Discovery and structure-activity relationships of ent-Kaurene diterpenoids as potent and selective 11 beta-HSD1 inhibitors: Potential impact in diabetes

	Discovery and structure-activity relationships of ent-Kaurene diterpenoids as potent and selective 11 beta-HSD1 inhibitors: Potential impact in diabetes
	Deng, Xu1 ; Shen, Yu 2; Yang, Jing1,2 ; He, Juan 1; Zhao, Yu 1; Peng, Li-Yan 1; Leng, Ying 2; Zhao, Qin-Shi1
通讯作者	Zhao, QS (reprint author), Chinese Acad Sci, Kunming Inst Bot, State Key Lab Phytochem & Plant Resources West Ch, Kunming 650204, Peoples R China. ; qinshizhao@mail.kib.ac.cn
	2013-07-01
发表期刊	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
ISSN	0223-5234
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
学科领域	Chemistry, Medicinal
收录类别	SCI ; IC
语种	英语
WOS记录号	WOS:000322850100039
引用统计
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
推荐引用方式 GB/T 7714	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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