Compounds For Enzyme Inhibition

Abstract

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 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 , preferably L is absent or C═O; 
         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, 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- (preferably 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 1-12 alkyl-, (R 10 ) 3 N + —Cl 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, preferably from hydrogen, metal cation, and C 1-6 alkyl, 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, 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 - 3 . (canceled) 
     
     
         4 . A compound of  claim 1 , wherein X is O, R 1  is 2-phenylethyl, R 2  is isobutyl, R 3  is phenylmethyl, and R 4  is isobutyl. 
     
     
         5 - 22 . (canceled) 
     
     
         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 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. 
 
     
     
         25 . A compound of  claim 24 , wherein Q is absent. 
     
     
         26 - 37 . (canceled) 
     
     
         38 . A compound of  claim 25 , wherein R 7  is heterocyclylM- and heterocyclyl is selected from morpholino, piperidino, piperazino, and pyrrolidino. 
     
     
         39 - 50 . (canceled) 
     
     
         51 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         52 . A method of inhibiting an N-terminal nucleophile hydrolase, comprising administering a therapeutically effective amount of a compound of  claim 1 . 
     
     
         53 . A method for the treatment of inflammation, comprising administering a therapeutically effective amount of a compound of  claim 1 . 
     
     
         54 . A method for inhibiting or reducing HIV infection, comprising administering a therapeutically effective amount of a compound of  claim 1 . 
     
     
         55 . A method for the treatment of neurodegenerative diseases, comprising administering a therapeutically effective amount of a compound of  claim 1 . 
     
     
         56 . A method for the treatment of muscle-wasting diseases, comprising administering a therapeutically effective amount of a compound of  claim 1 . 
     
     
         57 . A method for the treatment of cancer, comprising administering a therapeutically effective amount of a compound of  claim 1 . 
     
     
         58 . A method for the treatment of chronic infectious diseases, comprising administering a therapeutically effective amount of a compound of  claim 1 . 
     
     
         59 . A method for the treatment of fever, comprising administering a therapeutically effective amount of a compound of  claim 1 . 
     
     
         60 . A method for the treatment of immune-related conditions, comprising administering a therapeutically effective amount of a compound of  claim 1 . 
     
     
         61 . A method for the treatment of denervation or nerve injury, comprising administering a therapeutically effective amount of a compound of  claim 1 . 
     
     
         62 . A method for affecting the level of viral gene expression in a subject, comprising administering a therapeutically effective amount of a compound of  claim 1 . 
     
     
         63 . 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  claim 1 .