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ACS Med Chem Lett. 2015 Apr 7;6(5):573-8. doi: 10.1021/acsmedchemlett.5b00054. eCollection 2015 May 14.

Discovery of Benzimidazole CYP11B2 Inhibitors with in Vivo Activity in Rhesus Monkeys.

Author information

1
Merck Research Laboratories , Rahway, New Jersey 07065, United States.
2
Merck Research Laboratories , Newhouse, Lanarkshire ML1 5SH, United Kingdom.

Abstract

We report the discovery of a benzimidazole series of CYP11B2 inhibitors. Hit-to-lead and lead optimization studies identified compounds such as 32, which displays potent CYP11B2 inhibition, high selectivity versus related CYP targets, and good pharmacokinetic properties in rat and rhesus. In a rhesus pharmacodynamic model, 32 produces dose-dependent aldosterone lowering efficacy, with no apparent effect on cortisol levels.

KEYWORDS:

CYP11B2; aldosterone synthase; hypertension

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