RAGE抑制/5-HT1A激动/5-HT重摄取抑制三功能抗并发抑郁的AD活性化合物的发现

The Alzheimer’s disease (AD) accompanied with depression is an emerging disease field that has been discovered and focused in recent years. It has a large patient population, especially in the elderly, and there are no effective drugs on the market. Therefore, it is urgent to carry out the R&D work of corresponding drugs. Focusing on the frontier disease filed, this project uses a unique multi-target drug development strategy to rationally fuse the pharmacophores of Vilazodone (approved antidepressant) and Azeliragon (clinical phase III RAGE inhibitor) together, designing a series of trifunctional compounds with RAGE inhibitory/5-HT1A agonist/5-HT reuptake inhibitory activities. The multifunctional compounds may treat the AD with depression by regulating various signaling pathways associated with the disease. This project intends to design and synthesize 50 multifunctional compounds, which will be evaluated by various biological assays, in order to screen out the drug candidates with potent multiple activities, low toxicity, and significant animal efficacy. This project has a good early research foundation (Li Xiaokang et al, ACS Chem. Neurosci. 2017, 8, 2708-2721), and some work of this project has been completed and expected results have been obtained (see research basis). The successful implementation of this project is expected to explore new mechanisms and new development strategy for the drug discovery of AD accompanied with depression.

并发抑郁的AD是近年来发现和关注的新兴疾病领域，其具有庞大的患者人群，尤其在老年人口中高发，目前市场上没有针对性治疗药物，因此，急需开展相应药物研发工作。本项目聚焦前沿疾病领域，采用独辟蹊径的多靶点药物研发策略，将抗抑郁药Vilazodone和临床Ⅲ期RAGE抑制剂Azeliragon关键药效团合理融合，首次设计了具有RAGE抑制/5-HT1A激动/5-HT重摄取抑制活性的三靶点化合物，可以通过调节与疾病相关的多种信号通路以及协同作用共同发挥疗效。本项目拟设计合成50个多靶点衍生物，经生物活性评价，以发现活性强、毒性低、具有良好动物药效的候选化合物。本项目具有良好的前期基础（李晓康等，ACS Chem. Neurosci. 2017, 8, 2708-2721），已完成部分研究工作并得到预想结果（见研究基础）。本项目的顺利实施有望为并发抑郁的AD药物创制探索出新的作用机制和研发策略。

抑郁症是阿尔茨海默病（AD）最常见的精神并发症之一。并发抑郁的AD极大增加了患者的治疗和照看负担，且目前市场上没有针对性治疗药物，因此，急需开展相应药物研发工作。本项目聚焦前沿疾病领域，采用独辟蹊径的多靶点药物研发策略，将抗抑郁药Vilazodone和临床Ⅲ期RAGE抑制剂Azeliragon关键药效团合理融合，首次设计了具有RAGE/SERT双重抑制活性的多靶点化合物，可以通过调节与疾病相关的多种信号通路以及协同作用共同发挥疗效。经过一系列的结构修饰与优化，本项目共设计合成了44个Vilazodoen-Azeliragon嵌合体衍生物，并系统评价了他们对RAGE和SERT的抑制活性。其中一个候选化合物HL1310对RAGE和SERT表现出良好的双靶点抑制活性，比Azeliragon更好的安全性，良好的肝微粒体稳定性，弱的CYP抑制活性和可接受的药代动力学性质。此外，化合物HL1310能够对Aβ25-35诱导的SH-SY5Y细胞损伤起到保护作用，并且改善抑郁小鼠的抑郁样行为。上述结果表明HL1310是一个有潜力的抗并发抑郁的AD的候选化合物。本项目的顺利实施有望为患有抑郁并发症的AD药物创制探索出新的作用机制和研发策略。