基于促成体海马区神经形成的新型多靶点抗阿尔兹海默病喹啉-吲哚衍生物的设计、合成及生物活性研究

Alzheimer’s disease (AD) is one of the most prevalent and dreadful neurodegenerative diseases which severely affects the health of elderly people worldwide. Presently, the primary therapeutic options for AD treatment are acetylcholinesterase inhibitors (AChEIs) and the N-methyl-D-aspartate (NMDA) receptor (NMDAR) antagonist, which belong to single-target anti-AD drugs and can only offer short-term symptomatic relief without definitively cure this disease through replacing the lost or damaged neural cells from neurodegeneration with functioning normal cells. We have recently identified the quinoline-indole derivative WI-1758 as multi-target-directed candidate for treating AD with the function of promoting adult hippocampal neurogenesis (J. Med. Chem. 2018, 61, 1871-1894). In order to discover more efficient candidate compounds with better oral bioavailability as well as the function of promoting adult hippocampal neurogenesis, we will design and synthesize of 40-60 multi-target-directed anti-AD derivatives to disclose more detailed structure activity relationship (SAR) by using WI-1758 as lead compound in this project. Through SAR studies of multi-targeted anti-AD activities as well as promoting neurogenesis in neural stem cells, the potential compounds will be further studied for their metabolic stability and promotion of hippocampal neurogenesis in living adult mice. Finally, the pharmacokinetic profile and pharmacodynamics evaluation of the optimal compound will be performed. This study is significant since it could provide novel candidate drugs for treating AD.

阿尔茨海默病（AD）是日趋严重的重大疾病，当前上市药物主要是单靶点AChE抑制剂及NMDAR拮抗剂，无法修复已丢失的神经元，不能有效治疗AD。申请者前期发现，喹啉-吲哚衍生物WI-1758具有促成体神经形成的多靶点抗AD药效（J. Med. Chem. 2018）。为获得更高效的候选化合物，本项目拟开展新型喹啉-吲哚衍生物系统的构效关系研究，进一步提高该类衍生物的口服生物利用度、优化其促神经形成功能，内容包括：1）以WI-1758为先导化合物，通过结构改造及优化，设计合成40-60个新衍生物；2）测试衍生物促神经形成及多靶点抗AD活性，筛选出4-6优选活性分子；3）探讨优选分子促成年小鼠神经形成的活性及机制，发掘1-3个候选分子进行药代学及药效学评估；4）解析候选分子改善AD小鼠认知记忆功能，揭示其对海马区神经形成、Aβ沉积、抗氧化及胶质细胞增生等机制。本项目将为AD的治疗提供新的候选药物

项目执行中，基于设计、合成及活性研究新型抗阿尔兹海默病（AD）喹啉衍生物，我们筛选并全面研究了先导化合物WBQ5187的成药性潜能。内容包括：体内药代动力学、血脑屏障渗透性及体内药效学等。研究结果表明：采用静脉注射给药，先导化合物WBQ5187在SD大鼠体内的半衰期T1/2 = 17.78小时，清除率 = 0.07 L/h/kg，组织分布为Vz = 1.74 L/kg。采用口服给药，半衰期T1/2 = 18.87小时，血药浓度达峰时间Tmax = 1.5小时，口服生物利用度F = 17.39%。在达峰时间，血液与脑部中药物浓度比值B/P = 0.57，Log BB = -0.24，显著性优于药物血脑屏障临界值（B/P = 0.3-0.5，Log BB > -0.24），表明先导化合物WBQ5187可以通过口服给药的方式，很好的通过血脑屏障，具备中枢神经系统药物的基本性质。体内药效研究结果表明：长期性（连续给药80天）口服先导化合物WBQ5187治疗转基因APP/PS1小鼠（AD小鼠）不仅具有良好的安全性，而且可以显著性改善转基因小鼠的记忆能力，有效降低转基因小鼠脑内淀粉样蛋白沉积，神经胶质增生及神经元丢失，治疗效果显著优于临床抗AD药物氯碘喹啉（CQ）。体内副作用实验表明，在起效剂量下（40 mg/kg），先导化合物WBQ5187未显示出呕吐等副作用。综上研究结果表明，先导化合物WBQ5187在体内外实验中均显示出了抗阿尔兹海默病优异的效果，可作为潜在成药分子进一步研究，为将其开发成为多靶点抗阿尔兹海默病新型药物提供科学依据和理论基础。