Preclinial Development of JNK3 Inhibitors to Treat Parkinson's Disease

描述(申请人提供)：这个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，可用于治疗帕金森病(PD)的神经退行性变。开发一种防止多巴胺能神经退化的药物将是阻止疾病进展的首选药物，并将是对现有药物的临床补充，用于对症治疗帕金森病。我们组建了一支由具有丰富制药经验的生物化学家、细胞生物学家、药物化学家、结构生物学家、药理学家、分析化学家和行为药理学家组成的团队来执行这一药物开发计划。在目标1(1年至2年)，我们将优化JNK2/3抑制剂以选择临床前开发候选药物。到第二年年底，我们预计将有一种或多种化合物：1)是有效的和选择性的JNK2/3抑制剂，2)促进原代多巴胺能神经元的存活，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化学和以生化和细胞为基础的分析支持的基于结构的药物设计以及药物动力学来开发结构-活性-关系(SAR)来实现。在Aim 2(第3年)期间，我们将在MPTP-小鼠模型中展示大于或等于3种化合物的帕金森病疗效，证明与人类细胞色素P450缺乏相互作用，并在初步毒性研究中评估5至10种化合物。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在开发中失败的风险。在AIM 3(第4-5年)，我们将进行研究新药的遗传毒性、安全性药理学和毒理学研究，旨在帮助选择具有最佳代谢特征和最广泛治疗指数的临床候选药物。总的来说，这些研究旨在产生一个领先的临床候选者(和后备)，这些候选者拥有足够的数据来满足食品和药物管理局的标准，以支持帕金森氏症的第二阶段人类临床试验。

DESCRIPTION (provided by applicant): 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.