Abstract
In a continuing effort to obtain more potent platelet activating factor (PAF) antagonists, we tried to synthesize a series of PAF-sulfonamide isosteres in which the substituent at the 2-position was modified to an acetoxy equivalent other than the methoxy group. These modifications produced highly active PAF antagonists. Compound 3-[2-(5-methyl-2H-tetrazol-2-yl)-3-(octadecylcarbamoyloxy) propylaminosulfonyl]propylquinolinium iodide (52) showed the most potent activity in the in vitro inhibitory effect on PAF-induced platelet aggregation in rabbit platelet-rich plasma (IC50 = 125 nM) and also in the in vivo protective effect on PAF-induced lethality in mice, with prolonged duration of action. Optically active enantiomers of this compound were synthesized and the (S)-(-)-isomer (IC50 = 87 nM) was found to be three times more potent that the (R)-(+)-isomer (IC50 = 289 nM), clearly exemplifying the enantioselectivity in the PAF-antagonist action of this novel compound.
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