A Novel Class of Platelet Activating Factor (PAF) Antagonists. II. Modification of the 2-Position of the Glycerol Backbone of PAF-Sulfonamide Isosteres

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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 (IC_<50>=125nM) 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 (IC_<50>=87nM) was found to be three times more potent that the (R)-(+)-isomer (IC_<50>=289nM), clearly exemplifying the enantioselectivity in the PAF-antagonist action of this novel compound.
社団法人日本薬学会の論文
1992-01-25