Soyka R, Heckel A, Nickl J, Eisert W, Müller T H, Weisenberger H
Research Department, Dr. Karl Thomae GmbH, Biberach, Germany.
J Med Chem. 1994 Jan 7;37(1):26-39. doi: 10.1021/jm00027a004.
A series of omega-disubstituted alkenoic acid derivatives were designed and synthesized as antithrombotic inhibitors of thromboxane A2 synthetase and thromboxane A2 receptor antagonists. Hexenoic acid derivatives with a 3-pyridyl group and a 4-(2-benzenesulfonamidoethyl)phenyl substituent were found to be optimal with regard to the dual mode of action. The most potent compound, (E)-6-(4-(2-(((4-chlorophenyl)sulfonyl)amino)ethyl)phenyl)-6-(3-pyridyl) hex-5-enoic acid (36), inhibits thromboxane A2 synthetase in gel-filtered human platelets with an IC50 value of 4.5 +/- 0.5 nM (n = 4), whereas an inhibitory effect on cyclooxygenase is seen only at a much higher concentration (IC50: 240 microM). Radioligand-binding studies with [3H]SQ 29,548 in washed human platelets revealed that 36 blocks the prostaglandin H2/thromboxane A2 receptor with an IC50 of 19 +/- 5 nM (n = 5) and is therefore 85-fold more potent than another combined thromboxane A2 synthetase inhibitor/receptor antagonist, Ridogrel (4). Compound 36 inhibits the collagen-induced platelet aggregation in human platelet-rich plasma and whole blood with an EC50 of 1 microM (Ridogrel: 16 microM) and 100 nM, respectively, and was selected for further development.
设计并合成了一系列ω-二取代链烯酸衍生物，作为血栓素A2合成酶的抗血栓形成抑制剂和血栓素A2受体拮抗剂。发现具有3-吡啶基和4-(2-苯磺酰胺基乙基)苯基取代基的己烯酸衍生物在双重作用模式方面是最佳的。最有效的化合物，(E)-6-(4-(2-(((4-氯苯基)磺酰基)氨基)乙基)苯基)-6-(3-吡啶基)己-5-烯酸(36)，在凝胶过滤的人血小板中抑制血栓素A2合成酶，IC50值为4.5±0.5 nM(n = 4)，而对环氧化酶的抑制作用仅在高得多的浓度下才可见(IC50: 240 μM)。用[3H]SQ 29,548在洗涤过的人血小板中进行的放射性配体结合研究表明，36以19±5 nM(n = 5)的IC50阻断前列腺素H2/血栓素A2受体，因此比另一种血栓素A2合成酶抑制剂/受体拮抗剂利托格雷(4)强85倍。化合物36在富含人血小板的血浆和全血中抑制胶原诱导的血小板聚集，EC50分别为1 μM(利托格雷: 16 μM)和100 nM，并被选择用于进一步开发。
