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

概要

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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 C_<16>-PAF were measured in vitro (rabbit platelet aggregation, IC_<50>) and in vivo (hypotension in rates, ID_<50>). 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), IC_<50> 0.59μM and ID_<50> 0.054 mg/kg, i.v.; (2S, 3R)-3b, IC_<50> 4.7μM and ID_<50> 0.30 mg/kg, i.v.; (2R, 3S)-4a, IC_<50> 0.20 μM and ID_<50> 0.032 mg/kg, i.v.; (2S, 3R)-4b, IC_<50> 2.2μM and IC_<40> 0.21 mg/kg, i.v.; (2R, 3R)-5a, IC_<50> 1.1μM and ID_<50> 0.92 mg/kg, i.v.; (2S, 3S)-5b (R-74,717), IC_<50> 0.27μM and ID_<50> 0.064 mg/kg, i.v.
社団法人日本薬学会の論文
1989-09-25