Selective ETA antagonists.: 5.: Discovery and structure-activity relationships of phenoxyphenylacetic acid derivatives
Selective ETA antagonists.: 5.: Discovery and structure-activity relationships of phenoxyphenylacetic acid derivatives
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DOI：
10.1021/jm990378b
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发表时间：
2000-03-09
影响因子：
7.3
通讯作者：
Walsh, RJA
中科院分区：
文献类型：
--
作者：
Astles, PC;Brown, TJ;Walsh, RJA
本系列的第五篇论文描述了我们研究开发一种有效的和选择性的ETA受体拮抗剂用于治疗ET-1介导的疾病的结果。先前制备的几种ETA拮抗剂的受体位点作图鉴定了一个共同的阳离子结合位点，其促进苯氧基苯乙酸衍生物13 a的合成，其显示出良好的体外活性（IC 50 59 nM，大鼠主动脉ETA）。13 a的优化导致鉴定出27 b，其表现出4 nM的IC 50。尽管这并未转化为预期的体内效价，但具有相当体外活性的化合物27 a（RPR 118031 A）显示出更好的药代动力学特征和体内效价（75 μ mol/kg），因此正式提出并接受其作为开发候选药物。
The fifth paper in this series describes the culmination of our investigations into the development of a potent and selective ETA receptor antagonist for the treatment of diseases mediated by ET-1. Receptor site mapping of several ETA antagonists prepared previously identified a common cationic binding site which prompted synthesis of phenoxyphenylacetic acid derivative 13a, which showed good in vitro activity (IC50 59 nM, rat aortic ETA). Optimization of 13a led to the identification of 27b, which exhibited an IC50 of 4 nM. Although this did not translate into the expected in vivo potency, a compound of comparable in vitro activity, 27a (RPR118031A), showed a far better pharmacokinetic profile and in vivo potency (75 mu mol/kg) and was duly proposed and accepted as a development candidate.