Preclinical Alzheimers Disease Drug Development of Novel MAPK Inhibitors

描述(申请人提供)：阿尔茨海默病(AD)是美国第六大死亡原因，但它是前十名中唯一一种无法预防、治愈或减缓其进展的疾病。AD导致的死亡人数比糖尿病、乳腺癌和前列腺癌的总和还要多。我们假设AD是一种进行性突触功能障碍，其中胶质细胞-神经元轴是一个关键角色，在寻找疾病修改疗法方面作为一种治疗发展范例是可行的。神经元和神经胶质细胞之间的适当沟通和相互作用是大脑动态平衡的关键，而这些动态在疾病中受到干扰。靶向应激诱导的胶质细胞和神经元的变化有助于病理，提供了减缓疾病进展机制的潜力，这些机制存在于各种中枢神经系统疾病中。无论这种机制是直接致病机制，还是疾病易感性和发病的贡献者，这个过程的小分子调节器都将是发展治疗机制的重要一步，从而增加干预的武器装备。 这一建议的重点是应激相关蛋白激酶p38？MAPK，它是真核细胞信号转导通路中的一个关键节点，将应激信号放大并转换为生理变化。该激酶是多种疾病的既定药物发现靶点，但直到最近才成为中枢神经系统药物发现努力的重点。对p38？MAPK作为AD靶点的追求增加是由于一系列里程碑的结合，从人类中枢神经系统疾病中的激酶激活的证明，动物模型研究的结果，以及产生能够改善动物模型结果的中枢神经系统穿透性抑制剂的可行性的证明。 我们建议使用一种经过验证的药物发现引擎，该引擎成功地交付了新的CNS小分子药物候选药物，这些候选药物进展到了与该建议相同的IND目标，并经历了第一阶段的非人类研究，没有不良事件。本项目的具体目标是：目标1.优化第二代抑制剂MW01-10-181SRM，以便在保留靶标活性、选择性和体内功能的情况下改善非GLP admet相关特性，以便能够优先考虑单个候选者进行GLP Ind-Enabling评估。目的2.对一种同类最佳候选化合物进行GLP临床前评估，以产生IND。目的3.向FDA提交一种新的分子实体IND的申请，用于未来临床开发的第一阶段人类临床评估。 目前，没有批准的药物可以改变AD的病理进展，也没有选择性的p38？MAPK抑制剂药物在AD临床试验中(现有的临床前开发工作 主要集中在多激酶抑制剂)。因此，拟议的开发活动将解决该领域的科学空白，并有可能产生新的小分子候选对象，作为首个人类研究的交付成果。

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.