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

该提案的目标是开发一种c-jun-N-末端激酶亚型选择性抑制剂， 用于治疗以下疾病的研究性新药（IND）的未来监管备案 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 重要性，因为目前没有神经保护、阻止疾病进展或 提供认知益处。我们的团队在遗传学上证明了靶向JNK 3的基本原理，其中， 从FAD小鼠中删除Jnk 3产生了Ab 42水平和总斑块负荷的显著降低 沿着增加的神经元数量和改善的认知。此外，我们的团队还开发了一个 具有良好DMPK特性的强效脑渗透性小分子JNK 3探针抑制剂。但这 这类化合物需要针对口服生物利用度进行优化。为了实现这一目标，我们将采用 经典的药物发现方法。我们组建了一个团队， 开发和基础研究经验，包括所有的方法（医学） 化学、生物化学、细胞生物学、神经生物学、体内和离体药理学、制剂， DMPK和毒理学）。我们将使用一个迭代复合 一种优化方法，将从多个结构类别产生一系列化合物， 具有有效的体内功效、口服给药的有利的药代动力学性质和良好的细胞毒性， 安全配置文件。我们产生的化合物结构新颖，设计创新， 与任何种类的已知JNK抑制剂，特别是同种型选择性抑制剂不同。的 研究计划的目的是最大限度地提高临床前成功的机会， 化合物，从多个类别，以减轻开发单一候选人的风险。来测试我们 假设具有低毒性， 有利的DMPK性质，以及在降低Ab水平，改善突触功能， 和提高认知可以产生，我们提出了以下目标：目标1：发展和 优化JNK 3亚型选择性抑制剂，其是有效的、选择性的并且具有有利的DMPK 提供良好的大脑暴露的特性。这一目标将通过利用药物来实现。 由生物化学和基于细胞的测定支持的化学。目的2：测试JNK抑制剂在细胞中的作用。 包括5XFAD和Tg 2576小鼠的两个实验模型以证明体内功效。在 此外，我们将证明与人CYP 450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.