Disubstituted Indazoles as Potent Antagonists of the Integrin αvβ3

A new series of indazole-containing αvβ3 integrin antagonists is described. Starting with lead compound 18a, variations in a number of structural features were explored with respect to inhibition of the binding of β3-transfected 293 cells to fibrinogen and to selectivity for αvβ3 over GPIIbIIIa, another RGD-binding integrin. Indazoles attached to a 2-aminopyridine or 2-aminoimidazole by a propylene linker at the indazole 1-position and to a diaminopropionate derivative via a 5-carboxylate amide provided the best potency with moderate selectivity. Several differences in the SAR of the diaminopropionate moiety were observed between this series and a series of isoxazoline-based selective GPIIbIIIa antagonists. Compound 34a (SM256) was a potent antagonist of αvβ3 (IC50 2.3 nM) with 9-fold selectivity over GPIIbIIIa.