Reverse-turn mimetics and methods relating thereto

Abstract

Conformationally constrained compounds which mimic the secondary structure of reverse-turn regions of biologically active peptides and proteins having the following structure are disclosed: wherein A, B, X, R 1 , and R 5 are as defined herein. Such compounds have utility over a wide range of fields, including use as diagnostic and therapeutic agents. In particular, compounds of this invention are useful in pharmaceutical compositions as anti-inflammatory agents as well as inhibitors of central nervous disorders. Libraries containing the compounds of this invention are also disclosed, as well as methods for screening the same to identify biologically active members.

1 . A method for treating a central nervous system disorder comprising administering to an animal in need thereof an effective amount of a compound having the structure:  
     
       
         
         
             
             
         
       
     
     or pharmaceutically acceptable salt or stereoisomer thereof, 
 wherein  
 A is —(CR 2 R 2a ) m — where m is 1, 2 or 3;  
 B is —(CR 3 R 3a ) n — where n is 1, 2, 3 or 4;  
 X is —N(R 4 )—, —O—, or —S—;  
 R 2  and R 3  are, at each occurrence, the same or different and independently an amino acid side chain moiety or amino acid side chain derivative, a peptide or peptide derivative, a linker or a solid support;  
 R 5  is an amino acid side chain moiety or amino acid side chain derivative;  
 R 2a  and R 3a  are, at each occurrence, the same or different and independently hydrogen, hydroxy, —COOH, —CONH 2 , —R 6 , —OR 6 , —COOR 6 , —COR 6  or —CONHR 6 , where R 6  is lower alkyl optionally substituted with halogen or hydroxy;  
 R 1  and R 4  are the same or different and represent the remainder of the molecule; and  
 wherein R 1  and R 2  taken together optionally form a fused heterocycle or substituted heterocycle.  
 
   
   
       2 . The method of  claim 1  wherein the compound has the structure:  
     
       
         
         
             
             
         
       
     
   
   
       3 . The method of  claim 2  wherein the compound has the structure:  
     
       
         
         
             
             
         
       
     
   
   
       4 . The method of  claim 2  wherein the compound has the structure:  
     
       
         
         
             
             
         
       
     
   
   
       5 . The method of  claim 2  wherein the compound has the structure:  
     
       
         
         
             
             
         
       
     
   
   
       6 . The method of  claim 2  wherein the compound has the structure:  
     
       
         
         
             
             
         
       
     
   
   
       7 . The method of  claim 2  wherein the compound has the structure:  
     
       
         
         
             
             
         
       
     
   
   
       8 . The method of  claim 1  wherein the compound has the structure:  
     
       
         
         
             
             
         
       
     
   
   
       9 . The method of  claim 8  wherein the compound has the structure:  
     
       
         
         
             
             
         
       
     
   
   
       10 . The method of  claim 8  wherein the compound has the structure:  
     
       
         
         
             
             
         
       
     
   
   
       11 . The method of  claim 8  wherein the compound has the structure:  
     
       
         
         
             
             
         
       
     
   
   
       12 . The method of  claim 8  wherein the compound has the structure:  
     
       
         
         
             
             
         
       
     
   
   
       13 . The method of  claim 8  wherein the compound has the structure:  
     
       
         
         
             
             
         
       
     
   
   
       14 . The method of  claim 1  wherein the compound has the structure:  
     
       
         
         
             
             
         
       
     
   
   
       15 . The method of  claim 1  wherein the compound has the structure:  
     
       
         
         
             
             
         
       
     
     wherein R′ is one or more optional heterocycle substituents.  
   
   
       16 . The method of  claim 15  wherein the compound has the structure:  
     
       
         
         
             
             
         
       
     
     wherein R′ is —OR or —OC(O)R where R is an amino acid side chain moiety or an amino acid side chain derivative.  
   
   
       17 . The method of  claim 1  wherein R 1 , R 2 , R 3  and R 4  are the same or different and are independently an amino acid side chain moiety or an amino acid side chain derivative.  
   
   
       18 . The method of  claim 1  wherein R 1 , R 2 , R 3  and R 4  are the same or different and are independently: 
 (i) —H, —CH 3 , —CH(CH 3 ) 2 , —CH 2 CH(CH 3 ) 2 , —CH(CH 3 )CH 2 CH 3 , —(CH 2 ) 4 NH 2 ,    —CH 2 ) 3 NHC(NH 2 )NH 2 ,                           —CH 2 COOH, —CH 2 CH 2 COOH, CH 2 CONH 2 , —CH 2 CH 2 CONH 2 , —CH 2 SH, —CH 2 CH 2 SCH 3 , —CH 2 OH, —CH(OH)CH 3 , or    (ii) a side chain moiety of 3,5-dibromotyrosine, 3,5-diiodotyrosine, hydroxylysine, γ-carboxyglutamate, phosphotyrosine, phosphothreonine or phosphoserine; or    (iii) a moiety selected from alkyl, aryl, arylalkyl, heterocyclic or heterocyclicalkyl moieties, each moiety of (iii) being optionally substituted with a substituent selected from halogen, oxo, hydroxy, haloalkyl, —R, —OR, —C(═O)R, —C(═O)OR, —C(═O)NRR, —NRR, —NRC(═O)R, —NRC(═O)OR, —NRC(═O)NRR, —OC(═O)R, —OC(═O)OR, —OC(═O)NRR, —SH, —SR, —SOR, —SO 2 R, —NRSO 2 R, —Si(R) 3 , and —OP(OR) 3 , wherein each occurrence of R is the same or different and independently an amino acid side chain moiety, hydrogen, alkyl, aryl, arylalkyl, heterocycle or heterocyclealkyl, or wherein any two R groups attached to the same nitrogen atom, taken together with the nitrogen atom to which they are attached, form a heterocyclic ring or a substituted heterocyclic ring.    
   
   
       19 . The method of  claim 1  wherein the central nervous system disorder is anxiety, depression, psychosis, schizophrenia, epilepsy, or a neurodegenerative disorder.  
   
   
       20 . The method of  claim 1  wherein the central nervous system disorder is dementia, Alzheimer's disease, Down's syndrome, or AIDS dementia.