基于Aβ清除与聚集抑制双功能抗阿茨海默病化合物的设计、合成及活性评价

It is widely accepted that abnormal rising levels of Aβ and its aggregation drive AD pathogenesis. Combining the approaches of decreasing Aβ levels and inhibiting Aβ aggregation is a more promising strategy to impove AD therapy. As an important regulator of Aβ clearance process, ABCA1 facilitates the degradation of Aβ and has become a new therapeutic target of AD. In our earlier-stage work, a series of chalcone derivatives were found to up-regulate ABCA1’s expression and effectively enhance Aβ clearance. Meanwhile, these compounds also demonstrated a moderate inhibiting activity of Aβ aggregation. Based on the above work, we hypothesize that novel therapeutic agents against AD with dual activity of facilitating Aβ clearance and inhibiting Aβ aggregation will be achieved. In this project, a library of dual-functional compounds will be designed and synthesized according to the SAR。Drug candidates will be discovered through the screening and evaluation of efficancy. Molecular mechanism will be investigated as well. We believe that our findings would offer a new opportunity to develop novel therapeutic drugs of AD.

Aβ水平的异常升高和发生聚集被广泛认为是AD发生和发展的驱动性因素。联合降低Aβ水平和抑制其聚集双重策略是提高AD治疗效果的可靠途径。ABCA1作为Aβ清除机制中重要的调节蛋白，上调其表达可有效促进Aβ在体内的降解，已成为抗AD的新靶点。在前期工作中，我们发现一类可明显上调ABCA1表达、促进Aβ清除的查尔酮类活性分子，同时也表现出一定的抑制Aβ聚集能力。基于此，本项目提出一类新型、具有促进Aβ清除和抑制其聚集双功能抗AD化合物的设计和合成研究。研究工作将结合已有的构效关系，对原有活性分子进行结构优化，构建新化合物库，经过各类活性筛选、成药性衡量以及体内药效评价，以获得高效抗AD候选药物分子，另外，还将探讨其具体分子作用机制。本项目对发展新型抗AD药物做出了重要探索，具有极高的研究价值和意义。

Aβ水平的异常升高和发生聚集被认为是AD发生和发展的驱动性因素。增强机体对Aβ的降解清除和抑制其聚集是抗AD研究中广受肯定的治疗策略。基于ABCA1调控Aβ降解清除的机制，本项目提出了一类新型、具有促进Aβ清除和抑制其聚集双功能抗AD化合物的设计、合成和活性评价研究。本项目从天然活性黄酮出发，通过合理设计，成功构建了用于活性筛选的化合物分子库。经过各类活性筛选，发现了一类具有促进Aβ清除和抑制其聚集双重活性的化合物。分子作用机制探讨结果表明，活性化合物对LXR具有一定的激动活性，其作用靶标主要是LXRβ。另外，活性化合物能避免引起肝细胞内脂质过量蓄积的副作用，表现出了较好的安全性，具有很好的研究价值。本项目还发现部分化合物对其他抗AD靶点，如对铜离子具有良好的螯合作用，对单胺氧化酶B具有显著的抑制能力。这些研究成果将为研发新型多功能抗AD先导化合物提供了重要参考，达到预期研究目标。