Merck Frosst Center for Therapeutic Research, PO Box 1005, Pointe Claire-Dorval, Québec, Canada H9R 4P8.
Bioorg Med Chem Lett. 2012 Mar 1;22(5):1953-7. doi: 10.1016/j.bmcl.2012.01.044. Epub 2012 Jan 26.
The discovery and SAR of a series of potent renin inhibitors possessing a novel 3,4-diarylpiperidine scaffold are described herein. The resulting compound 38 exhibit low nanomolar plasma renin IC(50), had a clean CYP 3A4 profile and displayed micromolar affinity for the hERG channel. Furthermore, it was found to be efficacious in the double transgenic rat hypertension model and show good to moderate oral bioavailability in two animal species.
本文描述了一系列具有新型 3,4-二芳基哌啶骨架的强效肾素抑制剂的发现和 SAR 研究。得到的化合物 38 表现出低纳摩尔的血浆肾素 IC（50），具有清洁的 CYP 3A4 特征，并对 hERG 通道表现出微摩尔亲和力。此外，它在双转基因大鼠高血压模型中表现出疗效，并在两种动物中显示出良好至中等的口服生物利用度。
