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题名: Discovery and structure-activity relationships of ent-Kaurene diterpenoids as potent and selective 11 beta-HSD1 inhibitors: Potential impact in diabetes
作者: Deng, Xu1; Shen, Yu2; Yang, Jing1, 2; He, Juan1; Zhao, Yu1; Peng, Li-Yan1; Leng, Ying2; null(赵勤实)1
刊名: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
关键词: ent-Kaurene diterpenoids ; Structure-activity relationship studies ; Selective 11 beta-HSD1 inhibitors ; Urea derivatives ; Diabetes
英文摘要: 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.
出版日期: 2013-07-01
卷号: 65, 页码:403-414
语种: 英语
收录类别: SCI ; IC
学科分类: Chemistry, Medicinal
ISSN号: 0223-5234
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.kib.ac.cn/handle/151853/16751
Appears in Collections:植物化学与西部植物资源持续利用国家重点实验室_期刊论文

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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

Recommended Citation:
Deng, Xu; Shen, Yu; Yang, Jing; He, Juan; Zhao, Yu; Peng, Li-Yan; Leng, Ying; Zhao, Qin-Shi.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,2013,65():403-414
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