Isoxazolines as potent antagonists of the integrin alpha(v)beta(3)

Starting with lead compound 2, we sought to increase the selectivity for al pha(v)beta(3)-mediated cell adhesion by examining the effects of structural changes in both the guanidine mimetic and the substituent alpha to the car boxylate. To prepare some of the desired aminoimidazoles, a novel reductive amination utilizing a trityl-protected aminoimidazole was developed. It wa s found that guanidine mimetics with a wide range of pK(a)'s were potent an tagonists of alpha(v)beta(3). In general, it appeared that an acylated 2-am inoimidazole guanidine mimetic imparted excellent selectivity for alpha(v)b eta(3)-mediated adhesion versus alpha(IIb)beta(3)-mediated platelet aggrega tion, with selectivity of approximately 3 orders of magnitude observed for compounds 3g and 3h. It was also found in this series that the alpha-substi tuent was required for potent activity and that 2,6-disubstituted arylsulfo namides were optimal. In addition, the selective alpha(v)beta(3) antagonist 3h was found to be a potent inhibitor of alpha(v)beta(3)-mediated cell mig ration.