Discovery and structure-activity relationships of ent-Kaurene diterpenoids as potent and selective 11 beta-HSD1 inhibitors: Potential impact in diabetes
文献类型：期刊论文
| 作者 | Deng, Xu1; Shen, Yu2; Yang, Jing1,2; He, Juan1; Zhao, Yu1; Peng, Li-Yan1; Leng, Ying2 ; Zhao, Qin-Shi1
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| 刊名 | EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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| 出版日期 | 2013-07 |
| 卷号 | 65页码:403-414 |
| 关键词 | ent-Kaurene diterpenoids Structure-activity relationship studies Selective 11 beta-HSD1 inhibitors Urea derivatives Diabetes |
| ISSN号 | 0223-5234 |
| DOI | 10.1016/j.ejmech.2013.05.010 |
| 文献子类 | Article |
| 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. |
| WOS关键词 | 11-BETA-HYDROXYSTEROID DEHYDROGENASE TYPE-1 ; THERAPEUTIC TARGET ; ACCURATE DOCKING ; IDENTIFICATION ; HYPERTENSION ; ACTIVATION ; OBESITY ; GLIDE ; ACIDS |
| 资助项目 | National Natural Science Foundation of China[U0932602] ; National Natural Science Foundation of China[2011CB915503] ; National Natural Science Foundation of China[90813004] ; National Natural Science Foundation of China[2009CB522300] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000322850100039 |
| 出版者 | ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/277550]  |
| 专题 | 药理学第一研究室 |
| 通讯作者 | Zhao, Qin-Shi |
| 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. |
入库方式： OAI收割
来源：上海药物研究所
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