Design, synthesis and SAR of piperidyl-oxadiazoles as 11β-hydroxysteroid dehydrogenase 1 inhibitors.
The potential roles of 11β-HSD1 inhibitors in metabolic syndrome, T2D and obesity were well established and currently several classes of 11β-HSD1 inhibitors have been developed as promising agents against metabolic diseases. To find potent compounds with good pharmacokinetics, we used the bioisosterism approach, and designed the compound 2 and 3 bearing an 1,2,4-oxadiazole ring to replace the amide group in compound 1. Guided by docking study, we then transformed compound 3 into a potent lead compound 4a by changing sulfonamide group to amide. To elaborate this series of piperidyl-oxadiazole derivatives as human 11β-HSD1 inhibitors, we explored the structure-activity relationship of several parts of the lead compound. Based on their potency toward human 11β-HSD1 two compounds 4h and 4q were advanced to pharmacokinetic study. It was found that 4h and 4q are potent and selective human 11β-HSD1 inhibitors with better pharmacokinetic properties than those of the original piperidine-3-carboxamide compound 1, and suitable for further in vivo preclinical study in primate model.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China.
Guangxin
G
Xia
Xiaodi
X
You
Lin
L
Liu
Haiyan
H
Liu
Jianfa
J
Wang
Yufang
Y
Shi
Ping
P
Li
Bing
B
Xiong
Xuejun
X
Liu
Jingkang
J
Shen
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D010880:Piperidines; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1