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

文献类型：期刊论文

作者Xia, Guangxin1,2; You, Xiaodi1,2; Liu, Lin1,2; Liu, Haiyan2; Wang, Jianfa2; Shi, Yufang2; Li, Ping2; Xiong, Bing1; Liu, Xuejun2; Shen, Jingkang1,2
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2013-04
卷号62页码:1-10
关键词11 beta-HSD1 inhibitor Oxadiazole Bioisostere SAR Docking
ISSN号0223-5234
DOI10.1016/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.
WOS关键词METABOLIC SYNDROME ; TYPE-1 INHIBITOR ; 11-BETA-HSD1 INHIBITORS ; SELECTIVE INHIBITORS ; DISCOVERY ; POTENT ; MODULATION
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研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000318577500001
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
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.

入库方式： OAI收割

来源：上海药物研究所

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