Cell adhesion inhibitors

Abstract

The present invention relates to novel compounds that are useful for inhibition and prevention of cell adhesion and cell adhesion-mediated pathologies. This invention also relates to pharmaceutical formulations comprising these compounds and methods of using them for inhibition and prevention of cell adhesion and cell adhesion-mediated pathologies. The compounds and pharmaceutical compositions of this invention can be used as therapeutic or prophylactic agents. They are particularly well-suited for treatment of many inflammatory and autoimmune diseases.

1 . A cell adhesion inhibitor comprising a compound having Formula (I)  
       A-B   (I)  
     wherein A comprises a VLA-4 specificity determinant which does not impart significant IIb/IIIa activity, and B comprises an integrin scaffold derived from a compound having IIb/IIIa activity.  
   
   
       2 . The cell adhesion inhibitor of  claim 1  wherein B comprises a scaffold selected from the group consisting of Formula IVa, Formula IVb and Formula IVc:  
     
       
         
         
             
             
         
       
     
     wherein 
 A 4  is selected from the group consisting of (CR 1 R 2 ) n , O, S, NR 1 ,SO 2 NR 1 , CONR 1 , CH 2 NR 11 , NR 1 SO 2 , CH 2 O, CH 2 NCOR 11 , and CH 2 CONR 1 ;  
 n is 0-5;  
 m is 1-4;  
 W is selected from the group consisting of CO 2 H, SO 3 H, PO 4 H 2 , tetrazole, and H;  
 Z is CO, or (CR 1 R 2 ) n ;  
 R 1  and R 2  are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, heterocycle; alkyl optionally substituted with cycloalkyl, cycloalkenyl, heterocycle, alkenyl, alkynyl, alkoxyl, hydroxyl, halogen, aralkoxy, thioalkoxy, carboxy, alkoxycarbonyl, and carboxamide;  
 R 4  is selected from the group consisting of H, OR 1 , SR 1 , NR 1 R 2 , alkyl, NZR 1 , NSO 2 R 11 , and CO 2 R 1 ;  
 R 5  and R 6  are independently selected from the group consisting of H, OR 1 , halogen, alkyl, and NR 1 R 2 ; and  
 R 11  is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, heterocycle; alkyl optionally substituted with cycloalkyl, cycloalkenyl, heterocycle, alkenyl, alkynyl, alkoxyl, hydroxyl, halogen, aralkoxy, thioalkoxy, carboxy, alkoxycarbonyl, and carboxamide.  
 
   
   
       3 . The cell adhesion inhibitor of  claim 1  wherein A is selected from the group consisting of alkyl; aliphatic acyl optionally substituted with N-alkyl- or N-arylamido; aroyl; heterocycloyl; alkyl- or arylsulfonyl; aralkylcarbonyl optionally substituted with aryl; heterocycloalkylcarbonyl; alkoxycarbonyl; aralkyloxycarbonyl; cycloalkylcarbonyl optionally fused with aryl; heterocycloalkoxycarbonyl; alkylaminocarbonyl; arylamino carbonyl and aralkylaminocarbonyl optionally substituted with bis (alkylsulfonyl) amino, alkoxycarbonylamino or alkenyl; alkylsulfonyl; aralkylsulfonyl; arylsulfonyl; cycloalkylsulfonyl optionally fused with aryl; heterocyclylsulfonyl; heterocyclylalkylsulfonyl; aralkoxycarbonyl; aryloxycarbonyl; cycloalkyloxycarbonyl; heterocyclyloxycarbonyl; heterocyclylalkoxycarbonyl; mono- or di-alkylaminocarbonyl optionally substituted with aryl; (alkyl) (aralkyl) aminocarbonyl; mono- or di-aralkylaminocarbonyl; mono- or di-arylaminocarbonyl; (aryl) (alkyl) aminocarbonyl; mono- or di-cycloalkylaminocarbonyl; heterocyclylaminocarbonyl; heterocyclylalkylaminocarbonyl; (alkyl) (heterocyclyl) aminocarbonyl: (alkyl) (heterocyclylalkyl) aminocarbonyl; (aralkyl) (heterocyclyl) aminocarbonyl; (aralkyl) (heterocyclylalkyl) aminocarbonyl; alkenoyl optionally substituted with aryl; alkenylsulfonyl optionally substituted with aryl; alkynoyl optionally substituted with aryl; alkynylsulfonyl optionally substituted with aryl; cycloalkenylcarbonyl; cycloalkenylsulfonyl; cycloalkylalkanoyl; cylcoalkylalkylsulfonyl; arylaroyl, biarylsulfonyl; alkoxysulfonyl; aralkoxysulfonyl; alkylaminosulfonyl; aryloxysulfonyl; arylaminosulfonyl; N-arylurea-substituted alkanoyl; N-arylurea-substituted alkylsulfonyl; cycloalkenyl-substituted carbonyl; cycloalkenyl-substituted sulfonyl; alkenoxycarbonyl optionally substituted with aryl; alkenoxysulfonyl optionally substituted with aryl; alkynoxycarbonyl optionally substituted with aryl; alkynoxysulfonyl optionally substituted with aryl; alkenyl- or alkynyl-aminocarbonyl optionally substituted with aryl; alkenyl- or alkynyl-aminosulfonyl optionally substituted with aryl; acylamino-substituted alkanoyl; acylamino-substituted alkylsulfonyl; aminocarbonyl-substituted alkanoyl; carbamoyl-substituted alkanoyl; carbamoyl-substituted alkylsulfonyl; heterocyclylalkanoyl; heterocyclylaminosulfonyl; carboxyalkyl-substituted aralkoyl; carboxyalkyl-substituted aralkylsulfonyl; oxocarbocyclyl-fused aroyl; oxocarbocyclyl-fused arylsulfonyl; heterocyclylalkanoyl; N′,N′-alkyl, arylhydrazinocarbonyl; aryloxy-substituted alkanoyl and heterocyclylalkylsuflonyl; alkyl, alkenyl, alkynyl, cycloalkyl, aryl-fused cycloalkyl, cycloalkenyl, aryl, aryl-substituted alkyl, aryl-substituted alkenyl or alkynyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted cylcoalkyl, biaryl, alkoxy, alkenoxy, alkynoxy, aryl-substituted alkoxy, aryl-substituted alkenoxy or alkynoxy, alkylamino, alkenylamino or alkynylamino, aryl-substituted alkylamino, aryl-substituted alkenylamino or alkynylamino, aryloxy, arylamino, N-alkylurea-substituted alkyl, N-arylurea-substituted alkyl, alkylcarbonylamino-substituted alkyl, aminocarbonyl-substituted alkyl, heterocyclyl, heterocyclyl-substituted alkyl, heterocyclyl-substituted amino, carboxyalkyl substituted aralkyl, oxocarbocyclyl-fused aryl and heterocyclylalkyl.  
   
   
       4 . The cell adhesion inhibitor according to  claim 3 , wherein A is selected from the group consisting of alkyl; aliphatic acyl optionally substituted with N-alkyl- or N-arylamido; aroyl; heterocycloyl; alkyl- and arylsulfonyl; aralkylcarbonyl optionally substituted with aryl; heterocycloalkylcarbonyl; alkoxycarbonyl; aralkyloxycarbonyl; cycloalkylcarbonyl optionally fused with aryl; heterocycloalkoxycarbonyl; alkylaminocarbonyl; arylaminocarbonyl and aralkylaminocarbonyl optionally substituted with bis-(alkylsulfonyl)amino, alkoxycarbonylamino or alkenyl.  
   
   
       5 . The cell adhesion inhibitor according to  claim 4 , wherein A is selected from the group consisting of aliphatic acyl, aroyl, aralkylcarbonyl, heterocycloyl, alkoxycarbonyl, aralkyloxycarbonyl and heterocycloalkylcarbonyl.  
   
   
       6 . The cell adhesion inhibitor according to  claim 5 , wherein A is selected from the group consisting of (N—Ar′-urea)-para-substituted aralkylcarbonyl, (N—Ar′-urea)-para-substituted aralkyl and (N—Ar′-urea)-para-substituted aryl.  
   
   
       7 . The cell adhesion inhibitor according to  claim 6 , wherein A is selected from the group consisting of (N—Ar′-urea)-para-substituted phenylmethylcarbonyl, (N—Ar′-urea)-para-substituted phenylmethyl and (N—Ar′-urea)-para-substituted phenyl.  
   
   
       8 . The cell adhesion inhibitor according to  claim 6 , wherein: B is a structure selected from the group consisting of formula IVa, formula IVb and formula IVc:  
     
       
         
         
             
             
         
       
     
     wherein 
 A 4  is selected from the group consisting of (CR 1 R 2 ) n , O, S, NR 1 ,SO 2 NR 1 , CONR 1 , CH 2 NR 11 , NR 1 SO 2 , CH 2 O, CH 2 NCOR 11 , and CH 2 CONR 1 ;  
 n is 0-5;  
 m is 1-4;  
 W is selected from the group consisting of CO 2 H, SO 3 H, PO 4 H 2 , tetrazole, and H;  
 Z is CO, or (CR 1 R 2 ) n ;  
 R 1  and R2 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, heterocycle; alkyl optionally substituted with cycloalkyl, cycloalkenyl, heterocycle, alkenyl, alkynyl, alkoxyl, hydroxyl, halogen, aralkoxy, thioalkoxy, carboxy, alkoxycarbonyl, and carboxamide;  
 R 4  is selected from the group consisting of H, OR 1 , SR 1 , NR 1 R 2 , alkyl, NZR 1 , NSO 2 R 11 , and CO 2 R 1 ;  
 R 5  and R 6  are independently selected from the group consisting of H, OR 1 , halogen, alkyl, and NR 1 R 2 ; and  
 R 11  is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, heterocycle; alkyl optionally substituted with cycloalkyl, cycloalkenyl, heterocycle, alkenyl, alkynyl, alkoxyl, hydroxyl, halogen, aralkoxy, thioalkoxy, carboxy, alkoxycarbonyl, and carboxamide.  
 
   
   
       9 . A cell adhesion inhibitor according to  claim 1  wherein said inhibitor has an IC 50  of about 1 pM to about 10 μM, as measured by a VLA-4 direct binding assay.  
   
   
       10 . The cell adhesion inhibitor according to  claim 9  wherein said inhibitor has an IC 50  of about 1 pM to about 100 nM.  
   
   
       11 . The cell adhesion inhibitor according to  claim 10  wherein said inhibitor has an IC 50  of about 1 pM to about 10 nM.  
   
   
       12 . A cell adhesion inhibitor selected from the group consisting of  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       13 . A pharmaceutical composition comprising 
 (a) the cell adhesion inhibitor of  claim 1 , in an amount effective for the prevention, inhibition or suppression of cell adhesion; and    (b) a pharmaceutically acceptable carrier.