ABSTRACT Traditional mon-therapeutic, target driven approaches to drug development for Alzheimer’s disease (AD) are becoming increasingly expensive and in many cases disappointingly unsuccessful. Based on preliminary in vitro and in vivo studies we have identified a novel small molecule (methyl 2,4-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridine-1-carboxylate; (BNC-1)) that significantly decreases neuroinflammation and production of Aβ42 in mouse models of AD pathology through Elk-1 mediated transcriptional repression of presenilin-1 but not presenilin-2. Although our preliminary data show BNC-1 effectively modulates 2 of the main pathologic features of AD without the adverse effects associated with current mono- therapeutics, there is a need for characterization of its basic pharmacology/toxicity and for identification of the most efficacious treatment regimen in a well characterized mouse model of Aβ deposition and neuroinflammation (5X FAD mice). If successful, the data obtained in this proposal will provide necessary pharmacology/safety toxicology data to de-risk the drug for potential corporate partners thus increasing the likelihood of successful commercialization.

Narrative In preliminary studies, we identified a novel small molecule (methyl 2,4-dimethyl-5-oxo-5,6- dihydrobenzo[c][2,7]naphthyridine-1-carboxylate; (BNC-1) that lowers beta amyloid (Aβ) production and pro-inflammatory cytokines but increases anti-inflammatory cytokines and significantly improves behavioral measures in a mouse model of Alzheimer’s disease. Future studies described in this proposal aim to determine the pharmacokinetics and toxicology of BNC-1 and to test the efficacy for prevention of beta amyloid (Aβ) formation and deposition and neuroinflammation in a well-established, alternative mouse model of Aβ pathology (5X FAD mice). Together these studies will help de-risk BNC- 1 for potential partners and better position the compound for further commercialization.