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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