Holsworth Daniel D, Jalaie Mehran, Belliotti Thomas, Cai Cuiman, Collard Wendy, Ferreira Suzie, Powell Noel A, Stier Michael, Zhang Erli, McConnell Pat, Mochalkin Igor, Ryan Michael J, Bryant John, Li Tingsheng, Kasani Aparna, Subedi Rajendra, Maiti Samarendra N, Edmunds Jeremy J
Pfizer Global Research and Development, Michigan Laboratories, 2800 Plymouth Road, Ann Arbor, MI 48105, USA.
Bioorg Med Chem Lett. 2007 Jul 1;17(13):3575-80. doi: 10.1016/j.bmcl.2007.04.052. Epub 2007 Apr 25.
Novel 2,4-diaminopyrimidine-based small molecule renin inhibitors are disclosed. Through high throughput screening, parallel synthesis, X-ray crystallography, and structure based drug design, we have developed the first non-chiral, non-peptidic, small molecular template to possess moderate potency against renin. The designed compounds consist of a novel 6-ethyl-5-(1,2,3,4-tetrahydroquinolin-7-yl)pyrimidine-2,4-diamine ring system that exhibit moderate potency (IC(50): 91-650 nM) against renin while remaining 'Rule-of-five' compliant.
公开了新型基于2,4-二氨基嘧啶的小分子肾素抑制剂。通过高通量筛选、平行合成、X射线晶体学和基于结构的药物设计，我们开发出了首个非手性、非肽类的小分子模板，其对肾素具有中等效力。所设计的化合物由新型6-乙基-5-(1,2,3,4-四氢喹啉-7-基)嘧啶-2,4-二胺环系组成，该环系对肾素表现出中等效力（IC(50)：91 - 650 nM），同时符合“五规则”。
