[P3–057]: MODULATION OF MITOCHONDRIAL COMPLEX I ACTIVITY AS A DISEASE‐MODIFYING STRATEGY FOR AD

focused on synaptic dysfunction and innate immunity as a common pathophysiology progression theme, we developed a platform that delivers new in vivo molecular probes of different potential therapeutic intervention mechanisms. Methods: The platform is based on highly focused organic syntheses of new chemical entities designed by risk reduction using pharmacoinformatics combined with project-specific considerations. Key among pharmacoinformatic restrictions were multi-property profiles based on curated databases of in vivo CNS drugs and drug candidates. Initial sets of synthesized compounds were taken through non-GLP ADMETbased pharmacological screens as a Go or NoGo decision point. Compounds passing Go were taken through hierarchical screens of activity related to pharmacological mechanism and in vivo efficacy. A prototype single molecular target approach for CNS protein kinases was brain p38aMAPK, an established target whose activity is up-regulated in glia and neurons in stress responses. The phenotypic approach focused on early stage overproduction of proinflammatory cytokines causally linked to synaptic dysfunction. Results: The case study presentations are those based on an aminoarylpyridazine molecular fragment and its chemical diversification. Novel small molecule deliverables for each pharmacological intervention approach show efficacy in AD-relevant mouse models. Conclusions:Our validated discovery platform has generated efficacious, CNS-active, in vivo molecular probes. ADMET-optimized versions of these probes are in late stage, investigational new drug (IND) development or early stage first-in-human clinical trials.