权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
7663102
负责人：
Daniel Martin Watterson
金额：
$ 30.84万
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/7663102
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 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 lipophilicity meetings mouse model nervous system disorder novel painful neuropathy physical property pre-clinical programs protein kinase inhibitor public health relevance 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)：这项研究计划的长期目标是发现潜在的神经退行性疾病的疾病修改疗法。这项建议验证了一种假设，即新型p38 MAPK抑制剂可以口服生物利用，具有良好的脑摄取，并且无毒，可以开发成一类治疗中枢神经系统疾病的新药物。这项拟议的研究旨在开发p38 MAPK抑制剂，可以在动物模型中恢复与致炎细胞因子产生增加相关的病理改变，使其达到基础水平，并获得阳性的神经学结果。与长期目标的联系是，成功完成拟议研究后产生的可交付成果将构成治疗神经退行性疾病的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、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。在动物模型中，现有技术已经证明了在动物模型中脑前炎症细胞因子水平升高的动物模型具有病理生理学进展作用，并增强了对突触功能障碍和神经缺陷的敏感性。神经功能缺陷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有可能减轻中枢神经系统功能障碍。然而，对生物可用、中枢神经系统穿透小分子的需求尚未得到满足，以适应临床开发。我们计划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，以发现具有诱人物理特性和对中枢神经系统渗透性、安全性和有效性具有高潜力的新型先导化合物，然后对药物化学进行改进，以供未来临床开发。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，也是周围组织疾病的既定治疗靶点，在外周组织疾病中，促炎细胞因子水平升高是疾病进展机制的一部分。具体地说，我们建议：设计、合成和提炼具有口服生物利用度和中枢神经系统通透性潜力的新型p381MAPK抑制剂；筛选化合物，以确定口服生物可用、中枢神经系统渗透、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的选择性抑制者；以及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疗效。拟议研究的成功完成将为未来的IND临床前毒理学和药代动力学提供知识库和新的先导化合物，这是启动以后的临床研究所需的。公共卫生相关性拟议研究的成功完成将提供临床开发神经疾病新疗法所需的新的、有效的化合物。