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

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2015 May 26

PMID 26005536

Citations 6

Authors

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

Soon will be listed here.

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.

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