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.

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       11 . A method of inhibiting the binding of nerve growth factor to the p75 NTR  receptor, comprising contacting cells expressing the p75 NTR  receptor with an effective inhibiting amount of a compound having Formula 3:  
     
       
         
         
             
             
         
       
     
     or its pharmaceutically acceptable salt; 
 wherein:  
 D 1 , D 2 , E 1 , E 2 , E 3 , E 4  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 selected from the group consisting of carbonyl; thiocarbonyl; ester; imino; amido; boronic acid; sulfate ester; mercapto; cyanate; thiocyanate; isocyanate; isothiocyanate; carbonate; alkylcarbonyl; alkylthiocarbonyl; alkoxycarbonyl; aminocarbonyl; —OH; —CN; —CO 2 H; —SO 3 H; —SO 2 H; —PO 3 H 2 ; —NO 2 ; —NO 2 ; —CNO; —SH; —CNS; —OSO 3 H; —OC(O)(OH); a halomethyl group; a dihalomethyl group; a trihalomethyl group; fluorine; chlorine; bromine and iodine;  
 R and R 2  are each, independently, selected from the group consisting of ═O; ═S; —CH 2 ; —NR 3 , where R 3  is H, alkyl or aryl; carbonyl; thiocarbonyl; ester; imino; amido; boronic acid; sulfate ester; mercapto; cyanate; thiocyanate; isocyanate; isothiocyanate; carbonate; alkylcarbonyl; alkylthiocarbonyl; alkoxycarbonyl; aminocarbonyl; —OH; —CN; —O 2 H; —SO 3 H; —SO 2 H; —PO 3 H 2 ; —NO 2 ; —NO 2 N; CNO; —SH; —CNS; —OSO 3 H; —OC(O)(OH); a halomethyl group; a dihalomethyl group; a trihalomethyl group; fluorine; chlorine; bromine and iodine;  
 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 a member selected from the group consisting of carbonyl; thiocarbonyl; ester; imino; amido; boronic acid; sulfate ester; mercapto; cyanate; thiocyanate; isocyanate; isothiocyanate; carbonate; alkylcarbonyl; alkylthiocarbonyl; alkoxycarbonyl; aminocarbonyl; —OH; —CN; —CO 2 H; —SO 3 H; —SO 2 H; —PO 3 H 2 ; —NO 2 ; —ONO 2 ; —CNO; —SH; —CNS; —OSO 3 H; —OC(O)(OH); a halomethyl group; a dihalomethyl group; a trihalomethyl group; fluorine; chlorine; bromine and iodine;  
 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 selected from the group consisting of —(CH 2 ) a NO 2 ; —(CH 2 ) a OH; —(CH 2 ) a PO 3 H 2 ; —(CH 2 ) a SO 3 H; and (CH 2 ) a SO 2 H, wherein a is 1 to 12.  
 
   
   
       12 . The method defined in  claim 11 , wherein a is 1 to 4.  
   
   
       13 . The method defined in  claim 11 , wherein the compound having Formula 3 comprises:  
     
       
         
         
             
             
         
       
     
     or its pharmaceutically acceptable salt.  
   
   
       14 . A method of inhibiting the binding of nerve growth factor to the p75 NTR  receptor, comprising contacting cells expressing the p75 NTR  receptor with an effective inhibiting amount of a pharmaceutical composition comprising a compound having Formula 3:  
     
       
         
         
             
             
         
       
     
     or its pharmaceutically acceptable salt; 
 wherein:  
 D 1 , D 2 , E 1 , E 2 , E 3 , E 4  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 selected from the group consisting of carbonyl; thiocarbonyl; ester; imino; amido; boronic acid; sulfate ester; mercapto; cyanate; thiocyanate; isocyanate; isothiocyanate; carbonate; alkylcarbonyl; alkylthiocarbonyl; alkoxycarbonyl; aminocarbonyl; —OH; —CN; —CO 2 H; —SO 3 H; —SO 2 H; —PO 3 H 2 ; —NO 2 ; —ONO 2 ; —CNO; —SH; —CNS; —OSO 3 H; —OC(O)(OH); a halomethyl group; a dihalomethyl group; a trihalomethyl group; fluorine; chlorine; bromine and iodine;  
 R and R 2  are each, independently, selected from the group consisting of ═O; ═S; —CH 2 ; —NR 3 , where R 3  is E 1 , alkyl or aryl; carbonyl; thiocarbonyl; ester; imino; amido; boronic acid; sulfate ester; mercapto; cyanate; thiocyanate; isocyanate; isothiocyanate; carbonate; alkylcarbonyl; alkylthiocarbonyl; alkoxycarbonyl; aminocarbonyl; —OH; —CN; —CO 2 H; —SO 3 H; —SO 2 H; —PO 3 H 2 ; —NO 2 ; —ONO 2 ; —CNO; —SH; —CNS; —OSO 3 H; —OC(O) (OH); a halomethyl group; a dihalomethyl group; a trihalomethyl group; fluorine; chlorine; bromine and iodine;  
 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 a member selected from the group consisting of carbonyl; thiocarbonyl; ester; imino; amido; boronic acid; sulfate ester; mercapto; cyanate; thiocyanate; isocyanate; isothiocyanate; carbonate; alkylcarbonyl; alkylthiocarbonyl; alkoxycarbonyl; aminocarbonyl; —OH; —CN; —CO 2 H; —SO 3 H; —SO 2 H; —PO 3 H 2 ; —NO 2 ; —ONO 2 ; —CNO; —SH; —CNS; —OSO 3 H; —OC(O)(OH); a halomethyl group; a dihalomethyl group; a trihalomethyl group; fluorine; chlorine; bromine and iodine;  
 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 selected from the group consisting of —(CH 2 ) a NO 2 ; —(CH 2 ) a OH; —(CH 2 ) a PO 3 H 2 ; —(CH 2 ) a SO 3 H; and —(CH 2 ) a SO 2 H, wherein a is 1 to 12,  
 together with a pharmaceutically acceptable carrier or excipient.  
 
   
   
       15 . The method defined in  claim 14 , wherein a is 1 to 4.  
   
   
       16 . The method defined in  claim 14 , wherein the compound having Formula 3 comprises:  
     
       
         
         
             
             
         
       
     
     or its pharmaceutically acceptable salt.  
   
   
       17 . A method of treating a condition in a patient, the condition being mediated by binding of nerve growth factor to the p75 NTR  receptor, the method comprising the step of administering to the patient a therapeutically effective amount of a compound having Formula 3:  
     
       
         
         
             
             
         
       
     
     or its pharmaceutically acceptable salt; 
 wherein:  
 D 1 , D 2 , E 1 , E 2 , E 3 , E 4  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 selected from the group consisting of carbonyl; thiocarbonyl; ester; imino; amido; boronic acid; sulfate ester; mercapto; cyanate; thiocyanate; isocyanate; isothiocyanate; carbonate; alkylcarbonyl; alkylthiocarbonyl; alkoxycarbonyl; aminocarbonyl; —OH; —CN; —CO 2 H; —SO 3 H; —SO 2 H; —PO 3 H 2 ; —NO 2 ; —ONO 2 ; —CNO; —SH; —CNS; —OSO 3 H; —OC(O)(OH); a halomethyl group; a dihalomethyl group; a trihalomethyl group; fluorine; chlorine; bromine and iodine;  
 R and R 2  are each, independently, selected from the group consisting of ═O; ═S; —CH 2 ; —NR 3 , where R 3  is H, alkyl or aryl; carbonyl; thiocarbonyl; ester; imino; amido; boronic acid; sulfate ester; mercapto; cyanate; thiocyanate; isocyanate; isothiocyanate; carbonate; alkylcarbonyl; alkylthiocarbonyl; alkoxycarbonyl; aminocarbonyl; —OH; —CN; —O 2 H; —SO 3 H—; —SO 2 H; —PO 3 H 2 ; —NO 2 ; —ONO 2 ; —CNO; —SH; —CNS; —OSO 3 H; —OC(O)(OH), a halomethyl group; a dihalomethyl group; a trihalomethyl group; fluorine; chlorine; bromine and iodine;  
 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 a member selected from the group consisting of carbonyl; thiocarbonyl; ester; imino; amido; boronic acid; sulfate ester; mercapto; cyanate; thiocyanate; isocyanate; isothiocyanate; carbonate; alkylcarbonyl; alkylthiocarbonyl; alkoxycarbonyl; aminocarbonyl; —OH; —CN; —CO 2 H; —SO 3 H; —SO 2 H; —PO 3 H 2 ; —NO 2 , —ONO 2 ; —CNO; —SH; —CNS; —OSO 3 H; —OC(O)(OH); a halomethyl group; a dihalomethyl group; a trihalomethyl group; fluorine, chlorine; bromine and iodine;  
 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 selected from the group consisting of —(CH 2 ) a NO 2 ; —(CH 2 ) a OH; —(CH 2 ) a PO 3 H 2 ; —(CH 2 ) a SO 3 H; and —(CH 2 ) a SO 2 H, wherein a is 1 to 12.  
 
   
   
       18 . The method defined in  claim 17 , wherein a is 1 to 4.  
   
   
       19 . The method defined in  claim 17 , wherein the compound having Formula 3 comprises:  
     
       
         
         
             
             
         
       
     
     or its pharmaceutically acceptable salt.  
   
   
       20 . A method of treating a condition in a patient, the condition being mediated by binding of nerve growth factor to the p75 NTR  receptor, the method comprising the step of administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising a compound having Formula 3:  
     
       
         
         
             
             
         
       
     
     or its pharmaceutically acceptable salt; 
 wherein:  
 D 1 , D 2 , E 1 , E 2 , E 3 , E 4  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 selected from the group consisting of carbonyl; thiocarbonyl; ester; imino; amido; boronic acid; sulfate ester; mercapto; cyanate; thiocyanate; isocyanate; isothiocyanate; carbonate; alkylcarbonyl; alkylthiocarbonyl; alkoxycarbonyl; aminocarbonyl; —OH; —CN; —CO 2 H, —SO 3 H; —SO 2 H; —PO 3 H 2 ; —NO 2 ; —NO 2 ; —CNO; —SH; —CNS; —OSO 3 H; —OC(O)(OH); a halomethyl group; a dihalomethyl group; a trihalomethyl group; fluorine; chlorine; bromine and iodine;  
 R and R 2  are each, independently, selected from the group consisting of ═O; ═S; —CH 2 ; —NR 3 , where R 3  is H, alkyl or aryl; carbonyl; thiocarbonyl; ester; imino; amido; boronic acid; sulfate ester, mercapto; cyanate; thiocyanate, isocyanate; isothiocyanate; carbonate; alkylcarbonyl; alkylthiocarbonyl; alkoxycarbonyl; aminocarbonyl; —OH; —CN; —CO 2 H; —SO 3 H; —SO 2 H; —PO 3 H 2 ; —NO 2 ; —ONO 2 ; —CNO 2 ; —SH; —CNS; —OSO 3 H; —C(O)(OH); a halomethyl group; a dihalomethyl group; a trihalomethyl group; fluorine; chlorine; bromine and iodine;  
 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 a member selected from the group consisting of carbonyl; thiocarbonyl; ester; imino; amido; boronic acid; sulfate ester; mercapto; cyanate; thiocyanate; isocyanate; isothiocyanate; carbonate; alkylcarbonyl; alkylthiocarbonyl; alkoxycarbonyl; aminocarbonyl; —OH; —CN; —CO 2 H; —SO 3 H; —SO 2 H; —PO 3 H 2 ; —NO 2 ; —ONO 2 ; —CNO; —SH; CNS; —OSO 3 H; —OC(O)(OH); a halomethyl group; a dihalomethyl group; a trihalomethyl group; fluorine; chlorine; bromine and iodine;  
 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 selected from the group consisting of —(CH 2 ) a NO 2 ; —(CH 2 ) a OH; —(CH 2 ) a PO 3 H 2 ; —(CH 2 ) a SO 3 H; and —(CH 2 ) a SO 2 H, wherein a is 1 to 12,  
 together with a pharmaceutically acceptable carrier or excipient.  
 
   
   
       21 . The method defined in  claim 20 , wherein a is 1 to 4.  
   
   
       22 . The method defined in  claim 20 , wherein the compound having Formula 3 comprises:  
     
       
         
         
             
             
         
       
     
     or its pharmaceutically acceptable salt.  
   
   
       23 . The method defined in  claim 17 , wherein the condition is selected from the group consisting of Alzheimer's disease, epilepsy, multiple sclerosis, amyotrophic lateral sclerosis, stroke and pain.  
   
   
       24 . The method defined in  claim 18 , wherein the condition is selected from the group consisting of Alzheimer's disease, epilepsy, multiple sclerosis, amyotrophic lateral sclerosis, stroke and pain.  
   
   
       25 . The method defined in  claim 19 , wherein the condition is selected from the group consisting of Alzheimer's disease, epilepsy, multiple sclerosis, amyotrophic lateral sclerosis, stroke and pain.  
   
   
       26 . The method defined in  claim 20 , wherein the condition is selected from the group consisting of Alzheimer's disease, epilepsy, multiple sclerosis, amyotrophic lateral sclerosis, stroke and pain.  
   
   
       27 . The method defined in  claim 21 , wherein the condition is selected from the group consisting of Alzheimer's disease, epilepsy, multiple sclerosis, amyotrophic lateral sclerosis, stroke and pain.  
   
   
       28 . The method defined in  claim 22 , wherein the condition is selected from the group consisting of Alzheimer's disease, epilepsy, multiple sclerosis, amyotrophic lateral sclerosis, stroke and pain.