title: Design and synthesis of (R)-1-arylsulfonylpiperidine-2-carboxamides as 11β-hydroxysteroid dehydrogenase type 1 inhibitors.
abstract: 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.
authors.affiliation: Central Research Institute, Shanghai Pharmaceutical Holding Co. Ltd. 898 Ha Lei Rd., Zhangjiang Hi-Tech Park, Shanghai 201203, China.
authors.forename: Guangxin
authors.initials: G
authors.lastname: Xia
authors.forename: Lin
authors.initials: L
authors.lastname: Liu
authors.forename: Haiyan
authors.initials: H
authors.lastname: Liu
authors.forename: Jianxin
authors.initials: J
authors.lastname: Yu
authors.forename: Zhenmin
authors.initials: Z
authors.lastname: Xu
authors.forename: Qian
authors.initials: Q
authors.lastname: Chen
authors.forename: Chen
authors.initials: C
authors.lastname: Ma
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.forename: Bing
authors.initials: B
authors.lastname: Xiong
authors.forename: Xuejun
authors.initials: X
authors.lastname: Liu
authors.forename: Jingkang
authors.initials: J
authors.lastname: Shen
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D000818:Animals; D001665:Binding Sites; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D006207:Half-Life; D006801:Humans; D007536:Isomerism; D051379:Mice; D062105:Molecular Docking Simulation; D010880:Piperidines / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D004791:Enzyme Inhibitors; D010880:Piperidines; C032727:piperidine; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1