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. 2019 Jun 7;10(7):1056-1060.
doi: 10.1021/acsmedchemlett.9b00152. eCollection 2019 Jul 11.

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

Steven M Sparks  1 , Dana P Danger  2 , William J Hoekstra  1 , Tony Leesnitzer  2 , Robert J Schotzinger  1 , Christopher M Yates  1 , J David Becherer  1
Affiliations

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

Steven M Sparks et al. ACS Med Chem Lett. .

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.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Indole and benzimidazole based CYP11B2 scaffolds.
Figure 2
Figure 2
Effects of compound 22 and LCI699 on plasma steroid response to ACTH administration in cynomolgus monkeys.
See this image and copyright information in PMC

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