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可能改善神经退行性疾病的疾病疗法。该提案检验了以下假设：新型的p38 MAPK抑制剂具有口服生物利用，具有良好的脑部摄取，并且无毒，可以将其发展为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，以恢复病理学，将促炎性细胞因子的产生向基础水平增加，并在动物模型中具有阳性的神经系统结局。与长期目标的联系是，从成功完成拟议的研究中出现的可交付成果将构成神经退行性疾病的后续药物开发运动的基础。临床研究提供了神经退行性疾病，神经胶质激活和促炎细胞因子水平升高之间的联系，并使用大分子疗法的可行性研究提示了促炎性细胞因子衰减在阿尔茨海默氏病中的阳性临床效应。动物模型中的先前艺术表明，在动物模型中，对突触功能障碍和神经系统缺陷的敏感性提高了病理生理的进展作用，在这些动物模型中，脑促炎细胞因子水平升高。通过抑制促炎性细胞因子产生的增加，可以恢复神经系统缺陷的衰减。因此，积累的证据表明，靶向促炎性细胞因子上调的潜力可能会导致CNS功能障碍的衰减。但是，对于可容纳临床发育的可生物可利用的，CNS渗透剂小分子的需求不足。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”生物学结合起来，以发现具有吸引人的物理特性的新型铅化合物，并具有CNS渗透性，安全性和有效性的高潜力，然后将药物化学改进为候选者，以供未来的临床开发。分子靶标是丝氨酸/苏氨酸蛋白激酶p381MAPK，这是促炎细胞因子产生的关键调节剂，也是周围组织疾病的既定治疗靶标，其中增加的促炎细胞因子水平是疾病进展机制的一部分。具体而言，我们建议：设计，合成和完善新型P381MAPK抑制剂，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可生物利用的CNS渗透剂，无毒，稳定的铅化合物，这些化合物是大脑中细胞因子产生增加的选择性抑制剂；并测试选定的铅化合物在阿尔茨海默氏病与疾病相关的动物模型中的功效。成功完成拟议的研究将为未来的临床前毒理学和药代动力学提供知识库和新型铅化合物，以启动以后的临床研究。公共卫生相关性成功地完成了拟议的调查，将为临床开发新的神经系统疾病疗法提供新颖，有效的化合物。