a compound of any one of claims 1 , 16 , 20 , 26 , and 30 .
48 . A method for affecting the level of viral gene expression in a subject, comprising administering a therapeutically effective amount of a compound of any one of claims 1 , 16 , 20 , 26 , and 30 .
49 . A method for altering the variety of antigenic peptides produced by the proteasome in an organism, comprising administering therapeutically effective amount of a compound of any one of claims 1 , 16 , 20 , 26 , and 30 .