Discovery of novel sulfonamides as potent and selective inhibitors against human and mouse 11 beta-hydroxysteroid dehydrogenase type 1
文献类型：期刊论文
| 作者 | Xia, Guangxin1,2; Liu, Lin1,2; Xue, Mengzhu1; Liu, Haiyan2; Yu, Jianxin2; Li, Ping2; Chen, Qian2; Xiong, Bing1 ; Liu, Xuejun2; Shen, Jingkang1,2
|
| 刊名 | MOLECULAR AND CELLULAR ENDOCRINOLOGY
 |
| 出版日期 | 2012-07-06 |
| 卷号 | 358期号:1页码:46-52 |
| 关键词 | 11 beta-HSD1 Inhibitor Sulfonamide Diabetes Docking |
| ISSN号 | 0303-7207 |
| DOI | 10.1016/j.mce.2012.02.017 |
| 文献子类 | Article |
| 英文摘要 | Several classes of non-steroid 11 beta-HSD1 inhibitors have been developed as promising treatments for Type 2 Diabetes (T2D). Using a human 11 beta-HSD1 selective inhibitor as a starting point, we designed and synthesized a new class of derivatives of 1-arylsulfonyl piperidine-3-carboxamides. It was found that the large lipophilic group on the amino moiety may lead to cross-species potency towards human and mouse, allowing drug development by evaluating compounds in rodent model. By exploring structure-activity-relationship, the (R)-(+)-bornylamine derivative is identified as the most potent inhibitor of mouse enzyme 11 beta-HSD1 with an IC50 of 18 nM. Docking studies revealed the different possible interaction modes of the S-enantiomer and R-enantiomer bound to h11 beta-HSD1, and explained why the S-enantiomer is more active than the R-enantiomer. Finally, two potent and isoform-selective compounds, (+)-isopinocampheylamine derivative 8m and (R)-(+)-bornylamine derivative 81, with suitable in vitro properties, could be selected for future PK/PD evaluation in rodent models. Then, 81 was subjected a pharmacodynamics study in vivo with rodent model. It was shown that 81 have 71% and 63% inhibition in adipose and liver tissue at 1 h after administration, but it was a short-acting compound displaying a significant drop in potency in the subsequent 3 h. This study not only provides compounds as novel h11 beta-HSD1 inhibitors, but also presents structure-activity relationships for designing potent human/mouse 11 beta-HSD1 inhibitors suitable for in vivo evaluation in rodent models. (c) 2012 Elsevier Ireland Ltd. All rights reserved. |
| WOS关键词 | 11-BETA-HSD1 INHIBITORS ; IDENTIFICATION ; DOCKING |
| 资助项目 | National Science and Technology Major Foundation of China[2010ZX09401-404] ; Shanghai Postdoctoral Sustentation Fund, China[07R214213] ; Chinese Academy of Sciences[KSCX2-EW-Q-3-01] |
| WOS研究方向 | Cell Biology ; Endocrinology & Metabolism |
| 语种 | 英语 |
| WOS记录号 | WOS:000304638800006 |
| 出版者 | ELSEVIER IRELAND LTD |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/278020]  |
| 专题 | 药物化学研究室 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 |
| 通讯作者 | Xiong, Bing |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 2.Shanghai Pharmaceut Holding Co Ltd, Cent Res Inst, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Xia, Guangxin,Liu, Lin,Xue, Mengzhu,et al. Discovery of novel sulfonamides as potent and selective inhibitors against human and mouse 11 beta-hydroxysteroid dehydrogenase type 1[J]. MOLECULAR AND CELLULAR ENDOCRINOLOGY,2012,358(1):46-52. |
| APA | Xia, Guangxin.,Liu, Lin.,Xue, Mengzhu.,Liu, Haiyan.,Yu, Jianxin.,...&Shen, Jingkang.(2012).Discovery of novel sulfonamides as potent and selective inhibitors against human and mouse 11 beta-hydroxysteroid dehydrogenase type 1.MOLECULAR AND CELLULAR ENDOCRINOLOGY,358(1),46-52. |
| MLA | Xia, Guangxin,et al."Discovery of novel sulfonamides as potent and selective inhibitors against human and mouse 11 beta-hydroxysteroid dehydrogenase type 1".MOLECULAR AND CELLULAR ENDOCRINOLOGY 358.1(2012):46-52. |
入库方式： OAI收割
来源：上海药物研究所
浏览0
下载0
收藏0
其他版本
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。