Preclinical Development of JNK3 Inhibitors to Treat Parkinson's Disease

该项目的目标是开发一种c-Jun氨基末端激酶2/3(JNK2/3)抑制剂，该抑制剂可用于 帕金森病(PD)神经退行性变的治疗。开发一种预防疾病的药物 多巴胺能神经退行性变将是阻止疾病进展的第一类药物，临床上 是对帕金森病对症治疗的现有药物的补充。我们已经组建了一支团队 生物化学家、细胞生物学家、药物化学家、结构生物学家、药理学家、分析化学家， 和具有丰富制药经验的行为药理学家来执行这种药物开发 程序。在目标1(1-2年)中，我们将优化JNK2/3抑制剂以选择临床前开发 候选人。到第二年年底，我们预计会有一种或多种化合物：1)有效和 选择性JNK2/3抑制剂，2)促进原代多巴胺能神经元存活，3)具有良好的 药代动力学特性和脑渗透。这一目标将通过利用药物来实现 由生化和细胞分析支持的基于化学和结构的药物设计，以及 药物动力学以发展结构-活性-关系(SAR)。在目标2(第3年)期间，我们将 在MPTP-小鼠模型中证明了大于或等于三种化合物的帕金森病的有效性， 证明缺乏与人类细胞色素P450的相互作用，并初步评估五到十种化合物 毒性研究。评估我们最有希望的五到十种化合物的原因是优化 临床成功的机会，并降低开发单个分子可能失败的风险 发展。在目标3(第4-5年)，我们将进行使基因毒性、安全性的新药的研究 药理学和毒理学研究，旨在帮助选择具有最佳新陈代谢的临床候选人 简介和最宽的治疗指数。总而言之，这些研究旨在产生一个领先的临床 有足够数据满足食品和药物管理局标准的候选人(和备份) 支持帕金森氏症的第二阶段人类临床试验。

The goal of this project is to develop a c-jun N-terminal kinase 2/3 (JNK2/3) inhibitor that may be used in the treatment of neurodegeneration in Parkinson's disease (PD). Development of a drug that prevents dopaminergic neurodegeneration would be first in class for halting progression of the disease and a clinical complement to existing medication used in symptomatic treatment of PD. We have assembled a team of biochemists, cell biologists, medicinal chemists, structural biologists, pharmacologists, analytical chemists, and behavioral pharmacologists with extensive pharmaceutical experience to execute this drug development program. In Aim 1 (years 1-2) we will optimize JNK2/3 inhibitors to select a preclinical development candidate. By the end of year 2 we anticipate having one or more compounds that: 1) are potent and selective JNK2/3 inhibitors, 2) promote primary dopaminergic neuronal survival, and 3) have good pharmacokinetic properties and brain penetration. This aim will be accomplished by utilizing medicinal chemistry and structure-based drug design supported by biochemical and cell-based assays, and pharmacokinetics to develop structure-activity-relationships (SAR). During Aim 2 (year 3) we will demonstrate efficacy in MPTP-mouse models of PD for greater than or equal to three compounds, demonstrate lack of interaction with human CYP450s, and evaluate five to ten compounds in preliminary toxicity studies. The reason for evaluating five to ten of our most promising compounds is to optimize the chance for clinical success and mitigate the risk of developing a single molecule that may fail in development. In Aim 3 (years 4-5) we will conduct Investigation New Drug enabling genotoxicity, safety pharmacology, and toxicology studies aimed at helping select a clinical candidate that has the best metabolic profile and widest therapeutic index. Collectively these studies are intended at generating a lead clinical candidate (and back ups) that have sufficient data to meet Food and Drug Administration standards to support up through Phase II human clinical trials in Parkinson's disease.