Inhibition of Bid-Induced Cell-Death Using Small Organic Molecules

Abstract

Various phenylamine derivatives are described as well as the use of compounds to inhibit BID protein for controlling apoptotic cascade.

1 . A compound having the formula B 
       
         
           
           
               
               
           
         
         wherein each of R 1  and R 2  is independently selected from a group consisting of: 
       
       
         
           
           
               
               
           
         
         Y is a moiety selected from a group consisting of: 
       
       
         
           
           
               
               
           
         
         X is a moiety selected from a group consisting of: 
       
       
         
           
           
               
               
           
         
         n is an integer having the value between 1 and 5; and 
         Ph in any of R 1  and R 2  is independently selected from an unsubstituted phenyl ring and a substituted phenyl ring having between one and five substitutents in ortho-, meta-, or para-position of the benzene ring, wherein the substitutents in the ring are selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . The compound of  claim 1 , having the formula VI 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         3 . The compound of  claim 1 , having the formula VII 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         4 . The compound of  claim 1 , having the formula VIII 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         5 . The compound of  claim 1 , having the formula IX 
       
         
           
           
               
               
           
         
       
     
     
         6 . A method for treating a disorder, comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound of  claim 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof. 
     
     
         7 . The method of  claim 6 , wherein the treatment includes inhibition of BID, modulating caspase activity, or protection against cell death. 
     
     
         8 . The method of  claim 6 , wherein the disorder is selected from a group consisting of a neurodegenerative disease, heart disease, liver inflammation, cerebral injury, ischemic injury, myocardial infarction, sepsis, liver failure, spinal cord injury and BID-implicated diseases. 
     
     
         9 . A pharmaceutical composition comprising at least one compound of  claim 1 , and a pharmaceutically acceptable carrier therefor. 
     
     
         10 . An article of manufacture comprising packaging material and a pharmaceutical composition contained with the packaging material, wherein the packaging material comprises a label which indicates that the pharmaceutical composition can be used for treatment of disorders associated with associated with uncontrolled cell death, and wherein the pharmaceutical composition comprises at least one compound of  claim 1 , and a pharmaceutically acceptable carrier therefor. 
     
     
         11 . An article of manufacture comprising packaging material and a pharmaceutical composition contained with the packaging material, wherein the packaging material comprises a label which indicates that the pharmaceutical composition can be used for treatment of disorders selected from a group consisting of a neurodegenerative disease, heart disease, liver inflammation, cerebral injury, myocardial infarction, sepsis, liver failure, spinal cord injury, BID-implicated diseases and ischemic injury, and wherein the pharmaceutical composition comprises at least one compound of  claim 1 , and a pharmaceutically acceptable carrier therefor. 
     
     
         12 . The article of manufacture of  claim 11 , wherein the neurodegenerative disease is selected from a group consisting of Alzheimer's disease, Parkinson's disease, a polyglutamine-repeat disorder, Huntington's disease, Down's syndrome, multiple sclerosis, and amyotrophic lateral sclerosis. 
     
     
         13 . A method for modulating the formation of complexes between at least one BCL-2 protein, and the BH3 domain, comprising:
 (a) contacting BCL-2 with BH3 under conditions suitable to form a BCL-2-BH3 complex; and   (b) contacting the BCL-2-BH3 complex with at least one compound of  claim 1 ,   
       thereby modulating the complex formation. 
     
     
         14 . The method of  claim 12 , wherein the BCL-2 protein is selected from a group consisting of BCL-x L , BCL-2, Mcl-1, BCL-W, and BCL-B. 
     
     
         15 . The method of  claim 13 , wherein the BH3 domain is the domain of pro-apoptotic BCL-2 family members and compounds that are useful for modulating the amount or stability of the BCL-2-BH3 complex. 
     
     
         16 . A method for identifying compounds capable of effectively modulating the binding of at least one BCL-2 protein to the BH3 domain, comprising:
 (a) contacting BCL-2 with BH3 under conditions suitable to form a BCL-2-BH3 complex;   (b) contacting the BCL-2-BH3 complex with at least one compound of  claim 1 , under conditions suitable for reaction between the BCL-2-BH3 complex and the compound; and   (c) determining the ability of the compound to modulate the binding of BCL-2 to BH3, where modulation of the binding of BCL-2 to BH3 is indicative of the effectiveness of the compound as an effective modulating compound.   
     
     
         17 . The method of  claim 16 , wherein the BCL-2 protein is selected from a group consisting of BCL-x L , BCL-2, Mcl-1, BCL-W, and BCL-B. 
     
     
         18 . The method of  claim 16 , wherein the BH3 domain is the domain of pro-apoptotic BCL-2 family members and compounds that are useful for modulating the amount or stability of the BCL-2-BH3 complex. 
     
     
         19 . A method for screening compounds to determine the ability of the compounds to bind to of at least one BCL-2 protein, comprising:
 (a) contacting the BCL-2 protein with at least one compound of  claim 1  under conditions suitable for reaction between the BCL-2-protein and the compound; and   (b) analyzing the product of reaction between the BCL-2-protein and the compound for determining the ability of the compound to bind to the BCL-2 protein.   
     
     
         20 . The method of  claim 19 , wherein the analyzing comprises nuclear magnetic resonance binding assays, fluorescence polarization assay, computational-docking analysis, or a combination thereof.