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Discovery of LFF269, a Cortisol-Sparing CYP11B2 Inhibitor that Lowers Aldosterone in Human Subjects

lou, changgang and Singh, Alok and Adams, Christopher and Ksander, Gary and Beil, Michael and Leung-Chu, Jennifer and Fu, Fumin and Gan, Lu and Hu, Chii-Whei and Jeng, Arco and Lasala, Daniel and Liang, Guiqing and Rigel, Dean and Russell, Kerry and Vest, John and Watson, Catherine (2015) Discovery of LFF269, a Cortisol-Sparing CYP11B2 Inhibitor that Lowers Aldosterone in Human Subjects. Journal of Medicinal Chemistry, 58 (23). pp. 9382-9394. ISSN 0022-26231520-4804

Abstract

Human clinical studies conducted with LCI699 established aldosterone synthase (CYP11B2) inhibition as a promising novel mechanism to lower arterial blood pressure. However, LCI699’s low CYP11B1/CYP11B2 selectivity resulted in blunting of adrenocorticotropic hormone-stimulated cortisol secretion. This property of LCI699 prompted its development in Cushing’s disease, but limited more extensive clinical studies in hypertensive populations, and provided an impetus for the search for cortisol-sparing CYP11B2 inhibitors. This paper summarizes the discovery, pharmacokinetics, and pharmacodynamics data in pre-clinical species and human subjects of the selective CYP11B2 inhibitor LFF269 (8).

Item Type: Article
Date Deposited: 12 Aug 2016 00:45
Last Modified: 12 Aug 2016 00:45
URI: https://oak.novartis.com/id/eprint/26995

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