Development of a lead candidate for the treatment of Alzheimer's disease

摘要 阿尔茨海默病(AD)是一种与年龄相关的神经退行性疾病，已成为全球性的 全球有4000多万人受到影响，预计2050年将有1.15亿人受到影响。今天是6号 是美国最大的死因。广告对健康、社会和 经济舱。批准的治疗充其量只能部分缓解一些症状。迫切需要 新的、能改善疾病的治疗方法。AD是一种复杂的疾病，有多个参与者可能成为目标 进行治疗干预。一个核心致病机制是AB42肽低聚物的细胞毒性。 与神经元寡聚体AB42结合后的激活和磷酸化事件的级联 和内部化。这些结果，特别是氧化应激，线粒体功能障碍，突触 功能障碍，异常的钙信号和兴奋性毒性。该项目的总体目标是开发 一种针对神经毒性AB42信号的药物。在该项目的第1阶段组件中，我们将演示 将我们的候选化合物优化为治疗先导的可行性。我们将进行几项 几轮构效关系研究旨在提高该化合物的效力，选择性， 代谢和药代动力学特性，包括脑渗透。一系列基于体外/细胞的 在小鼠AD模型中的化验、DMPK研究和测试将指导化合物的进展。这个 第一阶段的成功完成将提供一种优化的铅化合物，可供开发和 第二阶段支持IND的研究。

SUMMARY Alzheimer’s disease (AD) is an age-related neurodegenerative disease that has become a global epidemic with over 40 million people affected worldwide and a projected 115 million in 2050. It is the 6th leading cause of death in the United States. AD has a tremendous impact on health, society and the economy. Approved treatments at best partially ameliorate some symptoms. There is an urgent need for novel, disease-modifying treatments. AD is a complex disease with multiple players that may be targeted for therapeutic intervention. A core pathogenic mechanism is the cellular toxicity of Ab42 peptide oligomers with the cascade of activation and phosphorylation events that follow neuronal oligomeric Ab42 binding and internalization. These result, inter alia, in oxidative stress, mitochondrial dysfunction, synaptic dysfunction, abnormal Ca2+ signaling and excitotoxicity. The overarching goal of this project is to develop a drug targeting neurotoxic Ab42 signaling. In this phase 1 component of the project, we will demonstrate the feasibility of optimizing our candidate compound into a therapeutic lead. We will conduct several rounds of structure-activity relationship studies aimed at increasing the compound’s potency, selectivity, metabolic and pharmacokinetic properties, including brain penetration. A series of in vitro/cell-based assays, DMPK studies and testing in a murine AD model will guide compound progression. The successful completion of phase 1 will deliver an optimized lead compound ready for development and IND-enabling studies in phase 2.