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, R 1 , R 2 , R 2a , R 3 , R 3a and R 4 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. Libraries containing the compounds of this invention are also disclosed, as well as methods for screening the same to identify biologically active members.

We claim:  
     
         1 . A compound having the structure:  
       
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts and stereoisomers thereof, 
 wherein 
 A is —(CR 5 R 5a ) n — where n is 1, 2 or 3;  
 R 2 , R 3  and R 5  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 2a , R 3a , and R 5a  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; and  
 R 1  and R 4  represent the remainder of the molecule, with the proviso that when R 1  is —C(═O)OMe and R 4  is benzyl, R 2  is not isopropyl when R 3  is methyl and R 2  is not methyl when R 3  is isopropyl.  
 
 
     
     
         2 . The compound of  claim 1  wherein R 2a  and R 3a  are hydrogen, and the compound has the structure:  
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 2  wherein n is 1, R 5a  is hydrogen, and the compound has the structure:  
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 3  wherein R 5  is hydrogen.  
     
     
         5 . The compound of  claim 2  wherein n is 2, R 5a  is hydrogen at each occurrence, and the compound has the structure:  
       
         
           
           
               
               
           
         
       
     
     
         6 . The compound of  claim 5  wherein R 5  is hydrogen at each occurrence, and the compound has the structure:  
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound of  claim 1  wherein R 3a  is hydrogen, and the compound has the structure:  
       
         
           
           
               
               
           
         
       
     
     
         8 . The compound of  claim 2  or  7  wherein 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.  
     
     
         9 . The compound of  claim 1  wherein R 1  is —C(═O)OR 7 , —C(═O)NHR 7  or —SO 2 R 7  where R 7  is an amino acid side chain moiety or an amino acid side chain derivative.  
     
     
         10 . The compound of  claim 9  wherein R 7  aryl or arylalkyl optionally substituted with halogen, —OH, —COOH, —NH 2  or alkyl.  
     
     
         11 . The compound of  claim 9  wherein R 2a  and R 3a  are hydrogen.  
     
     
         12 . The compound of  claim 9  wherein R 2  is —(CH 2 ) 2 COOH.  
     
     
         13 . The compound of  claim 9  wherein R 3  is benzyl or substituted benzyl.  
     
     
         14 . The compound of  claim 9  wherein R 1  is —SO 2 R 7    
     
     
         15 . The compound of  claim 14  wherein the compound has the structure:  
       
         
           
           
               
               
           
         
       
     
     
         16 . The compound of  claim 14  wherein the compound has the structure:  
       
         
           
           
               
               
           
         
       
     
     
         17 . The compound of  claim 14  wherein the compound has the structure:  
       
         
           
           
               
               
           
         
       
     
     
         18 . The compound of  claim 14  wherein the compound has the structure:  
       
         
           
           
               
               
           
         
       
     
     
         19 . The compound of  claim 14  wherein the compound has the structure:  
       
         
           
           
               
               
           
         
       
     
     
         20 . The compound of  claim 14  wherein the compound has the structure:  
       
         
           
           
               
               
           
         
       
     
     
         21 . The compound of  claim 14  wherein the compound has the structure:  
       
         
           
           
               
               
           
         
       
     
     
         22 . The compound of  claim 14  wherein the compound has the structure:  
       
         
           
           
               
               
           
         
       
     
     
         23 . The compound of  claim 14  wherein the compound has the structure:  
       
         
           
           
               
               
           
         
       
     
     
         24 . A composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         25 . A library of compounds comprising a plurality of library members, wherein at least one library member is a compound of  claim 1 .  
     
     
         26 . A method of identifying a biologically active compound, comprising screening the library of compounds of  claim 25  for biological activity.  
     
     
         27 . A method for treating an inflammatory or cell adhesion-mediated disease comprising administering to a warm-blooded animal in need thereof an effective amount of the composition of  claim 24 .  
     
     
         28 . The method of  claim 27  wherein the disease is an inflammatory disease.  
     
     
         29 . The method of  claim 27  wherein the disease is a cell adhesion-mediated disease.  
     
     
         30 . The method of  claim 27  wherein the disease is rheumatoid arthritis, Alzheimer's disease, AIDS dementia, ARDS, asthma, allergies, inflammatory bowel disease, CNS inflammation, atopic dermatitis, encephalitis, multiple sclerosis, meningitis, nephritis, retinitis or psoriasis.  
     
     
         31 . The method of  claim 27  wherein the disease is type I diabetes, atherosclerosis, myocardial ischemia, restenosis, stroke or tumor metastasis.