基于药物代谢性质的神经炎症抑制剂的结构优化与抗阿尔茨海默症药效学研究

项目名称： 基于药物代谢性质的神经炎症抑制剂的结构优化与抗阿尔茨海默症药效学研究

项目编号： No.81502911

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 周渭

作者单位： 广东工业大学

项目金额： 17.9万元

中文摘要： 阿尔茨海默症（Alzheimer’s disease，AD）至今缺乏有效的治疗药物。病人脑部持续的神经炎症是导致神经元凋亡和疾病恶化的重要因素之一。越来越多的研究报道了各种神经炎症抑制剂能够通过延缓脑部的恶性炎症反应，在AD疾病模型中改善动物的记忆和认知能力。然而，不理想药代动力学性质是限制这些在体外有效的神经炎症抑制剂进入后续药物研发的关键阻碍。我们发现并报道了神经炎症抑制剂AD69能够抑制激活的小胶质细胞过度释放促炎症细胞因子IL-1β，本课题拟在此先导物的基础上探索该化合物的吸收和代谢方面的弊端，进一步开展结构优化，解决其口服生物利用度低（大鼠17.4%）和血浆半衰期短（0.72 h）的关键问题，以期综合提高该类神经炎症抑制剂的成药性，改善其在AD模型动物体内对记忆和认知功能的提升作用，为抗AD的药物研发提供基础。

中文关键词： 药物代谢性质；结构优化；神经炎症；阿尔茨海默症；抑制剂

英文摘要： Currently there is no disease-modifying drug for the treatment of Alzheimer’s disease (AD). Regardless of the causes of AD, neuronal death in Alzheimer brains plays a key role in AD progression and it is directly linked to chronic sustained neuroinflammation. Though accumulating evidence has revealed that neuroinflammatory inhibitors attenuated detrimental effect of activated microglia and counteracted cognitive decline in AD model animals. Poor pharmacokinetic properties became a key barrier that prevented many of them from further drug development. Previously, we identified a novel neuroinflammatory inhibitor (AD69) capable of reducing IL-1β released by activated microglia in vitro. In this study, we will focus on the key issues of absorption and metabolism of the lead compound, and go on conducting a structural optimization to improve its poor oral bioavailability (17.4% in rat) and short half-life (0.72 h). Hopefully, a refined neuroinflammatory inhibitor with enhanced druglikeness will provide elevated therapeutic potential in AD animals by restoring memory impairments and cognition decline, and may serve as scientific evidence for anti-AD drug discovery.

英文关键词： Pharmacokinetic property;Structural optimization;Neuroinflammation;Alzheimer’s disease;inhibitor