Beta-sheet mimetics and methods relating to the use thereof

Abstract

β-sheet mimetics and methods relating to the same are disclosed. The β-sheet mimetics have utility as protease and kinase inhibitors, as well as inhibitors of transcription factors and protein-protein binding interactions. Methods of the invention include administration of a β-sheet mimetic, or use of the same for the manufacture of a medicament for treatment of a variety of conditions associated with the targeted protease, kinase, transcription factor and/or protein-protein binding interaction.

1 . A method for inhibiting a protease, comprising administering to an animal in need thereof an effective amount of a compound having the structure:  
     
       
         
         
             
             
         
       
     
     and pharmaceutically acceptable salts thereof, 
 wherein 
 A is selected from —C(═O)—, —(CH 2 ) 0-4 —, —C(═O)(CH 2 ) 1-3 —, —(CH 2 ) 1-2 O— and —(CH 2 ) 1-2 S—;  
 B is selected from N and CH;  
 C is selected from —C(═O)—, —C(═O)(CH 2 ) 1-3 —, —(CH 2 ) 0-3 —, —O—, —S—, —O—(CH 2 ) 1-2 — and —S(CH 2 ) 1-2 —;  
 D is selected from N and C(R 4 );  
 E is selected from  
                     
 F is an optional carbonyl moiety;  
 R 1  and R 4  are independently selected from amino acid side chain moieties and derivatives thereof;  
 R 2  and R 2 ′ represent one or more ring substituents individually selected from an amino acid side chain moiety and derivatives thereof, or R 2  taken together with C or Y forms a fused substituted or unsubstituted homocyclic or heterocyclic ring;  
 R 3  is selected from an amino acid side chain moiety and derivatives thereof, or taken together with C forms a bridging moiety selected from —(CH 2 ) 1-2 —, —O— and —S—;  
 Y and Z represent the remainder of the molecule; and  
 any two adjacent CH groups of the bicyclic ring may form a double bond.  
 
 
   
   
       2 . The method of  claim 1  wherein  
     
       
         
         
             
             
         
       
     
   
   
       3 . The method of  claim 1  wherein  
     
       
         
         
             
             
         
       
     
   
   
       4 . The method of  claim 1  wherein  
     
       
         
         
             
             
         
       
     
     with the proviso that Z does not contain an —NH— moiety attached to the carbon atom bearing the R 1  substituent.  
   
   
       5 . The method of  claim 1  wherein the protease is a serine protease.  
   
   
       6 . The method of  claim 5  wherein the serine protease is selected from thrombin, Factor X, Factor IX, Factor VII, Factor XI, urokinase, HCV protease, chymase, tryptase and kallikrein.  
   
   
       7 . The method of  claim 5  wherein the serine protease is thrombin.  
   
   
       8 . The method of  claim 5  wherein the serine protease is Factor VII  
   
   
       9 . The method of  claim 1  wherein the protease is selected from an aspartic, cysteine and metallo protease.  
   
   
       10 . A method for inhibiting a kinase, comprising administering to an animal in need thereof an effective amount of a compound having the structure:  
     
       
         
         
             
             
         
       
     
     and pharmaceutically acceptable salts thereof, 
 wherein 
 A is selected from —C(═O)—, —(CH 2 ) 0-4 —, —C(═O)(CH 2 ) 1-3 —, —(CH 2 ) 1-2 O— and —(CH 2 ) 1-2 S—;  
 B is selected from N and CH;  
 C is selected from —C(═O)—, —C(═O)(CH 2 ) 1-3 —, —(CH 2 ) 0-3 —, —O—, —S—, —O—(CH 2 ) 1-2 — and —S(CH 2 ) 1-2 —;  
 D is selected from N and C(R 4 );  
 E is selected from  
                     
 F is an optional carbonyl moiety;  
 R 1  and R 4  are independently selected from amino acid side chain moieties and derivatives thereof;  
 R 2  and R 2 ′ represent one or more ring substituents individually selected from an amino acid side chain moiety and derivatives thereof, or R 2  taken together with C or Y forms a fused substituted or unsubstituted homocyclic or heterocyclic ring;  
 R 3  is selected from an amino acid side chain moiety and derivatives thereof, or taken together with C forms a bridging moiety selected from —(CH 2 ) 1-2 —, —O— and —S—;  
 Y and Z represent the remainder of the molecule; and  
 any two adjacent CH groups of the bicyclic ring may form a double bond.  
 
 
   
   
       11 . The method of  claim 10  wherein  
     
       
         
         
             
             
         
       
     
   
   
       12 . The method of  claim 10  wherein  
     
       
         
         
             
             
         
       
     
   
   
       13 . The method of  claim 10  wherein  
     
       
         
         
             
             
         
       
     
     with the proviso that Z does not contain an —NH— moiety attached to the carbon atom bearing the R 1  substituent.  
   
   
       14 . The method of claims  10  wherein the kinase is a serine/threonine or tyrosine kinase.  
   
   
       15 . A method for inhibiting a transcription factor, comprising administering to an animal in need thereof an effective amount of a compound having the structure:  
     
       
         
         
             
             
         
       
     
     and pharmaceutically acceptable salts thereof, 
 wherein 
 A is selected from —C(═O)—, —(CH 2 ) 0-4 —, —C(═O)(CH 2 ) 1-3 —, —(CH 2 ) 1-2 O— and —(CH 2 ) 1-2 S—;  
 B is selected from N and CH;  
 C is selected from —C(═O)—, —C(═O)(CH 2 ) 1-3 —, —(CH 2 ) 0-3 —, —O—, —S—, —O—(CH 2 ) 1-2 — and —S(CH 2 ) 1-2 —;  
 D is selected from N and C(R 4 );  
 E is selected from  
                     
 F is an optional carbonyl moiety;  
 R 1  and R 4  are independently selected from amino acid side chain moieties and derivatives thereof;  
 R 2  and R 2 ′ represent one or more ring substituents individually selected from an amino acid side chain moiety and derivatives thereof, or R 2  taken together with C or Y forms a fused substituted or unsubstituted homocyclic or heterocyclic ring;  
 R 3  is selected from an amino acid side chain moiety and derivatives thereof, or taken together with C forms a bridging moiety selected from —(CH 2 ) 1-2 —, —O— and —S—;  
 Y and Z represent the remainder of the molecule; and  
 any two adjacent CH groups of the bicyclic ring may form a double bond.  
 
 
   
   
       16 . The method of  claim 15  wherein  
     
       
         
         
             
             
         
       
     
   
   
       17 . The method of  claim 15  wherein  
     
       
         
         
             
             
         
       
     
   
   
       18 . The method of  claim 15  wherein  
     
       
         
         
             
             
         
       
     
     with the proviso that Z does not contain an —NH— moiety attached to the carbon atom bearing the R 1  substituent.  
   
   
       19 . The method of  claim 15  wherein the ability of the transcription factor to bind DNA is controlled by reduction of a cysteine residue by a cellular oxidoreductase.  
   
   
       20 . The method of  claim 15  wherein the transcription factor is selected from NF-κB, AP-1, Myb, GRE, STAT-1 through -6, NFAT, IRF-1 and MAF.  
   
   
       21 . The method of  claim 15  wherein the transcription factor is NF-κB.  
   
   
       22 . The method of  claim 15  wherein the transcription factor is AP-1.  
   
   
       23 . The method of  claim 19  wherein the cellular oxidoreductase is ref-1.  
   
   
       24 . The method of  claim 15  wherein the warm-blooded animal has been diagnosed with, or is at risk of developing, a condition selected from Crohn's disease, asthma, rheumatoid arthritis, ischemia-reperfusion injury, GVHD, ALS, Alzheimer's disease, allograft rejection, adult T-cell leukemia, cancer and inflammatory bowel disease.  
   
   
       25 . A method for inhibiting protein-protein binding interactions, comprising administering to an animal in need thereof an effective amount of a compound having the structure:  
     
       
         
         
             
             
         
       
     
     and pharmaceutically acceptable salts thereof, 
 wherein 
 A is selected from —C(═O)—, —(CH 2 ) 0-4 —, —C(═O)(CH 2 ) 1-3 —, —(CH 2 ) 1-20 — and —(CH 2 ) 1-2 S—;  
 B is selected from N and CH;  
 C is selected from —C(═O)—, —C(═O)(CH 2 ) 1-3 —, —(CH 2 ) 0-3 —, —O—, —S—, —O—(CH 2 ) 1-2 — and —S(CH 2 ) 1-2 —;  
 D is selected from N and C(R 4 );  
 E is selected from  
                     
 F is an optional carbonyl moiety;  
 R 1  and R 4  are independently selected from amino acid side chain moieties and derivatives thereof;  
 R 2  and R 2 ′ represent one or more ring substituents individually selected from an amino acid side chain moiety and derivatives thereof, or R 2  taken together with C or Y forms a fused substituted or unsubstituted homocyclic or heterocyclic ring;  
 R 3  is selected from an amino acid side chain moiety and derivatives thereof, or taken together with C forms a bridging moiety selected from —(CH 2 ) 1-2 —, —O— and —S—;  
 Y and Z represent the remainder of the molecule; and  
 any two adjacent CH groups of the bicyclic ring may form a double bond.  
 
 
   
   
       26 . The method of  claim 25  wherein  
     
       
         
         
             
             
         
       
     
   
   
       27 . The method of  claim 25  wherein  
     
       
         
         
             
             
         
       
     
   
   
       28 . The method of  claim 25  wherein  
     
       
         
         
             
             
         
       
     
     with the proviso that Z does not contain an —NH— moiety attached to the carbon atom bearing the R 1  substituent.  
   
   
       29 . The method of  claim 25  wherein the protein-protein binding interaction is between the SH2 domain or the PDZ domain and another protein.