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

  • ACS Med Chem Lett. 2015 Apr 7;6(5):573-8. doi: 10.1021/acsmedchemlett.5b00054.
Scott B Hoyt  1 Min K Park  1 Clare London  1 Yusheng Xiong  1 Jim Tata  1 D Jonathan Bennett  2 Andrew Cooke  2 Jiaqiang Cai  2 Emma Carswell  2 John Robinson  2 John MacLean  2 Lindsay Brown  2 Simone Belshaw  2 Thomas R Clarkson  2 Kun Liu  1 Gui-Bai Liang  1 Mary Struthers  1 Doris Cully  1 Tom Wisniewski  1 Ning Ren  1 Charlene Bopp  1 Andrea Sok  1 Tian-Quan Cai  1 Sloan Stribling  1 Lee-Yuh Pai  1 Xiuying Ma  1 Joe Metzger  1 Andreas Verras  1 Daniel McMasters  1 Qing Chen  1 Elaine Tung  1 Wei Tang  1 Gino Salituro  1 Nicole Buist  1 Jeff Kuethe  1 Nelo Rivera  1 Joe Clemas  1 Gaochao Zhou  1 Jack Gibson  1 Carrie Ann Maxwell  1 Mike Lassman  1 Theresa McLaughlin  1 Jose Castro-Perez  1 Daphne Szeto  1 Gail Forrest  1 Richard Hajdu  1 Mark Rosenbach  1 Amjad Ali  1
Affiliations
  • 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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