Merck Frosst Centre for Therapeutic Research, Kirkland, Québec, Canada.
Bioorg Med Chem Lett. 2012 Apr 15;22(8):2670-4. doi: 10.1016/j.bmcl.2012.03.014. Epub 2012 Mar 11.
The design and optimization of a novel isoxazole S(1) linker for renin inhibitor is described herein. This effort culminated in the identification of compound 18, an orally bioavailable, sub-nanomolar renin inhibitor even in the presence of human plasma. When compound 18 was found to inhibit CYP3A4 in a time dependent manner, two strategies were pursued that successfully delivered equipotent compounds with minimal TDI potential.
本文描述了一种新型异噁唑 S(1)连接子用于肾素抑制剂的设计和优化。这一努力的最终成果是确定了化合物 18，它是一种口服生物利用度的、亚纳摩尔级的肾素抑制剂，即使在人血浆存在的情况下也是如此。当发现化合物 18以时间依赖性方式抑制 CYP3A4 时，采用了两种策略，成功地提供了具有最小 TDI 潜力的等效化合物。
