Development of Novel p38 MAPK Inhibitors as Therapeutics for CNS Disorders

描述（由申请人提供）：本研究项目的长期目标是发现神经退行性疾病的潜在疾病修饰疗法。该提案检验了以下假设：口服生物可利用的、具有良好脑摄取并且无毒的新型p38 MAPK抑制剂可以开发成一类新的CNS疾病治疗剂。拟议的研究旨在开发p38 MAPK抑制剂，可以在动物模型中将病理相关的促炎细胞因子产生增加恢复到基础水平，并具有积极的神经学结果。与长期目标的联系是，成功完成拟议研究所产生的可交付成果将成为神经退行性疾病后续药物开发活动的基础。临床研究已经提供了神经退行性疾病、神经胶质活化和促炎细胞因子水平增加之间的联系，其中使用大分子疗法的可行性研究表明促炎细胞因子衰减在阿尔茨海默病中具有积极的临床效果。现有技术在动物模型中已经证明了病理生理学进展作用和对突触功能障碍和神经缺陷的敏感性增强，其中脑促炎细胞因子水平增加。神经功能缺损的减轻可以通过抑制促炎细胞因子产生的增加来恢复。因此，越来越多的证据表明，靶向促炎细胞因子上调可减轻CNS功能障碍。然而，对于可用于临床开发的生物可利用的CNS渗透性小分子存在未满足的需求。我们建议使用我们的综合药物发现平台，将“智能”化学与“智能”生物学相结合，以发现具有吸引人的物理特性和高潜力的CNS抑制剂，安全性和有效性的新型先导化合物，然后将药物化学精制成未来临床开发的候选物。分子靶点是丝氨酸/苏氨酸蛋白激酶p381 MAPK，其是促炎细胞因子产生的关键调节因子，也是外周组织疾病的既定治疗靶点，其中促炎细胞因子水平升高是疾病进展机制的一部分。具体而言，我们建议：设计、合成和改进新型p381 MAPK抑制剂，使其具有口服生物利用度和CNS渗透性的潜力;筛选化合物以鉴定口服生物可利用的、CNS渗透的、无毒的、稳定的先导化合物，这些先导化合物是脑中细胞因子产生增加的选择性抑制剂;并测试选定的先导化合物在阿尔茨海默病相关动物模型中的功效。成功完成拟定研究将为启动后续临床研究所需的未来IND临床前毒理学和药代动力学提供知识基础和新型先导化合物。公共卫生相关性成功完成拟议的研究将提供神经系统疾病新疗法临床开发所需的新型有效化合物。

DESCRIPTION (provided by applicant): The long-term goal of this research program is the discovery of potentially disease-modifying therapies for neurodegenerative disorders. This proposal tests the hypothesis that novel p38 MAPK inhibitors that are orally bioavailable, have good brain uptake, and are non-toxic can be developed into a new class of therapeutics for CNS disorders. The proposed research seeks to develop p38 MAPK inhibitors that can restore pathology associated increased proinflammatory cytokine production toward basal levels with positive neurologic outcomes in animal models. The linkage to the long term goals is that the deliverables emerging from successful completion of the proposed studies will form the foundation of follow-on drug development campaigns for neurodegenerative disorders. Clinical studies have provided a linkage among neurodegenerative disorders, glia activation and increased levels of proinflammatory cytokines, with feasibility studies using macromolecular therapeutics suggestive of a positive clinical effect of proinflammatory cytokine attenuation in Alzheimer's disease. Prior art in animal models has demonstrated a pathophysiology progression role and enhanced sensitivity to synaptic dysfunction and neurologic deficits in animal models where brain proinflammatory cytokine levels are increased. Attenuation of neurologic deficits can be restored by inhibiting the increase in proinflammatory cytokine production. Therefore, an accumulating body of evidence indicates the potential of targeting proinflammatory cytokine up-regulation for attenuation of CNS dysfunction. However, there is an unmet need for bioavailable, CNS-penetrant small molecules amenable to clinical development. We propose to use our integrative drug discovery platform that combines "smart" chemistry with "smart" biology to discover novel lead compounds with attractive physical properties and high potential for CNS penetrance, safety and efficacy, followed by medicinal chemistry refinement into candidates for future clinical development. The molecular target is the serine/threonine protein kinase p381MAPK, a key regulator of proinflammatory cytokine production and an established therapeutic target for peripheral tissue diseases where increased proinflammatory cytokine levels are part of the disease progression mechanism. Specifically, we propose to: design, synthesize, and refine novel p381MAPK inhibitors with potential for oral bioavailability and CNS penetrance; screen compounds to identify orally bioavailable, CNS-penetrant, non-toxic, stable lead compounds that are selective suppressors of increased cytokine production in the brain; and test selected lead compounds for efficacy in Alzheimer's disease-relevant animal models. Successful completion of the proposed investigations will provide a knowledgebase and novel lead compounds for future IND-enabling preclinical toxicology and pharmacokinetics required for initiation of later clinical investigations. PUBLIC HEALTH RELEVANCE Successful completion of the proposed investigations will provide novel, efficacious compounds required for clinical development of new therapies for neurological disorders.