Synthesis and Antagonistic Activities of Enantiomers of Cyclic Platelet-Activating Factor Analogues

Abstract

Enantiomers of platelet-activating factor (PAF) antagonists, 3-{6-[O-(trans-3-heptadecylcarbamoyloxytetrahydro-pyran-2-yl)methyl]phosphonoxy}hexylthiazolium (inner salt) (3), 3-[5-(trans-3-heptadecylcarbamoyloxytetrahydro-pyran-2-yl)methoxycarbonylamino]pentylthiazolium bromiede (4) and 3-{5-[O-(cis-3-heptadecylcarbamoylthiotetrahy-dropyran-2-yl)methyl]phosphonoxy}pentylthiazolium (inner salt) (5), were synthesized, starting from (2R, 2R)- and (2S, 2S)-tartaric acid.Antagonistic activities of these compounds against C₁₆-PAF were measured in vitro (rabbit platelet aggregation, IC₅₀) and in vivo (hypotension in rates, ID₅₀). In these three enantiomeric pairs, the (3S)-(tetrahydropyran numbering) enantiomers were one order more potein than the (3R)-isomers : (2R, 3S)-3a (R-74, 654), IC₅₀ 0.59μM and ID₅₀ 0.054 mg/kg, i.v.; (2S, 3R)-3b, IC₅₀ 4.7μM and ID₅₀ 0.30 mg/kg, i.v.; (2R, 3S)-4a, IC₅₀ 0.20 μM and ID₅₀ 0.032 mg/kg, i.v.; (2S, 3R)-4b, IC₅₀ 2.2μM and IC₄₀ 0.21 mg/kg, i.v.; (2R, 3R)-5a, IC₅₀ 1.1μM and ID₅₀ 0.92 mg/kg, i.v.; (2S, 3S)-5b (R-74, 717), IC₅₀ 0.27μM and ID₅₀ 0.064 mg/kg, i.v.