Pitts W J, Wityak J, Smallheer J M, Tobin A E, Jetter J W, Buynitsky J S, Harlow P P, Solomon K A, Corjay M H, Mousa S A, Wexler R R, Jadhav P K
DuPont Pharmaceuticals Company, P.O. Box 80500, Wilmington, Delaware 19880-0500, USA.
J Med Chem. 2000 Jan 13;43(1):27-40. doi: 10.1021/jm9900321.
Starting with lead compound 2, we sought to increase the selectivity for alpha(v)beta(3)-mediated cell adhesion by examining the effects of structural changes in both the guanidine mimetic and the substituent alpha to the carboxylate. To prepare some of the desired aminoimidazoles, a novel reductive amination utilizing a trityl-protected aminoimidazole was developed. It was found that guanidine mimetics with a wide range of pK(a)'s were potent antagonists of alpha(v)beta(3). In general, it appeared that an acylated 2-aminoimidazole guanidine mimetic imparted excellent selectivity for alpha(v)beta(3)-mediated adhesion versus alpha(IIb)beta(3)-mediated platelet aggregation, with selectivity of approximately 3 orders of magnitude observed for compounds 3g and 3h. It was also found in this series that the alpha-substituent was required for potent activity and that 2,6-disubstituted arylsulfonamides 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 migration.
