Pharmacological properties of YM264, a potent and orally active antagonist of platelet-activating factor.

The anti-platelet-activating factor effect of YM264 was examined in a variety of in vitro and in vivo test systems. YM264 inhibited [3H] platelet-activating factor binding to rabbit platelet membranes with a pKi value of 8.85. YM264 inhibited the platelet-activating factor-induced human, rabbit and guinea-pig platelet aggregation with pA2 values of 8.68, 8.33 and 8.14, respectively. However, at 10(-4) M the compound did not affect rabbit and human platelet aggregation induced by ADP, collagen arachidonic acid and epinephrine. YM264 reversed a platelet-activating factor-induced hypotension is anesthetized rats with an ED50 value of 0.005 mg/kg, i.v. Administered orally, YM264 inhibited platelet-activating factor-induced death in mice, hemoconcentration in rats and increase in vascular permeability in guinea-pigs with ED50 values of 0.19, 0.30 and 0.49 mg/kg, p.o., respectively. YM264, at 1 and 3 mg/kg, p.o., showed a significant anti-platelet-activating factor effect in a rat hemoconcentration model up to 6 hr after treatment. Moreover, in ex vivo experiments in guinea-pigs, YM264, at the doses of 0.3 to 3 mg/kg, p.o., shifted the dose-response curves of platelet-activating factor-induced platelet aggregation to the right in a parallel manner. These results indicate that YM264 is a selective, potent and orally active platelet-activating factor antagonist.