YM-461

Conversion of the 2-(3-pyridyl)thiazolidine part of 1-(3-phenylpropyl)-4-[2-(3-pyridyl)thiazolidine-4-carbonyl]piperazine (YM461), which is a potent platelet-activating factor (PAF) antagonist, to other rings was performed, and PAF antagonistic activities evaluated. The 2-(3-pyridyl)thiazolidine skeleton, which exists as a mixture of cis and trans diastereomers, played an important role in the potency of PAF antagonism. In this study, new effective skeletons were not uncovered, however, 2-(4-pyridyl)thiazolidine-4-carboxamides (1n and 1z) showed potent PAF antagonistic activities equal to the 3-pyridyl derivatives. From the results obtained for 1a, 1a(S), 1g and 1i, a cis-(2R,4R)-2-(3-pyridyl)thiazolidine-4-carboxamide was assumed to be the active configuration for PAF antagonism.

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 severalin vitro andin vivo systems. We found that YM461 inhibited [3H]PAF binding to rabbit platelet membranes with a pKi 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 10−4M 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/kgp.o. YM461 at doses above 0.3 mg/kgi.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/kgp.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/kgp.o. in rats. YM461 inhibited the bronchoconstriction induced by PAF with an ED50 value of 1.2 mg/kgp.o. in anesthetized guinea pigs. Furthermore, the compound at doses above 3 mg/kgp.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.