Discovery of Novel, Potent Benzamide Inhibitors of 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) Exhibiting Oral Activity in an Enzyme Inhibition ex Vivo Model
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- 作者：Lisa D. Julian ; Zhulun Wang ; Tracy Bostick ; Seb Caille ; Rebekah Choi ; Michael DeGraffenreid ; Yongmei Di ; Xiao He ; Randall W. Hungate ; Juan C. Jaen ; Jinsong Liu ; Mario Monshouwer ; Dustin McMinn ; Yosup
- 刊名：Journal of Medicinal Chemistry
- 出版年：2008
- 出版时间：July 10, 2008
- 年：2008
- 卷：51
- 期：13
- 页码：3953 - 3960
- 全文大小：439K
- 年卷期：v.51,no.13(July 10, 2008)
- ISSN：1520-4804
文摘
We report the discovery of potent benzamide inhibitors of 11β-hydroxysteroid dehydrogenase (11β-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 11β-HSD1 activity in a monkey ex vivo pharmacodynamic model.