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: T Yamada, M Saito, T Mase, H Hara, H Nagaoka, K Murase, K Tomioka
• Journal: Lipids (Lipids) Vol. 26 Issue 12 Pg. 1179-83 (Dec 1991) ISSN: 0024-4201 [Print] United States
• PMID: 1668114 (Publication Type: Journal Article)

Chemical References

• Azepines
• Platelet Activating Factor
• Platelet Aggregation Inhibitors
• Platelet Membrane Glycoproteins
• Pyridines
• Receptors, Cell Surface
• Receptors, G-Protein-Coupled
• Thiazoles
• Thiazolidines
• Triazoles
• platelet activating factor receptor
• WEB 2086
• YM 461

Topics

• Administration, Oral
• Animals
• Azepines (pharmacology, toxicity)
• Blood Platelets (metabolism)
• Blood Pressure (drug effects)
• Cell Membrane (metabolism)
• Dose-Response Relationship, Drug
• Guinea Pigs
• Humans
• Male
• Mice
• Mice, Inbred ICR
• Platelet Activating Factor (antagonists & inhibitors, metabolism, toxicity)
• Platelet Aggregation (drug effects)
• Platelet Aggregation Inhibitors (administration & dosage, pharmacology)
• Platelet Membrane Glycoproteins
• Pyridines (administration & dosage, pharmacology)
• Rabbits
• Rats
• Rats, Inbred Strains
• Receptors, Cell Surface (antagonists & inhibitors, metabolism)
• Receptors, G-Protein-Coupled
• Thiazoles (administration & dosage, pharmacology)
• Thiazolidines
• Triazoles (pharmacology, toxicity)