苯甲脒类BACE1抑制剂的设计和合成

doi:10.5246/jcps.2012.02.015

苯甲脒类BACE1抑制剂的设计和合成

高海飞, 牛彦^*, 许凤荣, 梁磊, 周博, 李勇剑, 王超, 刘鹏, 徐萍^*

北京大学医学部药学院药物化学系, 北京 100191

收稿日期:2011-05-26 修回日期:2011-10-20 出版日期:2012-03-15 发布日期:2012-03-15
通讯作者: 牛彦*, 徐萍*

Design and synthesis of benzimidamides as potential BACE1 inhibitors

Hai-Fei Gao, Yan Niu^*, Feng-Rong Xu, Lei Liang, Bo Zhou, Yong-Jian Li, Chao Wang, Peng Liu, Ping Xu^*

Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China

Received:2011-05-26 Revised:2011-10-20 Online:2012-03-15 Published:2012-03-15
Contact: Yan Niu*, Ping Xu*

摘要/Abstract

摘要： 本文通过对已有小分子库进行虚拟筛选, 得到了可与BACE1活性中心Asp228、Asp32形成氢键作用的苯甲脒片段, 并在其基础上, 设计出了3-苯乙基苯甲脒类BACE1抑制剂。虽然活性测试结果显示这些化合物对BACE1的抑制活性较弱, 但是可以通过进一步的结构优化3-苯乙基苯甲脒类化合物来提高对BACE1的抑制活性。

关键词: 阿尔茨海默症, BACE1抑制剂, 计算机辅助药物设计, 苯甲脒

Abstract:

Computer aided fragment-based lead discovery has been successfully applied to the design of inhibitors of aspartyl protease enzyme β-secretase (BACE1). A benzimidamide fragment, which binds to the two catalytic aspartic acid residues in the active site of the enzyme, was selected as the starting compound. A novel series of 3-phenethylbenzimidamide inhibitors were designed and synthesized. Although biological evaluation results showed that the compounds displayed poor inhibitory activity towards BACE1, 3-phenethylbenzimidamide analogs might be modified as potential BACE1 inhibitors.

Key words: Alzheimer's disease, BACE1 inhibitors, CADD, Benzimidamide

中图分类号:

R916

Supporting: Foundation items: National Natural Science Foundation of China (Grant No. 21002002), Specialized Research Fund for the Doctoral Program of Higher Education of China (Grant No. 200800011057).
^*Corresponding author. Tel.: 86-10-82801505

高海飞, 牛彦^*, 许凤荣, 梁磊, 周博, 李勇剑, 王超, 刘鹏, 徐萍^*. 苯甲脒类BACE1抑制剂的设计和合成[J]. , DOI: 10.5246/jcps.2012.02.015.

Hai-Fei Gao, Yan Niu^*, Feng-Rong Xu, Lei Liang, Bo Zhou, Yong-Jian Li, Chao Wang, Peng Liu, Ping Xu^* . Design and synthesis of benzimidamides as potential BACE1 inhibitors[J]. , DOI: 10.5246/jcps.2012.02.015.

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