DIBENZOXEPIN DERIVATIVES - THROMBOXANE-A(2) SYNTHASE INHIBITION AND THROMBOXANE A(2)-RECEPTOR ANTAGONISM COMBINED IN ONE MOLECULE

被引：11
|
作者：
OHSHIMA, E
SATO, H
OBASE, H
MIKI, I
ISHII, A
KAWAKAGE, M
SHIRAKURA, S
KARASAWA, A
KUBO, K
机构：
[1] Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, 411, 1188 Shimotogari, Nagaizumi-cho, Sunto-gun
来源：
JOURNAL OF MEDICINAL CHEMISTRY | 1993年 / 36卷 / 11期
关键词：
D O I：
10.1021/jm00063a011
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
A new series of 6,11-dihydrodibenz[b,e]oxepin derivatives exerting both thromboxane synthase inhibitory (TXS-I) and thromboxane receptor antagonist (TXRA) activities is described. (-)-ll-[(3-Pyridylmethyl)thio]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid [(-)-3] and (E)-11-[2-(3-pyridyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid methanesulfonate (11E) exhibited potent inhibitory effects on bovine platelet thromboxane synthase with IC50 values of 4.0 and 14 nM, respectively, and these derivatives also antagonized guinea pig platelet TXA2/PGH2 receptors with K(i) values of 85 and 180 nM, respectively. Compound 11E exhibited the dual inhibitory activity in ex vivo experiments and demonstrated a significant protective effect in a rat acute renal failure model.
引用
收藏
页码：1613 / 1618
页数：6
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