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Biphenyl/diphenyl ether renin inhibitors: filling the S1 pocket of renin via the S3 pocket |
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| Authors: | Yuan Jing Simpson Robert D Zhao Wei Tice Colin M Xu Zhenrong Cacatian Salvacion Jia Lanqi Flaherty Patrick T Guo Joan Ishchenko Alexey Wu Zhongren McKeever Brian M Scott Boyd B Bukhtiyarov Yuri Berbaum Jennifer Panemangalore Reshma Bentley Ross Doe Christopher P Harrison Richard K McGeehan Gerard M Singh Suresh B Dillard Lawrence W Baldwin John J Claremon David A |
| Affiliation: | a Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, PA 19034, USA b GlaxoSmithKline, 709 Swedeland Road, King of Prussia, PA 19406, USA |
| Abstract: | 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. |
| Keywords: | Renin inhibitors Hypertension Biphenyl Diphenyl ether Structure-based design X-ray crystallography |
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