Novel inhibitors of hepatitis c virus replication

Abstract

The embodiments provide compounds of the general Formula II, as well as compositions, including pharmaceutical compositions, comprising a subject compound. The embodiments also provide treatment methods, including methods of treating a hepatitis C virus infection and methods of treating liver fibrosis, the methods generally involving administering to an individual in need thereof an effective amount of a subject compound or composition.

1 . A compound of the formula (II): 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt, prodrug, or ester thereof wherein: 
       (a) Z 1  is a group configured to hydrogen bond to an NS3 protease His57 imidazole moiety and to hydrogen bond to a NS3 protease Gly137 nitrogen atom; 
       (b) P 1 ′ is a group configured to form a non-polar interaction with at least one NS3 protease S1′ pocket moiety selected from the group consisting of Lys136, Gly137, Ser138, His57, Gly58, Gln41, Gly42, and Phe43; 
       (c) L is a linker group consisting of from 1 to 5 atoms selected from the group consisting of carbon, oxygen, nitrogen, hydrogen, and sulfur; 
       (d) P 2  is selected from the group consisting of unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, substituted heteroaryl, unsubstituted heterocyclic and substituted heterocyclic; P 2  being positioned by L to form a non-polar interaction with at least one NS3 protease S2 pocket moiety selected from the group consisting of His57, Arg155, Va178, Asp79, and Gln80; and 
       (e) R 5  is a substituted or unsubstituted moiety selected from the group consisting of H, C 1-8  alkyl, C 3-7  cycloalkyl, C 4-10  cycloalkyl-alkyl, aryl, C 7-10  arylalkyl, heteroaryl, C 6-12  heteroarylalkyl, —C 1-8  alkyl-NHC(O)OR 1a , —C 3-7  cycloalkyl-NHC(O)OR 1a , —C 4-10  cycloalkyl-alkyl-NHC(O)OR 1a , -aryl-NHC(O)OR 1a , —C 7-10  arylalkyl-NHC(O)OR 1a , —heteroaryl-NHC(O)OR 1a , and —C 6-12  heteroarylalkyl-NHC(O)OR 1a ;
 wherein R 1a  is a substituted or unsubstituted group selected from the group consisting of H, C 1-6  alkyl, C 3-7  cycloalkyl, C 4-10  cycloalkyl-alkyl, aryl, C 7-10  arylalkyl, heteroaryl, and C 6-12  heteroarylalkyl. 
 
     
   
   
       2 . The compound of  claim 1  in which L consists of from 2 to 5 atoms. 
   
   
       3 . The compound of  claim 1  in which L comprises a —W—C(═V)— group, where V and W are each individually selected from O, S or NH. 
   
   
       4 . The compound of  claim 1  in which L is selected from the group consisting of ester, amide, carbamate, thioester, and thioamide. 
   
   
       5 . The compound of  claim 1  in which P 2  is further positioned by L to form a hydrogen bonding interaction with at least one NS3 protease S2 pocket moiety selected from the group consisting of His57, Arg155, Va178, Asp79, and Gln80. 
   
   
       6 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound according to  claim 1 . 
   
   
       7 . A method of inhibiting NS3/NS4 protease activity comprising contacting a NS3/NS4 protease with a compound according to  claim 1 . 
   
   
       8 . The method of  claim 7  in which the contacting is conducted in vivo. 
   
   
       9 . The method of  claim 8 , further comprising identifying a subject suffering from a hepatitis C infection and administering the compound to the subject in an amount effective to treat the infection. 
   
   
       10 . The method of  claim 7 , wherein the method further comprises administering to an individual an effective amount of a nucleoside analog. 
   
   
       11 . The method of  claim 10 , wherein the nucleoside analog is selected from ribavirin, levovirin, viramidine, an L-nucleoside, and isatoribine. 
   
   
       12 . The method of  claim 9 , wherein the method further comprises administering to the subject an effective amount of a human immunodeficiency virus 1 protease inhibitor. 
   
   
       13 . The method of  claim 12 , wherein the protease inhibitor is ritonavir. 
   
   
       14 . The method of  claim 9 , wherein the method further comprises administering to the subject an effective amount of an NS5B RNA-dependent RNA polymerase inhibitor. 
   
   
       15 . The method of  claim 9 , wherein the method further comprises administering to the subject an effective amount of interferon-gamma (IFN-γ). 
   
   
       16 . The method of  claim 15 , wherein the IFN-γ is administered subcutaneously in an amount of from about 10 μg to about 300 μg. 
   
   
       17 . The method of  claim 9 , wherein the method further comprises administering to the subject an effective amount of interferon-alpha (IFN-α). 
   
   
       18 . The method of  claim 17 , wherein the IFN-α is monoPEG-ylated consensus IFN-α administered at a dosing interval of every 8 days to every 14 days. 
   
   
       19 . The method of  claim 17 , wherein the IFN-α is monoPEG-ylated consensus IFN-α administered at a dosing interval of once every 7 days. 
   
   
       20 . The method of  claim 17 , wherein the IFN-α is INFERGEN consensus IFN-α. 
   
   
       21 . The method of  claim 9 , further comprising administering an effective amount of an agent selected from 3′-azidothymidine, 2′,3′-dideoxyinosine, 2′,3′-dideoxycytidine, 2-,3-didehydro-2′,3′-dideoxythymidine, combivir, abacavir, adefovir dipoxil, cidofovir, and an inosine monophosphate dehydrogenase inhibitor. 
   
   
       22 . The method of  claim 9 , wherein a sustained viral response is achieved. 
   
   
       23 . The method of  claim 7 , in which the contacting is conducted ex vivo. 
   
   
       24 . A method of of treating liver fibrosis in an individual, the method comprising administering to the individual an effective amount of a composition of  claim 6 . 
   
   
       25 . The method of  claim 24 , wherein the method further comprises administering to the individual an effective amount of a nucleoside analog. 
   
   
       26 . The method of  claim 25 , wherein the nucleoside analog is selected from ribavirin, levovirin, viramidine, an L-nucleoside, and isatoribine. 
   
   
       27 . The method of  claim 24 , wherein the method further comprises administering to the individual an effective amount of a human immunodeficiency virus 1 protease inhibitor. 
   
   
       28 . The method of method of  claim 27 , wherein the protease inhibitor is ritonavir. 
   
   
       29 . The method of  claim 24 , wherein the method further comprises administering to the individual an effective amount of an NS5B RNA-dependent RNA polymerase inhibitor. 
   
   
       30 . The method of  claim 24 , wherein the method further comprises administering to the individual an effective amount of interferon-gamma (IFN-γ). 
   
   
       31 . The method of  claim 30 , wherein the IFN-γ is administered subcutaneously in an amount of from about 10 μg to about 300 μg. 
   
   
       32 . The method of  claim 24 , wherein the method further comprises administering to the individual an effective amount of interferon-alpha (IFN-α). 
   
   
       33 . The method of  claim 32 , wherein the IFN-α is monoPEG-ylated consensus IFN-α administered at a dosing interval of every 8 days to every 14 days. 
   
   
       34 . The method of  claim 32 , wherein the IFN-α is monoPEG-ylated consensus IFN-α administered at a dosing interval of once every 7 days. 
   
   
       35 . The method of  claim 32 , wherein the IFN-α is INFERGEN consensus IFN-α. 
   
   
       36 . The method of  claim 24 , further comprising administering an effective amount of an agent selected from 3′-azidothymidine, 2′,3′-dideoxyinosine, 2′,3′-dideoxycytidine, 2-,3-didehydro-2′,3′-dideoxythymidine, combivir, abacavir, adefovir dipoxil, cidofovir, and an inosine monophosphate dehydrogenase inhibitor. 
   
   
       37 . A method of increasing liver function in an individual having a hepatitis C virus infection, the method comprising administering to the individual an effective amount of a composition of  claim 6 . 
   
   
       38 . The method of  claim 37 , wherein the method further comprises administering to the individual an effective amount of a nucleoside analog. 
   
   
       39 . The method of  claim 38 , wherein the nucleoside analog is selected from ribavirin, levovirin, viramidine, an L-nucleoside, and isatoribine. 
   
   
       40 . The method of  claim 37 , wherein the method further comprises administering to the individual an effective amount of a human immunodeficiency virus 1 protease inhibitor. 
   
   
       41 . The method of method of  claim 40 , wherein the protease inhibitor is ritonavir. 
   
   
       42 . The method of  claim 37 , wherein the method further comprises administering to the individual an effective amount of an NS5B RNA-dependent RNA polymerase inhibitor. 
   
   
       43 . The method of  claim 37 , wherein the method further comprises administering to the individual an effective amount of interferon-gamma (IFN-γ). 
   
   
       44 . The method of  claim 43 , wherein the IFN-γ is administered subcutaneously in an amount of from about 10 μg to about 300 μg. 
   
   
       45 . The method of  claim 37 , wherein the method further comprises administering to the individual an effective amount of interferon-alpha (IFN-α). 
   
   
       46 . The method of  claim 45 , wherein the IFN-α is monoPEG-ylated consensus IFN-α administered at a dosing interval of every 8 days to every 14 days. 
   
   
       47 . The method of  claim 45 , wherein the IFN-α is monoPEG-ylated consensus IFN-α administered at a dosing interval of once every 7 days. 
   
   
       48 . The method of  claim 45 , wherein the IFN-α is INFERGEN consensus IFN-α. 
   
   
       49 . The method of  claim 37 , further comprising administering an effective amount of an agent selected from 3′-azidothymidine, 2′,3′-dideoxyinosine, 2′,3′-dideoxycytidine, 2-,3-didehydro-2′,3′-dideoxythymidine, combivir, abacavir, adefovir dipoxil, cidofovir, and an inosine monophosphate dehydrogenase inhibitor.