Design, synthesis and SAR of piperidyl-oxadiazoles as 11 beta-hydroxysteroid dehydrogenase 1 inhibitors

doi:10.1016/j.ejmech.2012.12.059

	Design, synthesis and SAR of piperidyl-oxadiazoles as 11 beta-hydroxysteroid dehydrogenase 1 inhibitors
	Xia, Guangxin 1,2; You, Xiaodi 1,2; Liu, Lin 1,2; Liu, Haiyan 2; Wang, Jianfa 2; Shi, Yufang 2; Li, Ping 2; Xiong, Bing1 ; Liu, Xuejun 2; Shen, Jingkang 1,2
刊名	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
	2013-04
卷号	62 页码:1-10
关键词	11 beta-HSD1 inhibitor Oxadiazole Bioisostere SAR Docking
ISSN号	0223-5234
DOI	10.1016/j.ejmech.2012.12.059
文献子类	Article
英文摘要	The potential roles of 11 beta-HSD1 inhibitors in metabolic syndrome, T2D and obesity were well established and currently several classes of 11 beta-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 11 beta-HSD1 inhibitors, we explored the structure activity relationship of several parts of the lead compound. Based on their potency toward human 11 beta-HSD1 two compounds 4h and 4q were advanced to pharmacokinetic study. It was found that 4h and 4q are potent and selective human 11 beta-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. (C) 2013 Elsevier Masson SAS. All rights reserved.
资助项目	New Drug Creation Project of the National Science and Technology Major Foundation of China[2010ZX09401-404] ; Shanghai Postdoctoral Sustentation Fund, China[07R214213] ; Chinese Academy of Sciences[KSCX2-EW-Q-3-01]
WOS关键词	METABOLIC SYNDROME ; TYPE-1 INHIBITOR ; 11-BETA-HSD1 INHIBITORS ; SELECTIVE INHIBITORS ; DISCOVERY ; POTENT ; MODULATION
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
WOS记录号	WOS:000318577500001
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/277665]
专题	药物化学研究室中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Xiong, Bing
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 2.Shanghai Pharmaceut Holding Co Ltd, Cent Res Inst, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Xia, Guangxin,You, Xiaodi,Liu, Lin,et al. Design, synthesis and SAR of piperidyl-oxadiazoles as 11 beta-hydroxysteroid dehydrogenase 1 inhibitors[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2013,62:1-10.
APA	Xia, Guangxin.,You, Xiaodi.,Liu, Lin.,Liu, Haiyan.,Wang, Jianfa.,...&Shen, Jingkang.(2013).Design, synthesis and SAR of piperidyl-oxadiazoles as 11 beta-hydroxysteroid dehydrogenase 1 inhibitors.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,62,1-10.
MLA	Xia, Guangxin,et al."Design, synthesis and SAR of piperidyl-oxadiazoles as 11 beta-hydroxysteroid dehydrogenase 1 inhibitors".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 62(2013):1-10.