Discovery of potent beta-secretase (bace-1) inhibitors by the synthesis of isophthalamide-containing hybrids
文献类型：期刊论文
| 作者 | Zhu, Yi-ping1; Xiao, Kun1; Yu, Hai-ping2; Ma, Lan-ping1 ; Xiong, Bing1; Zhang, Hai-yan1; Wang, Xin1; Li, Jing-ya2; Li, Jia2; Shen, Jing-kang1
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| 刊名 | ACTA PHARMACOLOGICA SINICA
 |
| 出版日期 | 2009-02 |
| 卷号 | 30期号:2页码:259-269 |
| 关键词 | aspartyl protease beta-secretase hydroxyethylene solid phase biological evaluation molecular modeling |
| ISSN号 | 1671-4083 |
| DOI | 10.1038/aps.2008.26 |
| 文献子类 | Article |
| 英文摘要 | Aim: The aim of this study was to design and synthesize a series of high activity compounds against aspartyl protease beta-secretase (BACE-1) bearing hydroxyethylene (HE) framework. Methods: First, we designed the small library based on our previous work and rational analysis. Subsequently, thirteen compounds were selected and synthesized using skilled solid phase synthetic methods to explore the relationship between structure and activity. We then used molecular modeling to explain the possible binding mode. Results: Thirteen new compounds (6-18) have been designed, synthesized and bioassayed. Their structures were determined by nuclear magnetic resonance (NMR) spectra, low-and high-resolution mass spectra and optical rotation. Most compounds have shown moderate to excellent activities, and compound 10, which contains fewer amino acids and amide bonds than GRL-7234, was about 5-fold more potent than the control compound 4 discovered by Merck. The molecular modeling results have indicated the possible binding mode and explained the difference between compounds 10 and 16, providing direction for further study. Conclusion: This study yielded several high activity compounds bearing fewer amino acids and amide bonds than previous compounds, providing insight into the further development of potent BACE-1 inhibitors for the treatment of Alzheimer's disease. |
| WOS关键词 | STRUCTURE-BASED DESIGN ; ALZHEIMERS-DISEASE ; PEPTIDOMIMETIC INHIBITORS ; GENERATION ; DRUGS |
| 资助项目 | National Natural Science Foundation of China[30672538] |
| WOS研究方向 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| CSCD记录号 | CSCD:3628625 |
| WOS记录号 | WOS:000263416100015 |
| 出版者 | ACTA PHARMACOLOGICA SINICA |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/279323]  |
| 专题 | 国家新药筛选中心 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 药理学第二研究室 药物化学研究室 |
| 通讯作者 | Li, Jia |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 2.Natl Ctr Drug Screening, Shanghai 201203, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Zhu, Yi-ping,Xiao, Kun,Yu, Hai-ping,et al. Discovery of potent beta-secretase (bace-1) inhibitors by the synthesis of isophthalamide-containing hybrids[J]. ACTA PHARMACOLOGICA SINICA,2009,30(2):259-269. |
| APA | Zhu, Yi-ping.,Xiao, Kun.,Yu, Hai-ping.,Ma, Lan-ping.,Xiong, Bing.,...&Shen, Jing-kang.(2009).Discovery of potent beta-secretase (bace-1) inhibitors by the synthesis of isophthalamide-containing hybrids.ACTA PHARMACOLOGICA SINICA,30(2),259-269. |
| MLA | Zhu, Yi-ping,et al."Discovery of potent beta-secretase (bace-1) inhibitors by the synthesis of isophthalamide-containing hybrids".ACTA PHARMACOLOGICA SINICA 30.2(2009):259-269. |
入库方式： OAI收割
来源：上海药物研究所
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