Refinement of p38alpha MAPK Inhibitors for Alzheimer's Disease

The goal of this project is to de-risk a novel, CNS-penetrant, efficacious, small molecule in order to identify a new therapeutic candidate for Alzheimer's disease (AD). The initial lead compound and its more refined analog were developed through structure-assisted, selective ligand targeting of p38alphaMAPK, a key protein kinase that drives overproduction of proinflammatory cytokines in response to diverse stressors and is involved in neuronal homeostasis. The p38alphaMAPK isoform is considered a validated therapeutic target for peripheral tissue disorders, but the extension to CNS disorders was limited by the need for adequate CNS penetrance with retention of selective inhibitory activity. To initially address this problem, we used our validated discovery engine that integrates informatics and computational biology with pharmacology experimental filters. This provides a recursive, drug discovery focused effort. The initial novel small molecule, cmpd 069A, is a selective p38alphaMAPK inhibitor that is brain penetrant and shows efficacy in an AD-relevant animal model that exhibits the targeted mechanism of pathology progression. The recursive nature of the discovery engine yielded a variety of second-generation inhibitors, with cmpd 181 exhibiting promising pharmacology profiles with retention of p38alphaMAPK inhibitor activity. Growing evidence has implicated p38alphaMAPK in CNS disorders, including AD. The activation of p38alphaMAPK appears to be an early event in AD, and its activation is linked to cytokine overproduction and synaptic dysfunction, and correlates with pathology progression. This proposed research is an early step in testing the hypothesis that orally bioavailable, brain-penetrant, small molecule p38alphaMAPK inhibitors can be developed into effective therapeutics with potential for use in AD.