1. Biphenyl/diphenyl ether renin inhibitors: filling the S1 pocket of renin via the S3 pocket
- Author
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Lanqi Jia, Ross Bentley, Patrick T. Flaherty, Ishchenko Alexey, Colin M. Tice, Reshma Panemangalore, Gerard McGeehan, Richard K. Harrison, Robert D. Simpson, Salvacion Cacatian, Christopher P. Doe, Yuri Bukhtiyarov, Wei Zhao, Jennifer Berbaum, Jing Yuan, Lawrence W. Dillard, Brian M. McKeever, Zhenrong Xu, Joan Guo, Boyd B. Scott, David A. Claremon, Zhongren Wu, Baldwin John J, and Suresh B. Singh
- Subjects
Models, Molecular ,Stereochemistry ,Clinical Biochemistry ,Molecular Conformation ,Pharmaceutical Science ,Biological Availability ,Ring (chemistry) ,Crystallography, X-Ray ,Biochemistry ,chemistry.chemical_compound ,Structure-Activity Relationship ,Renin–angiotensin system ,Drug Discovery ,Renin ,Potency ,Animals ,Cytochrome P-450 CYP3A ,Humans ,Enzyme Inhibitors ,Molecular Biology ,Antihypertensive Agents ,Biphenyl ,CYP3A4 ,Dose-Response Relationship, Drug ,Phenyl Ethers ,Organic Chemistry ,Diphenyl ether ,Stereoisomerism ,Recombinant Proteins ,Bioavailability ,Rats ,Disease Models, Animal ,chemistry ,Hypertension ,Molecular Medicine ,Cytochrome P-450 CYP3A Inhibitors ,Rats, Transgenic ,Selectivity - 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.
- Published
- 2011