苯氨甲酸酯类AChE抑制剂的设计、合成和双重作用研究

项目名称： 苯氨甲酸酯类AChE抑制剂的设计、合成和双重作用研究

项目编号： No.30801435

项目类型： 青年科学基金项目

立项/批准年度： 2009

项目学科： 轻工业、手工业

项目作者： 谢琼

作者单位： 复旦大学

项目金额： 19万元

中文摘要： 乙酰胆碱酯酶（AChE）、β#28096;粉样肽（Aβ#65289;和Aβ#21069;体蛋白（APP）是阿尔茨海默症治疗的主要靶点。具AChE和APP/Aβ#21452;重抑制作用的苯氨甲酸酯类化合物具有良好的研究前景。本研究中，我们设计和合成了XQ528取代苯氨甲酸酯衍生物和XQ528结构简化物，AChE/BChE抑制活性测试表明，4-甲基苯氨甲酸(-)-美普他酚酯9和四氢异喹啉类苯氨甲酸酯QQ609是强效AChE抑制剂；构效关系研究表明，苯氨甲酰基苯环4-位小体积的供电子基取代对活性最有利；药效团模型比对结果显示，结构简化系列物与苯环相连的α30899;原子上取代有甲基时，有利于AChE抑制活性的提高。研究发现，XQ528能有效降低APP和Aβ2，但对sAPPα12289;Aβ0含量无明显调节作用。这个作用机制比较独特，与乙酰胆碱引起的非Aβ#20195;谢通路激活作用无关，而是直接抑制APP代谢为Aβ2。综合活性评价表明，XQ528对AChE、APP/Aβ#21644;炎症等AD相关的多个靶点具有抑制作用，体内测试中XQ528对东莨菪碱诱发的学习记忆障碍的改善作用明显优于利斯的明，多靶点的协同作用使XQ528成为具有临床研究价值的新型候选药物。

中文关键词： 苯氨甲酸酯；阿尔茨海默病；AChE抑制剂；(-)-美普他酚；β28096;粉样前体蛋白

英文摘要： Acetylcholinesterase (AChE), βAmyloid (Aβ and βAmyloid precursor protein（APP） are the key drug targets for the treatment of Alzheimer's Disease (AD). Bifunctional phenylcarbamate compounds that inhibit both AChE and APP/Aβre a promising research field. In this research, we designed and synthesized substituted phenylcarbamate derivatives and structurally simplified analogues of XQ528. AChE/BChE inhibition test demonstrated that (-)-meptazinol 4-methylphenylcarbamate 9 and phenylcarbamate of a tetrahydroisoquinoline compound QQ609 were the most potent AChE inhibitors. SAR studies indicated that small electron-donating group substituted on the 4-position of the phenylcarbamate moiety benefited the activities. Pharmacophore model studies showed that substitutes on the αarbon of phenyl in the structurally simplified analgues increased the AChE inhibiting activity. We also found that XQ528 reduced APP and Aβffectively, however, no effects were found on the level of sAPPαnd Aβ. The unique anti-amyloidogenic effect was independent of the cholinergic action, which facilitated APP into nonamyloidogenic pathway. Instead, XQ528 inhibited the metabolism of APP into Aβ. Pharmacological tests of XQ528 demonstrated that XQ528 inhibited several AD targets including AChE, APP/Aβnd inflammation. It also improved schopolamine-induced memory damage in in-vivo test, better that rivastigmine. The synergic action of XQ528 on several targets related to AD made it a new drug candidate that deserved further clinic studies.

英文关键词： phenylcarbamate；Alzheimer's Disease （AD）；AChE inhibitors；(-)-meptazinol；βmyloid precursor protein（APP）