新型多靶向抗阿尔茨海默病先导物的优化、合成与活性评价

项目名称： 新型多靶向抗阿尔茨海默病先导物的优化、合成与活性评价

项目编号： No.21302228

项目类型： 青年科学基金项目

立项/批准年度： 2014

项目学科： 数理科学和化学

项目作者： 王冬梅

作者单位： 中国医学科学院药物研究所

项目金额： 25万元

中文摘要： 阿尔茨海默症(AD)是一种复杂的中枢神经系统退行性疾病，目前全球患者已超过3600万。临床上用于治疗AD的药物只有5个,均属于单靶点抑制剂。这类药物只能缓解AD的症状,不能从根本上改善疾病状态或终止疾病进程。"多靶点小分子"（MTDLs） 的设计策略已成为AD治疗药物研发的热点和趋势。本项目前期研究发现4个新结构类型的乙、丁酰胆碱酯酶双靶点抑制剂，其中DL0410兼具抑制Aβ聚集、阻断Aβ对神经血管单元的毒性作用，并能够提高AD小鼠的学习记忆能力。先导物DL0410具有自主知识产权，前期工作比较扎实。我们以DL0410为先导物，在前期初步构效关系基础上，利用药物化学原理及药物分子设计理论，设计了5个方案对其进行结构修饰，预计合成目标化合物60~80个，拟获得体外活性提高到纳摩尔级，体内活性更好，更具成药性的新型多靶点候选药物。

中文关键词： 多靶向药物设计；阿尔茨海默病；乙酰胆碱酯酶；丁酰胆碱酯酶；β-淀粉样蛋白

英文摘要： Alzheimer's disease (AD) is a complex neurodegenerative process occurring in the central nervous system. At present，it is estimated that over 36 million people suffer from the disease Worldwide. There are only 5 drugs approved for AD therapy as single-target inhibitors . They have limited efficacy and can only be employed to alleviate the symptomatic treatment of AD. However, they can not address AD's etiology or the neurodegeneration has not been prevented. Thus，multi-target-directed legands(MTDLs) raises as a potentially more effective strategy for search for improved drugs of AD. Base on our preliminary research, four lead compounds were found with dual inhibitory activities of both AChE and BuChE.Among them, the lead DL0410 can also inhibit the aggregation of Aβ, block Aβ toxic effects for the neurovascular unit and improve learning and memory ability in AD mice. Regarding DL0410 as the lead, five approaches of structural modification of DL0410 are designed applying the principles of Medicinal Chemistry and drug design theory on the basis of our pre-preliminary structure-activity relationship. About 60-80 compounds will be designed , synthesized and evaluated their inhibitory activity of acetylcholinesterase and butyrylcholinesterase and (or) Aβ aggregation using the MTDLs strategy. It will be helpful to

英文关键词： multi-target-directeddrugdesign；Alzheimer；acetylcholinesterase；butyrylcholinesterase；amyloid-β