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

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.

SUBMITTER: Hoyt SB 

PROVIDER: S-EPMC4434468 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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

Hoyt Scott B SB   Park Min K MK   London Clare C   Xiong Yusheng Y   Tata Jim J   Bennett D Jonathan DJ   Cooke Andrew A   Cai Jiaqiang J   Carswell Emma E   Robinson John J   MacLean John J   Brown Lindsay L   Belshaw Simone S   Clarkson Thomas R TR   Liu Kun K   Liang Gui-Bai GB   Struthers Mary M   Cully Doris D   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   Kuethe Jeff J   Rivera Nelo 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   Ali Amjad A  

ACS medicinal chemistry letters 20150407 5

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. ...[more]

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