Conformational considerations in the design of dual antagonists of platelet-activating factor (PAF) and histamine

Following the discovery of the first dual antagonist of platelet-activating factor (PAF) and histamine, 1-acetyl-4-(8-chloro-5,6-dihydro-11H-benzo[5,6 ]cyclohepta[1,2-b]pyridin-11-ylidene)piperidine, Sch 37370, 1, a related se ries of structures, exemplified by (+/-)-1-acetyl-4-(8-chloro-5,6-dihydro-1 1H-benzo[5,6]-cyclohepta[1,2b]pyridin-11-yl)piperazine, Sch 40338, 2, were pre pared. Interestingly, the compounds exhibited a parallel structure-anti allergy activity relationship, suggesting that the two series may adopt a c ommon conformation at the PAF receptor. Conformational analysis led to a pr oposal for this bioactive conformation accessible to both series. The synth esis of novel conformationally constrained analogues that might mimic the p roposed bioactive conformation of these compounds, and the evaluation of th eir in vitro antiallergy activity form the subject matter of this report. ( C) 1999 Elsevier Science Ltd. All rights reserved.