2-[3-[2-(4,5-DIPHENYL-2-OXAZOLYL)ETHYL]PHENOXY] ACETIC-ACID (BMY-42393) .2. ORAL ACTIVITY AND EFFICACY IN ANIMAL-MODELS OF ARTERIAL THROMBOSIS

The oral activity and antithrombotic efficacy of BMY 42393 was examine d in ex vivo platelet aggregation studies and arterial thrombosis anim al models. In a heterologous ex vivo platelet aggregation assay, ADP-i nduced human platelet aggregation was inhibited when washed human plat elets were combined with rat platelet-poor plasma, taken from rats pre viously 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 p revented in a dose-dependent fashion with an ED50 of about 2 mg/kg. A relatively long duration of anti-thrombotic activity was observed in t he rabbit ear laser-induced thrombus study and the ex vivo platelet st udies. Inhibition of thrombus formation was also demonstrated in a can ine model of electrically-induced coronary artery thrombosis. BMY 4239 3 also prevented cyclic flow reductions in a monkey stenotic renal art ery model. These studies indicate that BMY 42393 is orally active and capable of preventing laser and electric current-induced thrombus form ation in animal models of arterial thrombosis.