阿尔茨海默症（AD）是老年人中发病率和致死率最高的疾病之一。应用于临床治疗AD的药物多数为“对症治疗”药物，缺乏有效“对因治疗”药物。寻找高效、高选择性的GSK-3β抑制剂对AD治疗具有重要意义。目前，还没有任何基于GSK-3β的抗AD药物上市。已见报道的GSK-3β抑制剂大都为ATP竞争性的小分子，而这些化合物普遍存在的问题是对大部分激酶的选择性不高。本项目拟在前期工作基础上，探索新型高选择性的GSK-3β抑制剂：设计、合成新结构胺基吡唑类和异噁唑酮类化合物库，完善ZTS系列化合物库，并通过对GSK-3β 的抑制活性筛选获得较为明确的构效关系。发现的高选择性、高活性的化合物将进行初步抗AD生物评价工作，希望得到具有抗AD活性的高选择性GSK-3β抑制剂，为寻找理想的AD治疗药物提供重要线索和理论依据。

Alzheimer’s disease (AD), most often diagnosed in people over 65 years of age, is responsible for significant worldwide morbidity and mortality. Current treatments of Alzheimer’s disease only help with the symptoms of the disease. There are no available treatments that stop or reverse the progression of the disease. GSK-3β inhibitors are currently of significant interest and being tested for therapeutic effects in Alzheimer’s disease. So far, a number of synthetic, small-molecule GSK-3β inhibitors have been reported. All of these compounds are ATP-competitive GSK-3β inhibitors, most of which show nonselective protein kinase inhibition profiles including activity against the cyclin-dependent kinases (CDKs) and PKCs (protein kinase C). On the basis of preliminary results we have already obtained, this project will be focused on the design and synthesis of new aminopyrazole and isoxazolone compounds, aiming to discover new compounds with extremely high selectivity towards GSK3β. In this project, we will also complement the library of ZTS series of compounds, with the intention of clarifying Structure-Activity-Relationship (SAR) for the GSK3β inhibition. Those compounds, which shown high activity as well as selectivity, will be scaled up and further tested in biological assays for Alzheimer’s disease . Hopefully, important clues and theory could be concluded for the adventure of pursuing ideal anti AD drugs after our studies.

阿尔茨海默症（AD）是老年人中发病率和致死率最高的疾病之一。应用于临床治疗AD的药物多数为“对症治疗”药物，缺乏有效“对因治疗”药物。寻找高效、高选择性的GSK-3β抑制剂对AD治疗具有重要意义。目前，还没有任何基于GSK-3β的抗AD药物上市。已见报道的GSK-3β抑制剂大都为ATP竞争性的小分子，而这些化合物普遍存在的问题是对大部分激酶的选择性不高。本项目探索发展了新型GSK-3β抑制剂，构建了具有新母核结构的胺基吡唑类化合物库，并通过对GSK-3β 的抑制活性筛选获得较为明确的构效关系，对较好活性的GSK-3β抑制剂进行了初步抗AD生物评价工作。同时还利用自主发展的新方法高效构建了一批多环并杂环类化合物，初筛表明部分化合物具有良好的GSK-3β抑制活性。此外，完善了ZTS系列化合物库，发现了部分化合物在Aβ模型中具有显著的神经保护作用，在对Aβ神经毒性有保护作用的抗AD药物研究方面取得了一定的进展。