Pharmacological properties of YM461, a new orally active platelet‐activating factor antagonist

• Published in: Lipids Vol. 26; no. 12Part1; pp. 1179 - 1183
• Main Authors: Yamada, Toshimitsu, Saito, Munetoshi, Mase, Toshiyasu, Hara, Hiromu, Nagaoka, Hitoshi, Murase, Kiyoshi, Tomioka, Kenichi
• Format: Journal Article Conference Proceeding
• Language: English
• Published: Berlin/Heidelberg Springer‐Verlag 01.12.1991; Springer
• Subjects: Administration, Oral; Animals; Azepines - pharmacology; Azepines - toxicity; Biological and medical sciences; Blood Platelets - metabolism; Blood Pressure - drug effects; Blood. Blood coagulation. Reticuloendothelial system; Cell Membrane - metabolism; Dose-Response Relationship, Drug; Guinea Pigs; Humans; Male; Medical sciences; Mice; Mice, Inbred ICR; Pharmacology. Drug treatments; Platelet Activating Factor - antagonists & inhibitors; Platelet Activating Factor - metabolism; Platelet Activating Factor - toxicity; Platelet Aggregation - drug effects; Platelet Aggregation Inhibitors - administration & dosage; Platelet Aggregation Inhibitors - pharmacology; Platelet Membrane Glycoproteins; Pyridines - administration & dosage; Pyridines - pharmacology; Rabbits; Rats; Rats, Inbred Strains; Receptors, Cell Surface - antagonists & inhibitors; Receptors, Cell Surface - metabolism; Receptors, G-Protein-Coupled; Thiazoles - administration & dosage; Thiazoles - pharmacology; Thiazolidines; Triazoles - pharmacology; Triazoles - toxicity
• ISSN: 0024-4201; 1558-9307
• DOI: 10.1007/BF02536527

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.