Design and synthesis of benzimidamides as potential BACE1 inhibitors  

苯甲脒类BACE1抑制剂的设计和合成(英文)

作　　者：高海飞[1] 牛彦[1] 许凤荣[1] 梁磊[1] 周博[1] 李勇剑[1] 王超[1] 刘鹏[1] 徐萍[1] 

机构地区：[1]北京大学医学部药学院药物化学系,北京100191

出　　处：《Journal of Chinese Pharmaceutical Sciences》2012年第2期124-131,共8页中国药学（英文版）

基　　金：National Natural Science Foundation of China(Grant No. 21002002);Specialized Research Fund for the Doctoral Program of Higher Education of China (Grant No. 200800011057)

摘　　要：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.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：Alzheimer＇s disease BACE1 inhibitors CADD Benzimidamide 

分 类 号：R914[医药卫生—药物化学]