PHARMACOLOGICAL PROPERTIES OF YM461, A NEW ORALLY ACTIVE PLATELET-ACTIVATING-FACTOR ANTAGONIST

The antagonistic effect of YM461 [1-(3-phenylpropyl)4-[2( 3-pyridyl)thiazolidin-4-ylcarbonyl]piperazine fumarate] against platelet-activating factor (PAF) was examined in several in vitro and in vivo systems. We found that YM461 inhibited [H-3]PAF binding to rabbit platelet membranes with a pK(i) value of 8.90. YM461 inhibited PAF induced rabbit and human platelet aggregation with pA2 values of 7.52 and 7.29, respectively; the slopes of the Schild plots were 1.07 and 1.01, respectively. However, YM461 at 10(-4)M did not affect rabbit and human platelet aggregation induced by ADP, collagen, arachidonic acid or epinephrine. YM461 inhibited PAF induced death in mice with an ED50 (50% effective dose) value of 0.35 mg/kg p.o. YM461 at doses above 0.3 mg/kg i.v. inhibited PAF induced hypotension in rats. YM461 showed a dose-dependent inhibition of PAF induced hemoconcentration in rats with ED50 values of 0.15 and 0.21 mg/kg p.o., respectively, at 0.5 and 1 hr after oral administration. The anti-PAF effect of YM461 persisted more than 6 hr after 3 mg/kg po. in rats. YM461 inhibited the bronchoconstriction induced by PAF with an ED50 value of 1.2 mg/kg po. in anesthetized guinea pigs. Furthermore, the compound at doses above 3 mg/kg p.o. significantly inhibited antigen-induced anaphylactic asthma in conscious guinea pigs pretreated with mepyramine and propranolol. These results indicate that YM461 is a selective, potent and orally active PAF antagonist.