Rel inhibitors and methods of use thereof

Abstract

This invention provides REL inhibitors which interfere with the DNA binding capacity of a REL protein. Additionally this invention provides methods of treating, abrogating, or preventing diseases which respond with a positive clinical score to a REL inhibitor. Methods of identifying REL inhibitor based on a REL protein three dimensional model are described.

What is claimed is: 
     
         1 . A composition comprising a selective c-Rel: DNA binding inhibitor represented by: the structure of formula (I) 
       
         
           
           
               
               
           
         
       
       wherein Q 1 , Q 2 , Q 3  are independently H, halogen, CF 3 , OCH 2 Ph, O-alkyl, OCF 3 , alkyl, or Q 1  and Q 2  form a saturated or unsaturated, substituted or unsubstituted, carbocyclic or heterocyclic ring with the aniline ring;
 X and Y are independently H, alkyl, or form a saturated or unsaturated, substituted or unsubstituted, carbocyclic or heterocyclic ring with N(R 1 )(R 2 ). 
 X 1  and Y 1  are independently H, alkyl, or X and Y form together a double bond, or form saturated or unsaturated, substituted or unsubstituted, carbocyclic or heterocyclic ring with N(R 1 )(R 2 ). 
 R 1  and R 2  are independently H, NH 2 , —N=alkyl, -alkyl, —CH(Ph) 2 , substituted or unsubstituted aryl, carbocyclic or heterocyclic aryl, substituted or unsubstituted phenyl, C(O)-alkyl, or R 1  and R 2  form a saturated or unsaturated, substituted or unsubstituted, carbocyclic or heterocyclic ring with the nitrogen atom; 
 or by the structure of formula (II): 
 
       
         
           
           
               
               
           
         
         Wherein L 1 , L 2 , L 3  and L 4  are independently H, halogen, alkyl, —NH 2 , —COOAlkyl, —NO 2 , pyrrolidine, —O-alkyl, or L 1  and L 2  form a saturated or unsaturated, substituted or unsubstituted, carbocyclic or heterocyclic fused ring with the benzene ring; or L 4  together with R 2  forms a 6 membered fused ring with the imidazole and benzene rings; 
         R and R 1  are independently H, NHCO-alkyl, or form together a double bond (═), or CO group (═O); 
         R 2  is H, SH, OH, alkyl, -Ph-CF 3 , —CH═C(Ph)-OC(O)-Ph, CH 2 —S-Ph, CH 2 —S-heterocyclic ring, CH 2 OC(O)NH-Ph, —NHCH 2 CH 2 OH, -alkylene-OH, O-aryl, —O-alkyl, O—CH 2 -Ph, O-phenyl, O-phenyl-alkyl, O-Ph-O-alkylene-Ph, —OCH 2 Ph, —OCH 2 CH═CH-Ph, —S-Phenyl, NH-alkyl, NH-phenyl, NH-aryl, —N(Me)-alkylene-phenyl, —NH-alkylene-phenyl, —NH-alkylene-OMe, —NH—N═CH-Ph, —NH—N—C(O)-alkyl, —NH-heterocyclic ring, NH-carbocyclic ring, —C(O)Ph, substituted or unsubstituted, saturated or unsaturated hetrocyclic ring, substituted or unsubstituted, saturated or unsaturated carbocyclic ring, or R 2  together with L 4  forms a 6 membered fused ring with the imidazole and benzene rings; 
         R 3  is H, COO-alkyl, COOH, NO 2 , substituted or unsubstituted Ph, C(O)—N═NC(O)Ph or C(O)NH 2 ; and; 
         R4 is H, Ph, alkyl, NH 2 , OH, Ph-OH or CH 2 —OH; 
         or by the structure of formula (CXIX): 
       
       
         
           
           
               
               
           
         
         Wherein R 1  is substituted phenyl or unsubstituted phenyl; 
         R 2  is 
       
       
         
           
           
               
               
           
         
         wherein X 1 , X 2 , or X 3  are independently H, halogen, alkyl, CN, COOH, or NH 2 ; 
         or X 3  forms with the ═N + H 2  a five membered fused ring; or 
         R 2  forms with ═N + H 2  a five or six substituted or unsubstituted membered ring, or their pharmaceutical salt. 
       
     
     
         2 . The composition of  claim 1 , wherein the inhibitor interact with L1 cavity on the surface of the c-Rel. 
     
     
         3 . The composition of  claim 1 , wherein said L1 cavity comprises amino acids Arg 21, Cys 26, Glu 27, Lys 110, and Lys 111. 
     
     
         4 . The composition of  claim 1 , comprising the compound represented by the structure of formula (III), or its pharmaceutical salt: 
       
         
           
           
               
               
           
         
       
     
     
         5 . The composition of  claim 1 , comprising the compound represented by the structure of formula (IV), (V) or their pharmaceutical salt. 
     
     
         6 . The composition of  claim 1 , comprising the compound represented by the structure of formula (CXX), or its pharmaceutical salt: 
       
         
           
           
               
               
           
         
       
     
     
         7 . Use of the composition of  claim 1  for preventing, inhibiting, suppressing or ameliorating symptoms associated with inflammatory conditions that are multiple sclerosis, arthritis, diabetes, colitis, lupus, autoimmunity, graft rejection, or a combination thereof. 
     
     
         8 . A method of inhibiting or suppressing the interaction between c-Rel and a DNA, comprising the step of contacting the c-Rel with a compound capable of masking the L1 cavity of the c-Rel, thereby inhibiting or suppressing the interaction between c-Rel and a DNA and inflammatory immune response. 
     
     
         9 . The method of  claim 8 , whereby the compound capable of masking the L1 cavity of the c-Rel is represented by: the compound set forth by the structure of formula (I) 
       
         
           
           
               
               
           
         
       
       wherein Q 1 , Q 2 , Q 3  are independently H, halogen, CF 3 , OCH 2 Ph, O-alkyl, OCF 3 , alkyl, or Q 1  and Q 2  form a saturated or unsaturated, substituted or unsubstituted, carbocyclic or heterocyclic ring with the aniline ring;
 X and Y are independently H, alkyl, or form a saturated or unsaturated, substituted or unsubstituted, carbocyclic or heterocyclic ring with N(R 1 )(R 2 ). 
 X 1  and Y 1  are independently H, alkyl, or X and Y form together a double bond, or form saturated or unsaturated, substituted or unsubstituted, carbocyclic or heterocyclic ring with N(R 1 )(R 2 ). 
 R 1  and R 2  are independently H, NH 2 , —N=alkyl, -alkyl, —CH(Ph) 2 , substituted or unsubstituted aryl, carbocyclic or heterocyclic aryl, substituted or unsubstituted phenyl, C(O)-alkyl, or R 1  and R 2  form a saturated or unsaturated, substituted or unsubstituted, carbocyclic or heterocyclic ring with the nitrogen atom; 
 or by the compound set forth by the structure of formula (II): 
 
       
         
           
           
               
               
           
         
         Wherein L 1 , L 2 , L 3  and L 4  are independently H, halogen, alkyl, —NH 2 , —COOAlkyl, —NO 2 , pyrrolidine, —O-alkyl, or L 1  and L 2  form a saturated or unsaturated, substituted or unsubstituted, carbocyclic or heterocyclic fused ring with the benzene ring; or L 4  together with R 2  forms a 6 membered fused ring with the imidazole and benzene rings; 
         R and R 1  are independently H, NHCO-alkyl, or form together a double bond (═), or CO group (═O); 
         R 2  is H, SH, OH, alkyl, -Ph-CF 3 , —CH═C(Ph)-OC(O)-Ph, CH 2 —S-Ph, CH 2 —S-heterocyclic ring, CH 2 OC(O)NH-Ph, —NHCH 2 CH 2 OH, -alkylene-OH, O-aryl, —O-alkyl, O—CH 2 -Ph, O-phenyl, O-phenyl-alkyl, O-Ph-O-alkylene-Ph, —OCH 2 Ph, —OCH 2 CH═CH-Ph, —S-Phenyl, NH-alkyl, NH-phenyl, NH-aryl, —N(Me)-alkylene-phenyl, —NH-alkylene-phenyl, —NH-alkylene-OMe, —NH—N═CH-Ph, —NH—N—C(O)-alkyl, —NH-heterocyclic ring, NH-carbocyclic ring, —C(O)Ph, substituted or unsubstituted, saturated or unsaturated hetrocyclic ring, substituted or unsubstituted, saturated or unsaturated carbocyclic ring, or R 2  together with L 4  forms a 6 membered fused ring with the imidazole and benzene rings; 
         R 3  is H, COO-alkyl, COOH, NO 2 , substituted or unsubstituted Ph, C(O)—N═NC(O)Ph or C(O)NH 2 ; and; 
         R4 is H, Ph, alkyl, NH 2 , OH, Ph-OH or CH 2 —OH; 
         or by the compound set forth by the structure of formula (CXIX): 
       
       
         
           
           
               
               
           
         
         Wherein R 1  is substituted phenyl or unsubstituted phenyl; 
         R 2  is 
       
       
         
           
           
               
               
           
         
         wherein X 1 , X 2 , or X 3  are independently H, halogen, alkyl, CN, COOH, or NH 2 ; 
         or X 3  forms with the ═N + H 2  a five membered fused ring; or 
         R 2  forms with ═N + H 2  a five or six substituted or unsubstituted membered ring, or their pharmaceutical salt 
       
     
     
         10 . The method of  claim 9 , wherein said inhibitor further inhibits the production of interleukin-2, interferon-gamma, or the combination thereof. 
     
     
         11 . The method of  claim 9 , wherein said L1 cavity comprises the amino acids Arg 21, Cys 26, Glu 27, Lys 110, and Lys 111. 
     
     
         12 . The method of  claim 9 , whereby the compound capable of masking the L1 cavity of the c-Rel is represented by the structure of formula (III), or its pharmaceutical salt: 
       
         
           
           
               
               
           
         
       
     
     
         13 . The method of  claim 9 , whereby the compound capable of masking the L1 cavity of the c-Rel is represented by the structure of formula (IV), (V) or their pharmaceutical salt. 
     
     
         14 . The method of  claim 9 , whereby the compound capable of masking the L1 cavity of the c-Rel is represented by the structure of formula (CXX), or its pharmaceutical salt: 
       
         
           
           
               
               
           
         
       
     
     
         15 . A method of treating, inhibiting or suppressing, or meliorating symptoms associated with multiple sclerosis, arthritis, diabetes, graft rejection, or a combination thereof in a subject, comprising the step of contacting the subject with a composition comprising a selective c-Rel:DNA binding inhibitor wherein said c-Rel DNA binding inhibitor masks the L1 cavity of the c-Rel protein, thereby treating, inhibiting or suppressing, or meliorating symptoms associated with inflammatory conditions that are multiple sclerosis, arthritis, diabetes, colitis, lupus, autoimmunity, graft rejection, or a combination thereof in the subject. 
     
     
         16 . The method of  claim 15 , whereby the inhibitor further inhibits the production of interleukin-2, interferon-gamma, or both. 
     
     
         17 . The method of  claim 15 , whereby said L1 cavity comprises amino acids; Arg 21, Cys 26, Glu 27, Lys 110, and Lys 111. 
     
     
         18 . The method of  claim 15 , whereby said composition comprises a compound set forth by: the structure represented by formula (I): 
       
         
           
           
               
               
           
         
         wherein Q 1 , Q 2 , Q 3  are independently H, halogen, CF 3 , OCH 2 Ph, O-alkyl, OCF 3 , alkyl, or Q 1  and Q 2  form a saturated or unsaturated, substituted or unsubstituted, carbocyclic or heterocyclic ring with the aniline ring; 
         X and Y are independently H, alkyl, or form a saturated or unsaturated, substituted or unsubstituted, carbocyclic or heterocyclic ring with N(R 1 )(R 2 ). 
         X 1  and Y 1  are independently H, alkyl, or X and Y form together a double bond, or form saturated or unsaturated, substituted or unsubstituted, carbocyclic or heterocyclic ring with N(R 1 )(R 2 ). 
         R 1  and R 2  are independently H, NH 2 , —N=alkyl, -alkyl, —CH(Ph) 2 , substituted or unsubstituted aryl, carbocyclic or heterocyclic aryl, substituted or unsubstituted phenyl, C(O)-alkyl, or R 1  and R 2  form a saturated or unsaturated, substituted or unsubstituted, carbocyclic or heterocyclic ring with the nitrogen atom; 
         or by the structure of formula (II): 
       
       
         
           
           
               
               
           
         
         wherein L 1 , L 2 , L 3  and L 4  are independently H, halogen, alkyl, —NH 2 , —COOAlkyl, —NO 2 , pyrrolidine, —O-alkyl, or L 1  and L 2  form a saturated or unsaturated, substituted or unsubstituted, carbocyclic or heterocyclic fused ring with the benzene ring; or L 4  together with R 2  forms a 6 membered fused ring with the imidazole and benzene rings; 
         R and R 1  are independently H, NHCO-alkyl, or form together a double bond (═), or CO group (═O); 
         R 2  is H, SH, OH, alkyl, -Ph-CF 3 , —CH═C(Ph)-OC(O)-Ph, CH 2 —S-Ph, CH 2 —S-heterocyclic ring, CH 2 OC(O)NH-Ph, —NHCH 2 CH 2 OH, -alkylene-OH, O-aryl, —O-alkyl, O—CH 2 -Ph, O-phenyl, O-phenyl-alkyl, O-Ph-O-alkylene-Ph, —OCH 2 Ph, —OCH 2 CH═CH-Ph, —S-Phenyl, NH-alkyl, NH-phenyl, NH-aryl, —N(Me)-alkylene-phenyl, —NH-alkylene-phenyl, —NH-alkylene-OMe, —NH—N═CH-Ph, —NH—N—C(O)-alkyl, —NH-heterocyclic ring, NH-carbocyclic ring, —C(O)Ph, substituted or unsubstituted, saturated or unsaturated hetrocyclic ring, substituted or unsubstituted, saturated or unsaturated carbocyclic ring, or R 2  together with L 4  forms a 6 membered fused ring with the imidazole and benzene rings; 
         R 3  is H, COO-alkyl, COOH, NO 2 , substituted or unsubstituted Ph, C(O)—N═NC(O)Ph or C(O)NH 2 ; and; 
         R4 is H, Ph, alkyl, NH 2 , OH, Ph-OH or CH 2 —OH; 
         or by the structure of formula (CXIX): 
       
       
         
           
           
               
               
           
         
         Wherein R 1  is substituted phenyl or unsubstituted phenyl; 
         R 2  is 
       
       
         
           
           
               
               
           
         
         wherein X 1 , X 2 , or X 3  are independently H, halogen, alkyl, CN, COOH, or NH 2 ; 
         or X 3  forms with the ═N + H 2  a five membered fused ring; or 
         R 2  forms with ═N + H 2  a five or six substituted or unsubstituted membered ring, or their combination. 
       
     
     
         19 . The method of  claim 15 , whereby said composition comprises a compound set forth by formula (III): 
       
         
           
           
               
               
           
         
       
     
     
         20 . The method of  claim 15 , whereby said composition comprises a compound set forth by formula (CXX):