Discovery of novel dual functional agent as PPAR gamma agonist and 11 beta-HSD1 inhibitor for the treatment of diabetes
文献类型：期刊论文
| 作者 | Ye, Yang-liang2 ; Zhou, Zhou2; Zou, Han-jun2; Shen, Yu2; Xu, Ti-fei2; Tang, Jing2; Yin, Hua-zhong1; Chen, Min-li1; Leng, Ying2; Shen, Jian-hua2
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| 刊名 | BIOORGANIC & MEDICINAL CHEMISTRY
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| 出版日期 | 2009-08-01 |
| 卷号 | 17期号:15页码:5722-5732 |
| 关键词 | Type 2 diabetes PPAR gamma agonists 11 beta-HSD1 inhibitors Molecular modeling |
| ISSN号 | 0968-0896 |
| DOI | 10.1016/j.bmc.2009.05.082 |
| 文献子类 | Article |
| 英文摘要 | PPAR gamma and 11 beta-HSD1 are attractive therapeutic targets for type 2 diabetes. However, PPAR gamma agonists induce adipogenesis, which causes the side effect of weight gain, whereas 11 beta-HSD1 inhibitors prevent adipogenesis and may be beneficial for the treatment of obesity in diabetic patients. For the first time, we designed, synthesized a series of alpha-aryloxy-alpha-methylhydrocinnamic acids as dual functional agents which activate PPAR gamma and inhibit 11 beta-HSD1 simultaneously. The compound 11e exhibited the most potent inhibitory activity compared to that of the lead compound 2, with PPAR gamma (EC50 = 6.76 mu M) and 11 beta-HSD1 (IC50 = 0.76 mu M) in vitro. Molecular modeling study for compound 11e was also presented. Compound 11e showed excellent efficacy for lowering glucose, triglycerides, body fat, in well established mice and rats models of diabetes and obesity and had a favorable ADME profile. (C) 2009 Elsevier Ltd. All rights reserved. |
| WOS关键词 | 11-BETA-HYDROXYSTEROID DEHYDROGENASE TYPE-1 ; ACTIVATED-RECEPTOR-GAMMA ; ANTIDIABETIC THIAZOLIDINEDIONE ; 3T3-L1 ADIPOGENESIS ; INSULIN ; POTENT ; OBESITY ; DESIGN ; GLUCOCORTICOIDS ; DIFFERENTIATION |
| 资助项目 | National Natural Science Foundation of China[30623008] ; National Basic Research Program of China[2009CB522300] ; Shanghai Rising-Star Foundation[08QH14028] ; Shanghai Science and Technology Commission[064319015] |
| WOS研究方向 | Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:000268099700042 |
| 出版者 | PERGAMON-ELSEVIER SCIENCE LTD |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/279168]  |
| 专题 | 药理学第一研究室 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 药物发现与设计中心 |
| 通讯作者 | Chen, Min-li |
| 作者单位 | 1.Zhejiang Chinese Med Univ, Hangzhou 310053, Zhejiang, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Ye, Yang-liang,Zhou, Zhou,Zou, Han-jun,et al. Discovery of novel dual functional agent as PPAR gamma agonist and 11 beta-HSD1 inhibitor for the treatment of diabetes[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2009,17(15):5722-5732. |
| APA | Ye, Yang-liang.,Zhou, Zhou.,Zou, Han-jun.,Shen, Yu.,Xu, Ti-fei.,...&Shen, Jian-hua.(2009).Discovery of novel dual functional agent as PPAR gamma agonist and 11 beta-HSD1 inhibitor for the treatment of diabetes.BIOORGANIC & MEDICINAL CHEMISTRY,17(15),5722-5732. |
| MLA | Ye, Yang-liang,et al."Discovery of novel dual functional agent as PPAR gamma agonist and 11 beta-HSD1 inhibitor for the treatment of diabetes".BIOORGANIC & MEDICINAL CHEMISTRY 17.15(2009):5722-5732. |
入库方式： OAI收割
来源：上海药物研究所
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