The oral activity and antithrombotic efficacy of
BMY 42393 was examined in ex vivo platelet aggregation studies and arterial
thrombosis animal models. In a heterologous ex vivo platelet aggregation assay,
ADP-induced human platelet aggregation was inhibited when washed human platelets were combined with rat platelet-poor plasma, taken from rats previously orally-dosed with
BMY 42393. The IC50 for platelet aggregation inhibition was approximately 10 mg/kg. In a
laser-induced
thrombosis model,
thrombus formation in a revascularized rabbit ear chamber was prevented in a dose-dependent fashion with an ED50 of about 2 mg/kg. A relatively long duration of anti-thrombotic activity was observed in the rabbit ear
laser-induced
thrombus study and the ex vivo platelet studies. Inhibition of
thrombus formation was also demonstrated in a canine model of electrically-induced coronary artery
thrombosis.
BMY 42393 also prevented cyclic flow reductions in a monkey stenotic renal artery model. These studies indicate that
BMY 42393 is orally active and capable of preventing
laser and electric current-induced
thrombus formation in animal models of arterial
thrombosis.