Press J B, Wright W B, Chan P S, Haug M F, Marsico J W, Tomcufcik A S
J Med Chem. 1987 Jun;30(6):1036-40. doi: 10.1021/jm00389a013.
The title compounds were prepared as the heterocyclic analogues of thromboxane (TX) synthetase inhibitors and antihypertensive agents previously reported from our laboratories. These compounds were at least as active TX synthetase inhibitors as their benzene isosteres with the indole derivatives 50-55 having the most potent enzyme inhibiting activity measured to date in our laboratories. The best compound, 54, is more than 200-fold more potent than the standard, dazoxiben. In contrast, the antihypertensive activity of these series of compounds was no better than their benzene counterparts and is far lower than the isoindoledione derivatives prepared in a related series. The structure-activity relationship results from this study were similar to our previous observations and include the fact that the amide moiety effectively replaces a carboxylic acid for potent TX synthetase inhibition and that a four to six methylene unit separation (approximately 8.5 A) between amide and imidazole moieties achieves maximal activity.
标题化合物是作为血栓素（TX）合成酶抑制剂和降压剂的杂环类似物制备的，这些抑制剂和降压剂先前已由我们实验室报道。这些化合物作为TX合成酶抑制剂，其活性至少与其苯环类似物相当，其中吲哚衍生物50 - 55具有迄今为止在我们实验室中测得的最强酶抑制活性。最佳化合物54的效力比标准品达唑氧苯强200多倍。相比之下，这一系列化合物的降压活性并不优于其苯环类似物，且远低于在相关系列中制备的异吲哚二酮衍生物。本研究的构效关系结果与我们之前的观察结果相似，包括以下事实：酰胺部分有效地取代了羧酸以实现有效的TX合成酶抑制，并且酰胺和咪唑部分之间四到六个亚甲基单元的间隔（约8.5埃）可实现最大活性。
