A molecular design toward biologically significant compounds based on PAF structures.

Abstract

Since the identification of platelet activating factor (PAF) as alkylacetylglycerophosphocholine, a number of constitutional analogues have been prepared by many laboratories including ours. However those simple constitutional modification of PAF could not make any substantial advance toward the discovery of any useful compounds. At least, one of the most important synthetic goals may be the elaboration of a more selective analogue that keeps good antihypertensive activity with lower platelet aggregation. A molecular design was carried out in such a way to lock or localize the conformational isomers of PAF by introducing methyl group in the glycerine moiety. Thus, tartaric acid strategy allowed us to introduce methyl group at C1 or C3 diastereoselectively and enantioselectively to afford all isomers. Among them, 1 S -Me-PAF has been shown to be the first selective agonist, possessing much stronger antihypertensive activity than PAF itself by oral dose, and rather low platelet activation. The results will be discussed.