Development of Highly Selective Pyrimidine-Based Aldosterone Synthase (CYP11B2) Inhibitors

Excess aldosterone production and signaling are primary contributors to numerous cardiovascular disorders including primary aldosteronism and resistant hypertension. Recently, inhibition of aldosterone synthesis via the enzyme aldosterone synthase (CYP11B2) has been pursued to ameliorate the negativ...

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Published in:ACS medicinal chemistry letters 2019-07, Vol.10 (7), p.1056-1060
Main Authors: Sparks, Steven M, Danger, Dana P, Hoekstra, William J, Leesnitzer, Tony, Schotzinger, Robert J, Yates, Christopher M, Becherer, J. David
Format: Article
Language:English
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Letter
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Summary:Excess aldosterone production and signaling are primary contributors to numerous cardiovascular disorders including primary aldosteronism and resistant hypertension. Recently, inhibition of aldosterone synthesis via the enzyme aldosterone synthase (CYP11B2) has been pursued to ameliorate the negative effects of elevated aldosterone. Herein, we report the development of aldosterone synthase inhibitors using a pyrimidine-based metal binding group leading to the highly selective CYP11B2 inhibitor 22. Superior selectivity combined with robust pharmacokinetics afforded highly selective in vivo aldosterone suppression in a monkey model of adrenal steroidogenesis, demonstrating the potential for selective aldosterone lowering in humans with pyrimidine 22.
ISSN:1948-5875
1948-5875
DOI:10.1021/acsmedchemlett.9b00152