Karasawa A, Shirakura S, Higo K, Kubo K
Department of Pharmacology, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan.
Arzneimittelforschung. 1991 Dec;41(12):1237-41.
The effects of KW-3635 (sodium (E)-11-[2-(5,6-dimethyl-1-benzimidazolyl)- ethylidene]-6,11-dihydrodibenz[b,e]oxepine-2-carboxylate monohydrate, CAS 127166-41-0) on smooth muscle preparations were examined. In isolated guinea-pig aorta, KW-3635 competitively inhibited the U-46619 (a thromboxane mimetic) induced contractions (pA2 = 7.74), the effect being more potent than those of sulotroban and daltroban. In canine saphenous vein, KW-3635 also antagonized the U-46619-induced contraction (pA2 = 8.11). In this preparation, solutroban and daltroban, but not KW-3635, exhibited intrinsic agonistic action. KW-3635, even at a high concentration of 10(-5) mol/l did not affect the norepinephrine- or KCl-induced contractions of guinea-pig or rat aorta, prostaglandin (PG)E2- or PGF2 alpha-induced contractions of guinea-pig ileum nor the PGE2-induced contraction of rat fundus. KW-3635 at concentrations higher than its thromboxane A2- (TxA2-)antagonistic one, non-competitively inhibited the PGF2 alpha-induced contractions of guinea-pig aorta (pD2' = 6.23), as was the case with daltroban. The inhibitory effect of KW-3635 (3 x 10(-6) mol/l) on U-46619-induced contractions of guinea-pig aorta persisted for longer than 2 h following washout of the tissue, whereas that of daltroban (10(-5) mol/l completely disappeared at 1 h after the washout. In anesthetized guinea-pigs, KW-3635 at doses of 10 to 1000 micrograms/kg (i.v.) inhibited U-46619 (1 microgram/kg i.v.)-induced pressor responses in a dose-dependent manner. The effect of KW-3635 (0.1 to 1 mg/kg i.v.) persisted for longer than 3 h. These results demonstrate that KW-3635 is a potent and specific TxA2 antagonist without agonistic action in vascular smooth muscles. KW-3635 is considered to be a promising candidate for the treatment of patients with disorders mediated via TxA2.
研究了KW - 3635（(E)-11-[2-(5,6 - 二甲基 - 1 - 苯并咪唑基)-亚乙基]-6,11 - 二氢二苯并[b,e]氧杂卓 - 2 - 羧酸钠一水合物，CAS 127166 - 41 - 0）对平滑肌制剂的作用。在离体豚鼠主动脉中，KW - 3635竞争性抑制U - 46619（一种血栓素类似物）诱导的收缩（pA2 = 7.74），其作用比舒洛地班和达曲班更强。在犬隐静脉中，KW - 3635也拮抗U - 46619诱导的收缩（pA2 = 8.11）。在该制剂中，舒洛地班和达曲班表现出内在激动作用，而KW - 3635没有。即使在10⁻⁵mol/l的高浓度下，KW - 3635也不影响豚鼠或大鼠主动脉中去甲肾上腺素或氯化钾诱导的收缩、豚鼠回肠中前列腺素（PG）E2或PGF2α诱导的收缩以及大鼠胃底中PGE2诱导的收缩。KW - 3635在高于其血栓素A2（TxA2）拮抗浓度时，非竞争性抑制豚鼠主动脉中PGF2α诱导的收缩（pD2' = 6.23），达曲班也是如此。在冲洗组织后，KW - 3635（3×10⁻⁶mol/l）对豚鼠主动脉中U - 46619诱导收缩的抑制作用持续超过2小时，而达曲班（10⁻⁵mol/l）在冲洗后1小时完全消失。在麻醉的豚鼠中，静脉注射剂量为10至1000μg/kg的KW - 3635以剂量依赖方式抑制U - 46619（静脉注射1μg/kg）诱导的升压反应。KW - 3635（静脉注射0.1至1mg/kg）的作用持续超过3小时。这些结果表明，KW - 3635是一种强效且特异性的TxA2拮抗剂，在血管平滑肌中无激动作用。KW - 3635被认为是治疗由TxA2介导的疾病患者的有前景的候选药物。
