Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, PA 19034, USA.
Bioorg Med Chem Lett. 2011 Aug 15;21(16):4836-43. doi: 10.1016/j.bmcl.2011.06.043. Epub 2011 Jun 17.
Structure-based design led to the discovery of a novel class of renin inhibitors in which an unprecedented phenyl ring filling the S1 site is attached to the phenyl ring filling the S3 pocket. Optimization for several parameters including potency in the presence of human plasma, selectivity against CYP3A4 inhibition and improved rat oral bioavailability led to the identification of 8d which demonstrated antihypertensive efficacy in a transgenic rat model of human hypertension.
基于结构的设计导致了一类新型肾素抑制剂的发现，其中一个前所未有的苯基环填充 S1 位与填充 S3 口袋的苯基环相连。通过对包括在人血浆中的效力、对 CYP3A4 抑制的选择性和改善的大鼠口服生物利用度等几个参数进行优化，鉴定出了 8d，它在人类高血压的转基因大鼠模型中显示出了降压效果。
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