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Development of Novel p38 MAPK Inhibitors as Therapeutics for CNS Disorders

开发新型 p38 MAPK 抑制剂作为中枢神经系统疾病的治疗药物

基本信息

批准号：
8067063
负责人：
Daniel Martin Watterson
金额：
$ 29.35万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-01 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8067063
关键词：
AIDS Dementia Complex Address Age related macular degeneration Alzheimer&apos s Disease Amines Amyloid beta-Protein Amyotrophic Lateral Sclerosis Animal Model Area Arts Attenuated Bioavailable Biological Biological Availability Biology Blood - brain barrier anatomy Brain Budgets Cardiotoxicity Central Nervous System Diseases Chemicals Chemistry Clinical Clinical Research Clinical Trials Data Databases Development Disease Disease Progression Drug Kinetics Epilepsy Exercise Failure Feasibility Studies Feedback Foundations Functional disorder Future Goals Guidelines Health Human In Vitro Inflammatory Infusion procedures Injury Intellectual Property Investigation Lead Legal patent Licensing Link Liver MAP Kinase Gene MAPK14 gene Medical Medicine Metabolic Metabolism Mitogen-Activated Protein Kinase Inhibitor Modeling Molecular Molecular Target Molecular Weight Multiple Sclerosis Neurodegenerative Disorders Neuroglia Neurologic Neurologic Deficit Neurological outcome Oral Outcome Output Parkinson Disease Pathology Penetrance Performance Peripheral Pharmaceutical Chemistry Pharmaceutical Economics Pharmaceutical Preparations Phase Probability Process Production Property Protein Kinase Inhibitors Protein-Serine-Threonine Kinases Publications Regulation Research Risk Role Safety Savings Screening procedure Senile Plaques Specific qualifier value Staging Stroke Structure Synapses Synthesis Chemistry Technology Transfer Testing Therapeutic Time Tissues Toxic effect Toxicology Transgenic Mice Translating Traumatic Brain Injury Universities Up-Regulation attenuation base central nervous system injury chemical stability clinical effect cost cytokine design drug development drug discovery efficacy testing experience in vivo inhibitor/antagonist injured knowledge base lipophilicity meetings mouse model nervous system disorder novel painful neuropathy physical property pre-clinical programs protein kinase inhibitor response scaffold small molecule success therapeutic target uptake

项目摘要

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.

描述（由申请人提供）：该研究计划的长期目标是发现神经退行性疾病的潜在疾病缓解疗法。该提案测试了这样的假设：新型 p38 MAPK 抑制剂具有口服生物利用度、具有良好的脑吸收性且无毒，可以开发成一类新的中枢神经系统疾病疗法。拟议的研究旨在开发 p38 MAPK 抑制剂，可以将促炎细胞因子产生增加相关的病理恢复至基础水平，并在动物模型中产生积极的神经系统结果。与长期目标的联系是，成功完成拟议研究所产生的成果将构成神经退行性疾病后续药物开发活动的基础。临床研究提供了神经退行性疾病、神经胶质细胞激活和促炎细胞因子水平升高之间的联系，使用大分子疗法的可行性研究表明促炎细胞因子减弱对阿尔茨海默病具有积极的临床效果。动物模型中的现有技术已经证明了脑促炎细胞因子水平增加的动物模型中的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。神经功能缺损的减弱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，通过上调促炎细胞因子来减轻中枢神经系统功能障碍的潜力。然而，对适合临床开发的生物可利用的、中枢神经系统渗透性小分子的需求尚未得到满足。我们建议利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，发现具有有吸引力的物理特性和中枢神经系统渗透性、安全性和有效性的高潜力的新型先导化合物，然后将药物化学细化为未来临床开发的候选化合物。分子靶点是丝氨酸/苏氨酸蛋白激酶 p381MAPK，它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。具体来说，我们建议：设计、合成和精炼具有口服生物利用度和中枢神经系统渗透潜力的新型 p381MAPK 抑制剂；筛选化合物，以确定口服生物可利用、中枢神经系统渗透性、无毒、稳定的先导化合物，这些化合物是大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。成功完成拟议的研究将为未来启动后续临床研究所需的临床前毒理学和药代动力学提供知识库和新型先导化合物。公共卫生相关性成功完成拟议的研究将为神经系统疾病新疗法的临床开发提供所需的新颖、有效的化合物。