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

总结 阿尔茨海默病（Alzheimer's disease，AD）是一种与年龄相关的神经退行性疾病， 这一流行病在全世界有4 000多万人受到影响，预计2050年将有1.15亿人受到影响。今天是第六次 美国的主要死因。AD对健康、社会和人类健康都有着巨大的影响。 经济批准的治疗方法充其量只能部分缓解某些症状。迫切需要 新型的疾病缓解疗法AD是一种复杂的疾病，有多个参与者可能是靶向的 进行治疗干预。核心致病机制是Ab 42肽寡聚物的细胞毒性 随着神经元寡聚体Ab 42结合后的激活和磷酸化事件的级联 和内在化。这些结果阿利亚导致氧化应激、线粒体功能障碍、突触损伤、神经元损伤和神经元损伤。 功能障碍、异常Ca 2+信号传导和兴奋性毒性。该项目的总体目标是开发 一种靶向神经毒性Ab 42信号的药物。在项目的第一阶段，我们将演示 将我们的候选化合物优化为治疗先导药物的可行性。我们将进行几次 多轮结构-活性关系研究旨在提高化合物的效力，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 在鼠AD模型中的测定、DMPK研究和测试将指导化合物进展。的 第一阶段的成功完成将提供一种可供开发的优化的先导化合物， 2期IND赋能研究。

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.