(300 WORDS MAX) This project's goal is to decrease the inherent risk for future commercial development of a potential new molecular entity (NME) for Alzheimer's disease (AD). The NME candidate is a novel compound that is brain-penetrant with in vivo activity in an AD relevant animal model. The compound targets a key signal transduction enzyme, the protein kinase p38alphaMAPK (p38MAPK), that is an established therapeutic target for peripheral tissue, non-CNS diseases. Growing experimental and clinical evidence implicates p38MAPK in the pathology progression of CNS disorders, including AD. However, existing p38MAPK inhibitor drugs exhibit poor brain penetrance, variable metabolism among individuals due to metabolism by liver enzymes that exhibit high genetic variance, or adverse pharmacologies that rendered them inadequate for use in AD. Our discovery engine for novel small molecules is an innovation process that integrates "smart chemistry" with "smart biology" to address these and other later stage drug development issues early in the initial discovery process. We now have several potential NMEs as deliverables from recursive passage through this process. They are brain penetrant, avoid metabolism by the polymorphic human enzyme, and lack hot spots on the molecule correlated with adverse pharmacologies. Compound 181 (cmpd181) exhibits a promising initial profile and improvement in p38MAPK inhibitor activity. In order to facilitate future commercial development, clinical candidates must be identified and ranked, with the potential risk during investigational new drug (IND) development reduced. This focused project, therefore, will subject cmpd181 to a standard battery of preclinical screens related to stability and off target pharmacology as a way to reduce risk to future licensees. Dependent on the initial results, focused refinement of cmpd181 or an analog will be done in order to generate candidates for future clinical development of what we hope will be a disease-modifying AD drug.