Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Québec, Canada H9H 3L1.
Bioorg Med Chem Lett. 2011 Jul 1;21(13):3970-5. doi: 10.1016/j.bmcl.2011.05.013. Epub 2011 May 14.
An SAR campaign aimed at decreasing the overall lipophilicity of renin inhibitors such as 1 is described herein. It was found that replacement of the northern appendage in 1 with an N-methyl pyridone and subsequent re-optimization of the benzyl amide handle afforded compounds with in vitro and in vivo profiles suitable for further profiling. An unexpected CV toxicity in dogs observed with compound 20 led to the employment of a time and resource sparing rodent model for in vivo screening of key compounds. This culminated in the identification of compound 31 as an optimized renin inhibitor.
本文描述了一项旨在降低肾素抑制剂（如 1）整体亲脂性的 SAR 研究。研究发现，用 N-甲基吡啶酮替换 1 中的北部侧链，并对苄基酰胺侧链进行重新优化，得到了具有适合进一步研究的体外和体内特征的化合物。化合物 20 在狗体内观察到的意外心血管毒性，导致采用耗时和资源较少的啮齿动物模型进行关键化合物的体内筛选。这最终确定了化合物 31 为优化的肾素抑制剂。
