Discovery and preliminary pharmacology of Sch 37370, a dual antagonist of PAF and histamine

From a series of amide analogs of the histamine H₁ antagonist, azatadine, a potent, orally active, dual platelet-activating factor (PAF) and histamine antagonist, Sch 37370, namely 1-acetyl-4-(8-chloro-5,6-dihydro-11H-benzo-5,6]cyclohepta1,2-b]pyridin-11-ylidine)piperidine, was discovered. Sch 37370 selectively inhibits PAF-induced aggregation of human plateletsin vitro (IC₅₀=0.6 μM), andin vivo inhibits PAF- and histamine-induced bronchospasm in guinea pigs with ED₅₀ values of 6.0 and 2.4 mg/kg p.o., respectively. Sch 37370 is expected to be more efficacious than single mediator antagonists in allergic diseases, such as asthma. Based on papers presented at the Third International Conference on Platelet-Activating Factor and Structurally Related Alkyl Ether Lipids, Tokyo, Japan, May 1989.