Method of inhibiting neurotrophin-receptor binding

Abstract

The present invention relates to compositions which inhibit the binding of nerve growth factor to the p75 NTR common neurotrophin receptor and methods of use thereof. In one embodiment, the compound which inhibits binding of nerve growth factor to p75 NTR comprises, particularly when bound to nerve growth factor, at least two of the following: (1) a first electronegative atom or functional group positioned to interact with Lys 34 of nerve growth factor; (2) a second electronegative atom or functional group positioned to interact with Lys 95 of nerve growth factor; (3) a third electronegative atom or functional group positioned to interact with Lys 88 of nerve growth factor; (4) a fourth electronegative atom or functional group positioned to interact with Lys 32 of nerve growth factor; and (5) a hydrophobic moiety which interacts with the hydrophobic region formed by Ile 31 , Phe 101 and Phe 86 of nerve growth factor.

What is claimed is:  
     
         1 . A compound which inhibits the binding of nerve growth factor to the p75 NTR  receptor, said compound being characterized by at least two of: 
 (a) a first electronegative atom positioned to interact with Lys 34  of nerve growth factor;    (b) a second electronegative atom positioned to interact with Lys 95  of nerve growth factor;    (c) a third electronegative atom positioned to interact with Lys 88  of nerve growth factor;    (d) a fourth electronegative atom positioned to interact with Lys 32  of nerve growth factor; and    (e) a hydrophobic moiety which interacts with the hydrophobic region formed by Ile 31 , Phe 101  and Phe 86  of nerve growth factor.    
     
     
         2 . A method of inhibiting the binding of nerve growth factor to the p75 NTR  receptor, comprising contacting the cells expressing the p75 NTR  receptor with an effective inhibiting amount of a compound which is characterized by 
 (a) a first electronegative atom positioned to interact with Lys 34  of nerve growth factor;    (b) a second electronegative atom positioned to interact with Lys 95  of nerve growth factor;    (c) a third electronegative atom positioned to interact with Lys 88  of nerve growth factor;    (d) a fourth electronegative atom positioned to interact with Lys 32  of nerve growth factor; and    (e) a hydrophobic moiety which interacts with the hydrophobic region formed by Ile 31 , Phe 101  and Phe 86  of nerve growth factor;    thereby inhibiting the binding of nerve growth factor to the p75 NTR  receptor.    
     
     
         3 . A pharmaceutical composition comprising 
 (a) a compound which is characterized by at least two of: 
 (i) a first electronegative atom positioned to interact with Lys 34  of nerve growth factor;  
 (ii) a second electronegative atom positioned to interact with Lys 95  of nerve growth factor;  
 (iii) a third electronegative atom positioned to interact with Lys 88  of nerve growth factor;  
 (iv) a fourth electronegative atom positioned to interact with Lys 32  of nerve growth factor; and  
 (v) a hydrophobic moiety which interacts with the hydrophobic region formed by Ile 31 , Phe 101  and Phe 86  of nerve growth factor; and  
   (b) a pharmaceutically acceptable carrier or excipient.    
     
     
         4 . A method of treating a condition characterized by nerve growth factor-mediated cell apoptosis in a patient; said method comprising the step of administering to the patient a therapeutically effective amount of a compound which is characterized by 
 (a) a first electronegative atom positioned to interact with Lys 34  of nerve growth factor;    (b) a second electronegative atom positioned to interact with Lys 95  of nerve growth factor;    (c) a third electronegative atom positioned to interact with Lys 88  of nerve growth factor;    (d) a fourth electronegative atom positioned to interact with Lys32 of nerve growth factor; and    (e) a hydrophobic moiety which interacts with the hydrophobic region formed by Ile 31 , Phe 101  and Phe 86  of nerve growth factor;    thereby inhibiting the binding of nerve growth factor to the p75 NTR  receptor.    
     
     
         5 . The method of  claim 4  wherein the neurotrophin-mediated condition is selected from the group consisting of Alzheimer's disease, epilepsy, multiple sclerosis, amyotrophic lateral sclerosis, stroke, and pain.  
     
     
         6 . A method of inhibiting binding of nerve growth factor to the p75 NTR  receptor, comprising contacting the cells expressing the p75 NTR  receptor with an effective inhibiting amount of a compound of Formula 3,  
       
         
           
           
               
               
           
         
       
       wherein 
 D 1 , D 2 , E 1 , E 2  E3, E4 and G are each, independently, an sp 2 -hybridized carbon or nitrogen atom;  
 one of X 1  and X 2  is a hydrogen atom, while the other is an electronegative atom or an electronegative functional group;  
 R and R 2  are each, independently, an electronegative atom or an electronegative functional group;  
 Y, Y 1 , Y 2 , and Y 3  are each, independently, N, O, S, C—L or N—L, where L is H, alkyl or an electronegative atom or functional group;  
 Z and Z 1  are each, independently, O, S, CH, C(O), N, NH, N-alkyl, N-cycloalkyl or N—P, where P is a carbohydrate moiety;  
 T 1  and T 2  are each, independently, an sp 2 - or sp 3 -hybridized carbon or nitrogen atom;  
 d, h and c are each 0 or 1; and  
 R 1  is a monocyclic or polycyclic aryl or heteroaryl group group which is substituted with at least one substituent selected from the group consisting of hydroxyl and sulfonamide or an alky or alkylamino group substituted with a carboxyl or carbonate group.  
 
     
     
         7 . A method of inhibiting the binding of nerve growth factor to the p75 NTR  receptor, comprising contacting the cells expressing the p75 NTR  receptor with an effective inhibiting amount of a compound of Formula 1,  
       
         
           
           
               
               
           
         
       
       wherein 
 D 1 , D 2 , E 1 , E 2  E3, E4 and G are each, independently, an sp 2 -hybridized carbon or nitrogen atom;  
 one of X 1  and X 2  is a hydrogen atom, while the other is an electronegative atom or an electronegative functional group;  
 R and R 2  are each independently, an electronegative atom or an electronegative functional group;  
 Y, Y 1 , Y 2 , and Y 3  are each, independently, N, O, S, C—L or N—L, where L is H, alkyl or an electronegative atom or functional group;  
 Z and Z 1  are each, independently, O, S, CH, C(O), N, NH, N-alkyl, N-cycloalkyl or N—P, where P is a carbohydrate moiety;  
 T 1  and T 2  are each, independently, an sp 2 - or sp 3 -hybridized carbon or nitrogen atom;  
 d, h and c are each 0 or 1; and  
 R 1  is a monocyclic or polycyclic aryl or heteroaryl group group which is substituted with at least one substituent selected from the group consisting of hydroxyl and sulfonamide or an alky or alkylamino group substituted with a carboxyl or carbonate group.  
 
     
     
         8 . A method of treating a condition characterized by nerve growth factor-mediated cell apoptosis in a patient; said method comprising the step of administering to the patient a therapeutically effective amount of a compound of Formula 3,  
       
         
           
           
               
               
           
         
       
       wherein 
 D 1 , D 2 , E 1 , E 2  E3, E4 and G are each, independently, an sp 2 -hybridized carbon or nitrogen atom;  
 one of X 1  and X 2  is a hydrogen atom, while the other is an electronegative atom or an electronegative functional group;  
 R and R 2  are each, independently, an electronegative atom or an electronegative functional group;  
 Y, Y 1 , Y 2 , and Y 3  are each, independently, N, O, S, C—L or N—L, where L is H, alkyl or an electronegative atom or functional group;  
 Z and Z 1  are each, independently, O, S, CH, C(O), N, NH, N-alkyl, N-cycloalkyl or N—P, where P is a carbohydrate moiety;  
 T 1  and T 2  are each, independently, an sp 2 - or sp 3 -hybridized carbon or nitrogen atom;  
 d, h and c are each 0 or 1; and  
 R 1  is a monocyclic or polycyclic aryl or heteroaryl group group which is substituted with at least one substituent selected from the group consisting of hydroxyl and sulfonamide or an alky or alkylamino group substituted with a carboxyl or carbonate group.  
 
     
     
         9 . The method of  claim 8  wherein the neurotrophin-mediated condition is selected from the group consisting of Alzheimer's disease, epilepsy, multiple sclerosis, amyotrophic lateral sclerosis, stroke and pain.  
     
     
         10 . A pharmaceutical composition comprising a compound of Formula 1,  
       
         
           
           
               
               
           
         
       
       wherein 
 D 1 , D 2 , E 1 , E 2  E3, E4 and G are each, independently, an sp 2 -hybridized carbon or nitrogen atom;  
 one of X 1  and X 2  is a hydrogen atom, while the other is an electronegative atom or an electronegative functional group;  
 R and R 2  are each, independently, an electronegative atom or an electronegative functional group;  
 Y, Y 1 , Y 2 , and Y 3  are each, independently, N, O, S, C—L or N—L, where L is H, alkyl or an electronegative atom or functional group;  
 Z and Z 1  are each, independently, O, S, CH, C(O), N, NH, N-alkyl, N-cycloalkyl or N—P, where P is a carbohydrate moiety;  
 T 1  and T 2  are each, independently, an sp 2 - or sp 3 -hybridized carbon or nitrogen atom;  
 d, h and c are each 0 or 1; and  
 R 1  is a monocyclic or polycyclic aryl or heteroaryl group group which is substituted with at least one substituent selected from the group consisting of hydroxyl and sulfonamide or an alky or alkylamino group substituted with a carboxyl or carbonate group; and  
 at least one pharmaceutically acceptable carrier or excipient.