NONPEPTIDE FIBRINOGEN RECEPTOR ANTAGONISTS .2. OPTIMIZATION OF A TYROSINE TEMPLATE AS A MIMIC FOR ARG-GLY-ASP

Inhibitors of platelet-fibrinogen binding offer an opportunity to inte rrupt the final, common pathway for platelet aggregation. Small molecu le inhibitors of the platelet fibrinogen receptor GPIIb/IIIa were prep ared and evaluated for their ability to prevent platelet aggregation. Compound 23m (L-700,462/MK-383) inhibited in vitro platelet aggregatio n with an IC50 of 9 nM and demonstrated a selectivity of > 24 000-fold between platelet and human umbilical vein endothelial cell fibrinogen receptors. Dose-dependent inhibition of ex vivo platelet aggregation induced by ADP was achieved with iv infusions of 0.1-10 mu g/kg/min of 23m in anesthetized dogs, with 10 mu g/kg/min completely inhibiting p latelet aggregation during the entire 6 h infusion protocol. Platelet aggregatability returned rapidly after the termination of the 23m infu sions. These features suggest that 23m may be useful in the treatment of arterial occlusive disorders.