Preclinial Development of JNK3 Inhibitors to Treat Parkinson's Disease

描述（由申请人提供）：本项目的目标是开发一种c-jun N-末端激酶2/3（JNK 2/3）抑制剂，可用于治疗帕金森病（PD）的神经变性。开发一种预防多巴胺能神经变性的药物将是阻止疾病进展的第一步，也是对现有PD对症治疗药物的临床补充。我们组建了一个由生物化学家、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，他们具有丰富的制药经验，可以执行该药物开发计划。在目标1（第1-2年）中，我们将优化JNK 2/3抑制剂，以选择临床前开发候选药物。到第2年结束时，我们预计会有一种或多种化合物：1）是有效和选择性JNK 2/3抑制剂，2）促进原发性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性。这一目标将通过利用药物化学和基于结构的药物设计来实现，这些药物设计由生物化学和基于细胞的测定以及药代动力学支持，以开发结构-活性-关系（SAR）。在目标2（第3年）期间，我们将在MPTP-小鼠PD模型中证明大于或等于3种化合物的疗效，证明与人CYP 450缺乏相互作用，并在初步毒性研究中评价5至10种化合物。我们评估五到十种最有前途的化合物的原因是为了优化临床成功的机会，并降低开发单一分子的风险。在目标3（4-5年），我们将进行新药研究，使遗传毒性，安全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人（和备份），这些候选人有足够的数据来满足食品和药物管理局的标准，以支持帕金森病的II期人体临床试验。

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.