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ACS Med Chem Lett. 2015 Apr 07;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.

ACS medicinal chemistry letters

Scott B Hoyt, Min K Park, Clare London, Yusheng Xiong, Jim Tata, D Jonathan Bennett, Andrew Cooke, Jiaqiang Cai, Emma Carswell, John Robinson, John MacLean, Lindsay Brown, Simone Belshaw, Thomas R Clarkson, Kun Liu, Gui-Bai Liang, Mary Struthers, Doris Cully, Tom Wisniewski, Ning Ren, Charlene Bopp, Andrea Sok, Tian-Quan Cai, Sloan Stribling, Lee-Yuh Pai, Xiuying Ma, Joe Metzger, Andreas Verras, Daniel McMasters, Qing Chen, Elaine Tung, Wei Tang, Gino Salituro, Nicole Buist, Jeff Kuethe, Nelo Rivera, Joe Clemas, Gaochao Zhou, Jack Gibson, Carrie Ann Maxwell, Mike Lassman, Theresa McLaughlin, Jose Castro-Perez, Daphne Szeto, Gail Forrest, Richard Hajdu, Mark Rosenbach, Amjad Ali

Affiliations

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

PMID: 26005536 PMCID: PMC4434468 DOI: 10.1021/acsmedchemlett.5b00054

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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