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


ABSTRACT: 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.

SUBMITTER: Sparks SM 

PROVIDER: S-EPMC6628572 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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

Sparks Steven M SM   Danger Dana P DP   Hoekstra William J WJ   Leesnitzer Tony T   Schotzinger Robert J RJ   Yates Christopher M CM   Becherer J David JD  

ACS medicinal chemistry letters 20190607 7


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 <  ...[more]

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