“隐藏式”AChE抑制/金属离子螯合双功能抗阿尔茨海默症化合物的设计、合成及其生物学评价

Because of the complexity and multiple etiologies of Alzheimer's disease, we focused on Dual-Target-Directed Ligands that can simultaneously impact on AChE and metal ions. In previous work, we have found the AChE inhibitor AM-117, which can be hydrolyzed to AM-117a to chelate metal ions. In order to improve the inhibitory rate of AChE and the ability to chelate metal ions, we used rational design and compouter-aided drug design to find 4H-chromen-4-one and quinoline derivatives. A virtual database consisting of two scaffold compounds was built and screened on a molecular docking model of AChE inhibiotr. According to the screening result, two series of compounds were picked out, and will be synthesized and evaluated for their AChE inhibitory activies, as well as the ability to chelate metal ions. The SAR of the first round compounds will be found to guide the second round design. Compounds with potent AChE inhibitory activies and abolity to chelate metal ions will be picked out to study their vitro metabolic mechanisms and in vivo pharmacology. We are striving to discover dual- functional AD drug candidatates with independent intellectual property rights and novel structure.

由于阿尔茨海默症（AD）的病因复杂，前期针对AD疾病网络中两个关键节点-乙酰胆碱酯酶（AChE）和金属离子，开展双功能抗AD化合物的研究，得到的"隐藏式"双功能化合物AM-117不仅具有AChE抑制活性，且可被AChE水解为AM-117a，进一步发挥金属离子螯合作用，达到了双功能治疗的目的。 本项目拟在AM-117的基础上，以提高其AChE抑制活性和金属离子螯合能力为目标，通过基于功能团杂合、分子骨架迁越、类药性分析等理性药物设计方法及基于AChE蛋白结构的计算机辅助设计方法，设计了一系列喹啉类及苯并吡喃-4-酮类化合物。通过构建定向化合物库，虚拟筛选，以确定优先合成的化合物。并根据体外药理活性评价结果总结SAR，开展新一轮的合成和活性评价工作。从两轮合成的化合物中优选1-5个化合物进行体外转运、代谢机制研究和体内药理学研究，力争发现1-2个具有自主知识产权、结构新颖的双功能抗AD药物。

由于老年痴呆疾病的复杂性以及发病机理的不清晰，目前多靶点药物为AD治疗药物研究的热点。在前期发现的“隐藏式”多靶点抗AD化合物AM117的基础上，设计合成了39个化合物。其中AM219及其活性代谢产物AM219a在ACHE抑制活性，金属离子鳌合能力和Abeta蛋白聚集抑制实验中都显示出良好的活性。进一步的多个动物药效学模型中也显示了良好的效果。初步安全性评价，药代药动学研究，稳定性研究都显示AM219是一个有潜力的候选药物，可以进一步开展全面的临床前评价。