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

Scott B Hoyt,Min K Park, Carla London, Yonghua Xiong,James R Tata, David J Bennett,Andrew Cooke, Jinlei Cai,Emma Carswell,John R C Robinson,John K Maclean, Lew Auteur Ou Responsable Intellectuel Brown, Simone Belshaw, T R Clarkson,Kun Liu, G B Liang,Mary Struthers,Doris F Cully,Thomas Wisniewski, Nan Ren, C Bopp, A Sok,T Q Cai,Sloan Stribling, L Y Pai, Xinliang Ma, J M Metzger,Andreas Verras,D Mcmasters,Q Chen, E Tung,Wei Tang,Gino M Salituro,N Buist,Jeffrey T Kuethe, N Rivera, Joseph Clemas,Gang Zhou, J P Gibson, Charleen Maxwell,Michael E Lassman, Theresa M Mclaughlin,Jose Castroperez,Daphne Szeto, George Auteur Ou Responsable Intellectuel Forrest,Richard Hajdu, Mark J Rosenbach, Anmar Ali

ACS medicinal chemistry letters（2015）

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摘要

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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关键词

CYP11B2,aldosterone synthase,hypertension

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