Design, synthesis, and pharmacology of 3-substituted sodium azulene-1-sulfonates and related compounds: non-prostanoid thromboxane A2 receptor antagonists.
Design, synthesis, and pharmacology of 3-substituted sodium azulene-1-sulfonates and related compounds: non-prostanoid thromboxane A2 receptor antagonists.
复制标题
3-取代薁-1-磺酸钠及相关化合物的设计、合成和药理学：非前列腺素类血栓素 A2 受体拮抗剂。
DOI：
10.1021/jm00059a001
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发表时间：
1993
影响因子：
7.3
通讯作者：
T. Yanagisawa
中科院分区：
文献类型：
--
作者：
T. Tomiyama;M. Yokota;S. Wakabayashi;K. Kosakai;T. Yanagisawa
合成了一系列新颖的甘菊环-1羧酸衍生物28-30、甘菊环-1磺酸钠盐41 a-c及相关化合物。测试这些化合物的TXA 2受体拮抗活性。获得了这些化合物对（15 S）-15-羟基-11 α，9 α-（环氧亚甲基）前列腺-5（Z），13（E）-二烯酸（U-46619）诱导的血管收缩（TXA 2 tau受体）和血小板聚集（TXA 2 α受体）的抑制浓度（IC 50）。甘菊环-1-磺酸钠盐41 a-c比甘菊环-1-羧酸28-30的效力高3倍以上。最有效的化合物41 b在抑制血管收缩（tau受体）方面比TXA 2拮抗剂BM 13，177强4个数量级，IC 50为9.0 × 10 - 10 M。还发现化合物41 b是tau受体选择性拮抗剂（收缩的IC 50/聚集的IC 50 = 378），在浓度高达10（-4）M时没有TXA 2合成酶抑制活性，在兔主动脉（tau受体）中浓度高达10（-5）M和在兔富血小板血浆（α受体）中浓度高达10（-4）M时没有部分激动活性。在使用兔凝胶过滤的血小板的放射性配体结合测定中，化合物41 b对TXA 2受体具有高亲和力结合。在体内研究中，化合物41 b以0.3 mg/kg的剂量抑制U-46619诱导的小鼠猝死，并且当以3 mg/kg口服给药时，其作用持续时间超过8小时。
A series of novel azulene-1 carboxylic acid derivatives 28-30, azulene-1 sulfonic acid sodium salts 41a-c, and related compounds were synthesized. These compounds were tested for TXA2 receptor antagonistic activity. The inhibitory concentrations (IC50) of these compounds for vascular contraction (TXA2 tau receptor) and platelet aggregation (TXA2 alpha receptor) induced by (15S)-15-hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5(Z),13(E)- dienoic acid (U-46619) were obtained. Azulene-1-sulfonic acid sodium salts 41a-c were over 3 times more potent than azulene-1-carboxylic acids 28-30. The most potent compound, 41b was 4 orders of magnitude more potent than a TXA2 antagonist, BM13,177, in inhibiting vascular contraction (tau receptor) and had an IC50 of 9.0 x 10(-10) M. Compound 41b was also found to be a tau receptor selective antagonist (IC50 of contraction/IC50 of aggregation = 378) and to have no TXA2 synthetase inhibitory activity at concentrations up to 10(-4) M and no partial agonistic activity at concentrations up to 10(-5) M in rabbit aorta (tau receptor) and up to 10(-4) M in rabbit platelet-rich plasma (alpha receptor). In a radioligand binding assay using rabbit gel-filtered platelets, compound 41b had a high-affinity binding for the TXA2 receptor. In an in vivo study, compound 41b inhibited U-46619-induced sudden death in mice at a dose of 0.3 mg/kg and its duration of action was over 8 h when administered orally at 3 mg/kg.