1. Academic Validation
  2. Discovery of Benzimidazole CYP11B2 Inhibitors with in Vivo Activity in Rhesus Monkeys

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

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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