Compunds 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 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, C═S, and SO 2 ; 
         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 , wherein Z is absent. 
     
     
         3 . A compound of  claim 1  or  2 , wherein R 4 , R 6 , and R 7  are independently selected from hydrogen and methyl. 
     
     
         4 . A compound of  claim 1  or  2 , wherein L is C═O. 
     
     
         5 . A compound of  claim 1  or  2 , wherein L is SO 2 . 
     
     
         6 . A compound of any one of  claims 1  to  5 , 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. 
     
     
         7 . A compound of  claim 6 , wherein any of R 1 , R 2 , and R 3  are independently C 1-6 alkyl. 
     
     
         8 . A compound of  claim 7 , wherein any of R 1 , R 2 , and R 3  are independently selected from methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and isobutyl. 
     
     
         9 . A compound of  claim 6  wherein any of R 1 , R 2 , and R 3  are independently propargyl. 
     
     
         10 . A compound of  claim 6 , wherein any of R 1 , R 2 , and R 3  are independently C 1-6 hydroxyalkyl. 
     
     
         11 . A compound of  claim 10 , wherein any of R 1 , R 2 , and R 3  are independently selected from hydroxymethyl and hydroxyethyl. 
     
     
         12 . A compound of  claim 6 , wherein any of R 1 , R 2 , and R 3  are independently C 1-6 alkoxyalkyl. 
     
     
         13 . A compound of  claim 12 , wherein any of R 1 , R 2 , and R 3  are independently selected from methoxymethyl and methoxyethyl. 
     
     
         14 . A compound of  claim 6 , wherein any of R 1 , R 2 , and R 3  are independently C 1-6 heteroaralkyl. 
     
     
         15 . A compound of  claim 14 , wherein any of R 1 , R 2 , and R 3  are independently selected from imidazolylmethyl, pyrazolylmethyl, and thiazolylmethyl, and pyridylmethyl. 
     
     
         16 . A compound of  claim 6 , wherein any of R 1 , R 2 , and R 3  are independently cyclohexylmethyl. 
     
     
         17 . A compound of any one of  claims 1  to  16 , wherein R 1 , R 2 , and R 3  are all different. 
     
     
         18 . A compound of any one of  claims 1  to  5 , wherein at least one of R 1  and R 2  is selected from C 1-6 hydroxyalkyl and C 1-6 alkoxyalkyl. 
     
     
         19 . A compound of  claim 18 , wherein at least one of R 1  and R 2  is C 1-6 alkoxyalkyl. 
     
     
         20 . A compound of  claim 19 , wherein at least one of R 1  and R 2  is selected from methoxymethyl and methoxyethyl. 
     
     
         21 . A compound of any one of  claims 1  to  5  or  18  to  20 , wherein R 3  is selected from C 1-6 alkyl and C 1-6 aralkyl. 
     
     
         22 . A compound of  claim 21 , wherein R 3  is C 1-6 alkyl. 
     
     
         23 . A compound of  claim 22 , wherein R 3  is selected from methyl, ethyl, isopropyl, sec-butyl, and isobutyl. 
     
     
         24 . A compound of  claim 23 , wherein R 3  is isobutyl. 
     
     
         25 . A compound of  claim 21 , wherein R 3  is C 1-6 aralkyl. 
     
     
         26 . A compound of  claim 25 , wherein R 3  is phenylmethyl. 
     
     
         27 . A compound of any one of  claims 1  to  26 , wherein R 5  is 5- or 6-membered heteroaryl. 
     
     
         28 . A compound of  claim 27 , wherein R 5  is selected from isoxazole, isothiazole, furan, thiophene, oxazole, thiazole, pyrazole, or imidazole. 
     
     
         29 . A compound of  claim 28 , wherein R 5  is selected from isoxazole, furan, or thiophene. 
     
     
         30 . A compound of  claim 29 , wherein R 5  is furan or thiophene. 
     
     
         31 . A compound of  claim 30 , wherein R 5  is unsubstituted furan-3-yl or thien-2-yl. 
     
     
         32 . A compound of  claim 29 , wherein R 5  is isoxazol-3-yl or isoxazol-5-yl. 
     
     
         33 . A compound of  claim 32 , wherein R 3  is isoxazol-3-yl that has a substituent at the 5-position. 
     
     
         34 . A compound of  claim 32 , wherein R 3  is isoxazol-5-yl that has a substituent at the 3-position. 
     
     
         35 . A compound of  claim 33  or  34 , 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. 
     
     
         36 . A compound of  claim 35 , wherein the substituent is selected from methyl, ethyl, isopropyl, and cyclopropylmethyl. 
     
     
         37 . A compound of  claim 35 , wherein the substituent is selected from C 1-6 heteroaralkyl and C 1-6 heterocycloalkyl. 
     
     
         38 . A compound of  claim 37 , wherein the substituent is 1,2,4-triazol-5-ylmethyl. 
     
     
         39 . A compound of  claim 37 , wherein the substituent is azetidin-1-ylmethyl. 
     
     
         40 . A compound of  claim 37 , wherein the substituent is 
       
         
           
           
               
               
           
         
       
       wherein W is O, NR, or CH 2 , and R is H or C 1-6 alkyl. 
     
     
         41 . A compound of  claim 40 , wherein W is O. 
     
     
         42 . A compound of  claim 37 , wherein the substituent is selected from C 1-6 alkoxy and C 1-6 alkoxyalkyl. 
     
     
         43 . A compound of  claim 42 , wherein the substituent is selected from methoxy, ethoxy, methoxymethyl, and methoxyethyl. 
     
     
         44 . A compound of  claim 37 , wherein the substituent is selected from carboxylic acid, aminocarboxylate, C 1-6 alkylaminocarboxylate, (C 1-6 alkyl) 2 aminocarboxylate, or C 1-6 alkylcarboxylate. 
     
     
         45 . A compound of  claim 44 , wherein the substituent is methyl carboxylate. 
     
     
         46 . A compound selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         47 . A pharmaceutical composition comprising a compound of any one of  claims 1  to  46  and a pharmaceutically acceptable diluent or carrier. 
     
     
         48 . A pharmaceutical composition of  claim 47 , which is orally bioavailable. 
     
     
         49 . A method for the treatment of inflammation, comprising administering a therapeutically effective amount of a pharmaceutical composition of  claim 48 . 
     
     
         50 . A method for inhibiting or reducing HIV infection, comprising administering a therapeutically effective amount of a pharmaceutical composition of  claim 48 . 
     
     
         51 . A method for the treatment of neurodegenerative disease, comprising administering a therapeutically effective amount of a pharmaceutical composition of  claim 48 . 
     
     
         52 . A method for the treatment of muscle-wasting diseases, comprising administering a therapeutically effective amount of a pharmaceutical composition of  claim 48 . 
     
     
         53 . A method for the treatment of cancer, comprising administering a therapeutically effective amount of a pharmaceutical composition of  claim 48 . 
     
     
         54 . A method for the treatment of chronic infectious diseases, comprising administering a therapeutically effective amount of a pharmaceutical composition of  claim 48 . 
     
     
         55 . A method for the treatment of a hyperproliferative condition, comprising administering a therapeutically effective amount of a pharmaceutical composition of  claim 48 . 
     
     
         56 . A method for the treatment of muscle disuse, comprising administering a therapeutically effective amount of a pharmaceutical composition of  claim 35 . 
     
     
         57 . A method for the treatment of immune-related conditions, comprising administering a therapeutically effective amount of a pharmaceutical composition of  claim 48 . 
     
     
         58 . A method for affecting the level of viral gene expression in a subject, comprising administering a therapeutically effective amount of a pharmaceutical composition of  claim 48 . 
     
     
         59 . A method for altering the variety of antigenic peptides produced by the proteasome in an organism, comprising administering therapeutically effective amount of a pharmaceutical composition of  claim 48 .