Preclinical drug development of isoform selective JNK3 inhibitors for Alzheimer's disease.

这项提议的目标是开发一种c-jun-N末端激酶异构体选择性抑制剂，它可以导致 到未来将用于治疗糖尿病的研究新药(IND)的监管申报 阿尔茨海默病(AD)。开发一种可以阻止疾病进展的药物至关重要 重要的是，目前还没有神经保护、阻止疾病进展或 提供认知方面的好处。我们的团队从基因上展示了针对JNK3的理由，其中， FAD小鼠的JNK3缺失导致AB42水平和总斑块负荷显著降低 伴随着神经元数量的增加和认知能力的提高。此外，我们的团队还开发了一种 强效、脑穿透性小分子JNK3探针抑制剂，具有良好的DMPK性能。不过，这个 需要优化化合物类别以实现口服生物利用度。为此，我们将采用一种 药物发现的经典药学方法。我们已经组建了一支拥有临床前药物的团队 开发和基础研究经验，涵盖所有方法学(医学 化学、生物化学、细胞生物学、神经生物学、体内和体外药理学、制剂、 DMPK和毒理学)，将在该项目中使用。我们将使用迭代复合体 一种优化方法，它将从多个结构类别中产生一系列化合物， 具有较强的体内药效、良好的口服药代动力学特性和良好的细胞毒性 安全配置文件。我们生成的化合物结构新颖，设计新颖，性能良好 区别于任何一类已知的JNK抑制剂，特别是异构体选择性抑制剂。这个 研究计划旨在通过后备最大限度地增加临床前成功的机会 来自多个类别的化合物，以降低开发单一候选对象的风险。测试我们的 假设新的结构类别的有效的、同种形式的低毒选择性JNK3抑制剂， 良好的DMPK特性，体内有效降低抗体水平，改善突触功能， 和改善认知，我们提出以下目标：目标1：发展和 优化JNK3亚型选择性抑制剂，使其具有高效、选择性和良好的DMPK 提供良好的大脑曝光率的特性。这一目标将通过利用药物来实现 以生化和细胞分析为基础的化学。目的2：检测JNK抑制剂对血管内皮细胞的作用 两种实验模型包括5XFAD和Tg2576小鼠，以展示体内疗效。在……里面 此外，我们将演示与人类细胞色素P450缺乏相互作用，并测试3-5铅的安全性 在大鼠毒性模型中开发化合物。

The goal of this proposal is to develop a c-jun-N-terminal kinase isoform selective inhibitor that can lead to a future regulatory filing for an investigational new drug (IND) to be used in the treatment of Alzheimer's Disease (AD). Development of a drug that can halt disease progression is of paramount importance as there are no current therapies that are neuroprotective, halt disease progression, or provide cognitive benefit. The rationale for targeting JNK3 was shown genetically by our team, wherein, deletion of Jnk3 from FAD mice produced a dramatic reduction in Ab42 levels and overall plaque load along with increased neuronal number and improved cognition. In addition our team has developed a potent, brain penetrant small molecule JNK3 probe inhibitor with good DMPK properties. However, this class of compounds needs to be optimized for oral bioavailability. To accomplish this we will employ a classical pharmaceutical approach to drug discovery. We have assembled a team with preclinical drug development and basic research experience that encompasses all of the methodologies (medicinal chemistry, biochemistry, cell biology, neurobiology, in vivo and ex vivo pharmacology, formulation, DMPK, and toxicology) that will be utilized in this project. We will employ an iterative compound optimization approach that will produce a series of compounds from multiple structural classes that have potent in vivo efficacy, favorable pharmacokinetic properties for oral dosing and a good cellular safety profile. The compounds we have generated are structurally novel, innovative in design, and well differentiated from known JNK inhibitors from any class, particularly isoform selective inhibitors. The research plan is designed to maximize the chance for preclinical success by having back-up compounds, from multiple classes, to mitigate the risk of developing a single candidate. To test our hypothesis that novel structural classes of potent, isoform selective JNK3 inhibitors with low toxicity, favorable DMPK properties, and in vivo efficacy in decreasing Ab levels, improving synaptic function, and improving cognition can be generated, we propose the following aims: Aim 1: Develop and optimize JNK3 isoform selective inhibitors that are potent, selective, and have favorable DMPK properties that provide good brain exposure. This aim will be accomplished by utilizing medicinal chemistry supported by biochemical and cell-based assays. Aim 2: Test the actions of JNK inhibitors in two experimental models including 5XFAD and Tg2576 mice to demonstrate in vivo efficacy. In addition, we will demonstrate lack of interaction with human CYP450s and test the safety of 3-5 lead development compounds in rat toxicity models.