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Discovery of Novel, Potent Benzamide Inhibitors of 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) Exhibiting Oral Activity in an Enzyme Inhibition ex Vivo Model▽
Journal of Medicinal Chemistry2008Vol. 51(13), pp. 3953–3960
Citations Over TimeTop 10% of 2008 papers
Lisa D. Julian, Zhulun Wang, Tracy Bostick, Seb Caille, Rebekah Choi, Michael DeGraffenreid, Yongmei Di, Xiaodong He, Randall W. Hungate, Juan C. Jaén, Jinsong Liu, Mario Monshouwer, Dustin L. McMinn, Yosup Rew, Athena Sudom, Daqing Sun, Hua Tu, Stefania Ursu, Nigel P.C. Walker, Xuelei Yan, Qiuping Ye, Jay P. Powers
Abstract
We report the discovery of potent benzamide inhibitors of 11beta-hydroxysteroid dehydrogenase (11beta-HSD1). The optimization and correlation of in vitro and in vivo metabolic stability will be described. Through modifications to our initial lead 2, we discovered pyridyl compound 13. This compound has a favorable pharmacokinetic profile across three species and showed a dose-dependent decrease in adipose 11beta-HSD1 activity in a monkey ex vivo pharmacodynamic model.
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