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.