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

A new series of indazole-containing alpha(v)beta(3) integrin antagonists is described. Starting with lead compound 18a, variations in a number of stru ctural features were explored with respect to inhibition of the binding of beta(3)-transfected 293 cells to fibrinogen and to selectivity for alpha(v) beta(3) over GPIIbIIIa, another RGD-binding integrin. Indazoles attached to a 2-aminopyridine or 2-aminoimidazole by a propylene linker at the indazol e 1-position and to a diaminopropionate derivative via a 5-carboxylate amid e provided the best potency with moderate selectivity. Several differences in the SAR of the diaminopropionate moiety were observed between this serie s and a series of isoxazoline-based selective GPIIbIIIa antagonists. Compou nd 34a (SM256) was a potent antagonist of alpha(v)beta(3) (IC50 2.3 nM) wit h 9-fold selectivity over GPIIbIIIa.