title: Pharmacological properties of YM461, a new orally active platelet-activating factor antagonist.
abstract: 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 [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(-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 p.o. in rats. YM461 inhibited the bronchoconstriction induced by PAF with an ED50 value of 1.2 mg/kg p.o. 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.
authors.affiliation: Medicinal Research Laboratories, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Yamada
authors.forename: M
authors.initials: M
authors.lastname: Saito
authors.forename: T
authors.initials: T
authors.lastname: Mase
authors.forename: H
authors.initials: H
authors.lastname: Hara
authors.forename: H
authors.initials: H
authors.lastname: Nagaoka
authors.forename: K
authors.initials: K
authors.lastname: Murase
authors.forename: K
authors.initials: K
authors.lastname: Tomioka
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001381:Azepines / Q000494:pharmacology / Q000633:toxicity; D001792:Blood Platelets / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D010980:Platelet Membrane Glycoproteins; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology*; D053778:Thiazolidines; D014230:Triazoles / Q000494:pharmacology / Q000633:toxicity
chemical_list: D001381:Azepines; D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D011725:Pyridines; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D013844:Thiazoles; D053778:Thiazolidines; D014230:Triazoles; C039351:platelet activating factor receptor; C052518:WEB 2086; C062972:YM 461