Discovery and structure-activity relationships of ent-Kaurene diterpenoids as potent and selective 11 beta-HSD1 inhibitors: Potential impact in diabetes
Deng, Xu1; Shen, Yu2; Yang, Jing1,2; He, Juan1; Zhao, Yu1; Peng, Li-Yan1; Leng, Ying2; Zhao, Qin-Shi1
2013-07-01
发表期刊EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
ISSN0223-5234
卷号65页码:403-414
摘要The biological screening of a collection of nature occurring diterpenoids against 11 beta-HSD1 resulted in the discovery of the lead compound 1b, which pointed to the therapeutic potential for type 2 diabetes. Subsequently, an optimization project was initiated. Starting from compound 1b and its counterpart 2, the hemi-synthesis was performed on kaurenic acid scaffolds yielding 36 derivatives. Further evaluations on both human and mouse 11 beta-HSD revealed that seven urea derivatives exhibited significant improved potency and selectivity. Especially, the urea 19a has an IC50 (human 11 beta-HSD1) = 9.4 nM and selectivity index (human 11 beta-HSD) > 10,649. The 2D and 3D binding models of the complex 19a/11 beta-HSD1 were generated using docking simulations. Based on the results, the structural activity relationships (SARs) of compounds 1b and 2 were also discussed. (C) 2013 Elsevier Masson SAS. All rights reserved.
关键词Ent-kaurene Diterpenoids Structure-activity Relationship Studies Selective 11 Beta-hsd1 Inhibitors Urea Derivatives Diabetes
资助信息National Natural Science Foundation of China [U0932602, 2011CB915503, 90813004, 2009CB522300]
学科领域Chemistry, Medicinal
收录类别SCI ; IC
语种英语
WOS研究方向Pharmacology & Pharmacy
WOS类目Chemistry, Medicinal
WOS记录号WOS:000322850100039
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被引频次:14[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.kib.ac.cn/handle/151853/16751
专题植物化学与西部植物资源持续利用国家重点实验室
作者单位1.Chinese Acad Sci, Kunming Inst Bot, State Key Lab Phytochem & Plant Resources West Ch, Kunming 650204, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
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Deng, Xu,Shen, Yu,Yang, Jing,et al. Discovery and structure-activity relationships of ent-Kaurene diterpenoids as potent and selective 11 beta-HSD1 inhibitors: Potential impact in diabetes[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2013,65:403-414.
APA Deng, Xu.,Shen, Yu.,Yang, Jing.,He, Juan.,Zhao, Yu.,...&Zhao, Qin-Shi.(2013).Discovery and structure-activity relationships of ent-Kaurene diterpenoids as potent and selective 11 beta-HSD1 inhibitors: Potential impact in diabetes.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,65,403-414.
MLA Deng, Xu,et al."Discovery and structure-activity relationships of ent-Kaurene diterpenoids as potent and selective 11 beta-HSD1 inhibitors: Potential impact in diabetes".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 65(2013):403-414.
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