Design and Synthesis of (R)‐1‐Arylsulfonylpiperidine‐2‐carboxamides as 11β‐Hydroxysteroid Dehydrogenase Type 1 Inhibitors

• DOI: 10.1002/cmdc.201300022
• Publication Date: 2013-03-07T20:08:04Z
• Authors: Guangxin Xia; Lin Liu; Haiyan Liu; Jianxin Yu; Zhenmin Xu; Qian Chen; Chen Ma; Ping Li; Bing Xiong; Xuejun Liu; Jingkang Shen
• Keywords: 0301 basic medicine; Binding Sites; Amides; Protein Structure, Tertiary; 3. Good health; Molecular Docking Simulation; Mice; Structure-Activity Relationship; 03 medical and health sciences; Isomerism; Piperidines; Drug Design; 11-beta-Hydroxysteroid Dehydrogenase Type 1; Animals; Humans; Enzyme Inhibitors; Half-Life

R adamantly beats S: 11β-HSD1 is a target for treating metabolic syndrome. The R isomer 5 was selected as a starting point for optimization and SAR studies. Inhibitor 8 w emerged after several rounds of optimization, showing cross-species inhibition of human and mouse 11β-HSD1. It also displays a good DMPK profile in vitro, and was advanced to PK/PD evaluations in vivo. The results confirmed its dose-dependent activity in mice.