前期通过细胞水平上的筛选，得到了能够显著降低Abeta含量的中药有效成分牛蒡子苷元(ATG)；发现其作用分子机制是通过减少BACE1表达而抑制Abeta生成，通过启动自噬而增强Abeta的清除；在AD转基因模型小鼠上，腹腔注射给药ATG能显著降低小鼠脑内Abeta的含量，减少老年斑的产生，明显改善小鼠的记忆力。急性毒性试验显示其具有较高的安全性；ATG在牛蒡子中的含量高达3%，因此ATG是一个优良的抗AD药物先导结构。本申请我们将探索ATG的化学反应性质，制备结构多样性的系列化合物库；对每一类型化合物库尽可能多的合成类似物，并测试它们降Abeta含量的活性，总结其构效关系；进一步结合已有的构效关系规律，设计、合成在多个位置同时连接最佳取代基的组合衍生物库；同时开展ATG的前药设计、合成及其相关评价研究；经体内系统的药效学评价、急性毒性和口服生物利用度评价，发现1-2个药物候选物。

By screening our in-house natural product library, we have found arctigenin (ATG), isolated from Arctium lappa, can significantly decrease Abeta?content in the HEK293-APPswe cell model; and ATG both inhibit Abeta production by suppressing beta-site amyloid precursor protein cleavage enzyme 1 expression and promote Abeta clearance by enhancing autophagy through AKT/mTOR signaling inhibition and AMPK/Raptor pathway activation as investigated in cells and APP/PS1 transgenic AD model mice. Moreover, treatment of arctigenin by ip administration in APP/PS1 transgenic AD model mice highly decreased Abeta?formation, senile plaques and efficiently ameliorated AD mouse memory impairment. It showed high safety in the acute toxicity experiment; its content in the plant is about 3% of its dry weight. Therefore, ATG is a good anti-AD drug lead for further structural optimiazation. In this project, we will focus on exploring chemical properties of ATG, preparing ATG derivative libraries with structure-diversity, synthesizing enough ATG analogues in each type library, testing their in vitro decreasing Abeta content activity in cells, summing up the structure-activity relationship; designing and synthesizing the combined derivative library with optimized substituents at different positions, designing and synthesizing prodrugs of ATG, evaluating their drug-like properties, acute toxicity, oral bioavailability, and in vivo anti-AD activity, and find 1-2 anti-AD drug candidates.