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Discovery of Triazole CYP11B2 Inhibitors with in Vivo Activity in Rhesus Monkeys.

ABSTRACT: Hit-to-lead efforts resulted in the discovery of compound 19, a potent CYP11B2 inhibitor that displays high selectivity vs related CYPs, good pharmacokinetic properties in rat and rhesus, and lead-like physical properties. In a rhesus pharmacodynamic model, compound 19 displays robust, dose-dependent aldosterone lowering efficacy, with no apparent effect on cortisol levels.

SUBMITTER: Hoyt SB

PROVIDER: S-EPMC4538427 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Discovery of Triazole CYP11B2 Inhibitors with in Vivo Activity in Rhesus Monkeys.

Hoyt Scott B SB Petrilli Whitney W London Clare C Liang Gui-Bai GB Tata Jim J Hu Qingzhong Q Yin Lina L van Koppen Chris J CJ Hartmann Rolf W RW Struthers Mary M Wisniewski Tom T Ren Ning N Bopp Charlene C Sok Andrea A Cai Tian-Quan TQ Stribling Sloan S Pai Lee-Yuh LY Ma Xiuying X Metzger Joe J Verras Andreas A McMasters Daniel D Chen Qing Q Tung Elaine E Tang Wei W Salituro Gino G Buist Nicole N Clemas Joe J Zhou Gaochao G Gibson Jack J Maxwell Carrie Ann CA Lassman Mike M McLaughlin Theresa T Castro-Perez Jose J Szeto Daphne D Forrest Gail G Hajdu Richard R Rosenbach Mark M Xiong Yusheng Y

ACS medicinal chemistry letters 20150717 8

Hit-to-lead efforts resulted in the discovery of compound 19, a potent CYP11B2 inhibitor that displays high selectivity vs related CYPs, good pharmacokinetic properties in rat and rhesus, and lead-like physical properties. In a rhesus pharmacodynamic model, compound 19 displays robust, dose-dependent aldosterone lowering efficacy, with no apparent effect on cortisol levels. ...[more]

PMID: 26288685

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