THROMBOXANE RECEPTOR ANTAGONISM COMBINED WITH THROMBOXANE SYNTHASE INHIBITION .5. SYNTHESIS AND EVALUATION OF ENANTIOMERS OF 8-[[(4-CHLOROPHENYL)SULFONYL]AMINO]-4-(3-PYRIDINYLALKYL)OCTANOIC ACID

被引:12
作者
BHAGWAT, SS
GUDE, C
COHEN, DS
DOTSON, R
MATHIS, J
LEE, W
FURNESS, P
机构
[1] Research Department, Pharmaceuticals Division, CIBA-GEIGY Corporation, Summit, New Jersey 07901
关键词
D O I
10.1021/jm00054a003
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The enantiomers of 8-[[(4-chlorophenyl)sulfonyl]amino]-4-(3-pyridinylpropyl)octanoic acid (1) and its pyridinyl ether analog (2) were synthesized using the highly diastereoselective method of alkylation of acyloxazolidinone. These enantiomerically pure compounds were compared with the corresponding racemic compounds 1 and 2 for their in vitro activity. Compounds 1, 1R, and 1S and 2,2S, and 2R were equipotent as thromboxane receptor antagonists (TxRAs) and thromboxane synthase inhibitors (TxSIs) (IC50 = 2-30 nM). Upon oral administration to guinea pigs, the enantiomers inhibited the ex vivo U 46619-induced platelet aggregation with potency similar to that of the corresponding racemic compound. This indicates that the enantiomers have pharmacologic profile and bioavailability similar to that of the corresponding racemic compound.
引用
收藏
页码:205 / 210
页数:6
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