Preclinical Alzheimers Disease Drug Development of Novel MAPK Inhibitors

阿尔茨海默病（AD）是美国第六大死亡原因，但它是前10名中唯一没有预防，治愈或减缓其进展的方法的疾病。AD导致的死亡人数超过糖尿病、乳腺癌和前列腺癌的总和。我们假设AD是一种进行性突触功能障碍性疾病，其中胶质神经元轴是关键参与者，并且在寻找疾病修饰疗法中作为治疗开发范例是可行的。神经元和神经胶质之间的适当沟通和相互作用是大脑稳态的关键，而这些动力学在疾病中受到干扰。针对神经胶质细胞和神经元中导致病理学的应激物诱导的变化，提供了减弱各种CNS疾病中存在的疾病进展机制的可能性。无论该机制是直接致病机制还是疾病易感性和发病的贡献者，该过程的小分子调节剂都将是开发治疗方案的主要步骤，其增加了用于干预的医疗设备。 该提案的重点是应激相关蛋白激酶p38 <$MAPK，这是真核细胞信号转导级联中的关键节点，其放大并将应激信号转化为生理变化。激酶是一个既定的药物发现目标的各种疾病，但最近才成为重点的中枢神经系统药物发现的努力。p38 <$MAPK作为AD靶点的追求增加是由于一系列标志性事件，包括人类CNS疾病中激酶激活的证明、动物模型研究的结果以及产生CNS渗透抑制剂的可行性的证明，这些抑制剂可以改善动物模型的结果。 我们建议使用一种经过验证的药物发现引擎，该引擎成功地提供了新的CNS小分子候选药物，这些候选药物进展到与本提案相同的IND目标，并通过了第一次非人道的1期研究，没有不良事件。该项目的具体目标是：目标1。优化第二代抑制剂MW 01 -10- 181 SRM，以改善非GLP ADMET相关特性，同时保留靶点活性、选择性和体内功能，从而可以优先选择单一候选药物进行GLP IND使能评价。目标2.对同类最佳候选化合物进行GLP临床前评价，以生成IND。目的3。向FDA提交新分子实体IND的申请，用于未来临床开发的1期首次人体临床评价。 目前，没有批准的改变AD病理学进展的药物，并且在AD临床试验中没有选择性p38 <$MAPK抑制剂药物（现有的临床前开发工作 集中于多激酶抑制剂）。因此，拟议的开发活动将解决该领域的科学空白，并有可能产生用于首次人体研究的新型小分子候选物作为交付物。 公共卫生相关性：最近的《国家阿尔茨海默病项目法》（NAPA;公法111-375）明确界定了这一问题迅速增长的性质，并要求在2012年制定一项国家计划。2013年启动的活动要到2020年或更晚才能达到明确的临床结果，根据药物开发、临床试验阶段和监管批准的时间轴先例，标准临床实践将在2020年后减少。如果在未来一年内启动拟议的活动，则福尔斯正好在这一时间轴内，并为新分子实体（NME）进入多药物库提供了潜力，这些药物库需要延迟发作、减缓进展并在疾病进展的长时间轴上治疗现有AD

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the sixth-leading cause of death in the United States, yet it is the only disease among the top 10 without a way to prevent, cure or slow its progression. AD kills more people than diabetes or breast cancer and prostate cancer combined. We hypothesize that AD is a progressive synaptic dysfunction disorder in which the glia-neuron axis is a key player and viable as a therapeutic development paradigm in the search for disease-modifying therapeutics. Appropriate communication and interactions between neurons and glia are key to brain homeostasis, and these dynamics are perturbed in disease. Targeting stressor-induced changes in both glia and neurons that contribute to pathology offers the potential to attenuate disease progression mechanisms present in a diverse array of CNS disorders. Regardless of whether the mechanism is a direct causative one or a contributor to disease susceptibility and onset, small molecule modulators of the process would be a major step in development of therapeutic regimes that add to the armamentarium for intervention. This proposal is focused on the stress-related protein kinase p38¿ MAPK, a key node in the signal transduction cascades of eukaryotic cells that amplify and transduce stress signals into physiological changes. The kinase is an established drug discovery target for diverse disorders, but only recently has become the focus of CNS drug discovery efforts. The increased pursuit of p38¿ MAPK as an AD target is due to a combination of landmarks, ranging from the demonstration of kinase activation in human CNS diseases, outcomes from animal model studies, and the demonstration of feasibility for generating CNS-penetrant inhibitors that can improve outcomes in animal models. We propose to use a validated drug discovery engine that successfully delivered novel CNS small molecule drug candidates that progressed to the same IND goal as this proposal and went through first-inhuman phase 1 studies with no adverse events. The specific aims for this project are: Aim 1. Optimize a second-generation inhibitor, MW01-10-181SRM, in order to improve non-GLP ADMET-related properties with retention of target activity, selectivity and in vivo function such that a single candidate can be prioritized for GLP IND-enabling evaluation. Aim 2. Perform GLP preclinical evaluation of a best-in-class candidate compound in order to generate an IND. Aim 3. Submit application for a new molecular entity IND to the FDA for phase 1 first-in-human clinical evaluation in future clinical development. Currently, there are no approved drugs that alter AD pathology progression, and no selective p38¿ MAPK inhibitor drugs in AD clinical trials (existing preclinical development efforts are focused on multi-kinase inhibitors). Therefore, the proposed development campaign will address scientific gaps in the field, and has the potential to yield novel small molecule candidates for first-in-human studies as deliverables. PUBLIC HEALTH RELEVANCE: The recent National Alzheimer's Project Act (NAPA; Public Law 111-375) clearly defines the rapidly growing nature of the problem and requires a national plan in 2012. Campaigns initiated in 2013 will not reach a clear clinical outcome until 2020 or later, with reduction to standard clinical practice being post-2020 based on timeline precedents in drug development, clinical trial phases, and regulatory approval. The proposed campaign, if initiated within the coming year, falls well within this timeline and offers the potential for new molecular entity (NME) entry into the multi-drug arsenal needed to delay onset, slow progression, and treat existing AD across the long timeline of disease progression