1. Discovery of indazole aldosterone synthase (CYP11B2) inhibitors as potential treatments for hypertension
- Author
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Joe Clemas, Jerry Andrew Taylor, Feroze Ujjainwalla, Jim Tata, Doris F. Cully, Tom Wisniewski, Wei Tang, Charlene Bopp, Clare London, Andreas Verras, Scott B. Hoyt, Andrea Sok, Elaine Tung, Douglas J. MacNeil, Gaochao Zhou, Amjad Ali, Qing Chen, Gino Salituro, Yusheng Xiong, Daniel R. McMasters, Mary Struthers, Ning Ren, and Ruth A. Duffy
- Subjects
Male ,0301 basic medicine ,Aldosterone synthase ,Indazoles ,Clinical Biochemistry ,High selectivity ,Pharmaceutical Science ,Pharmacology ,01 natural sciences ,Biochemistry ,Cell Line ,Rats, Sprague-Dawley ,03 medical and health sciences ,chemistry.chemical_compound ,Cricetulus ,Pharmacokinetics ,Cytochrome P-450 CYP2D6 Inhibitors ,Drug Discovery ,Animals ,Cytochrome P-450 CYP11B2 ,Humans ,Molecular Biology ,Antihypertensive Agents ,Indazole ,biology ,Aromatase Inhibitors ,Chemistry ,Organic Chemistry ,Stereoisomerism ,Hit to lead ,Macaca mulatta ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,030104 developmental biology ,Hypertension ,biology.protein ,Steroid 11-beta-Hydroxylase ,Molecular Medicine - Abstract
We report the discovery and hit-to-lead optimization of a structurally novel indazole series of CYP11B2 inhibitors. Benchmark compound 34 from this series displays potent inhibition of CYP11B2, high selectivity versus related steroidal and hepatic CYP targets, and lead-like physical and pharmacokinetic properties. On the basis of these and other data, the indazole series was progressed to lead optimization for further refinement.
- Published
- 2017