Alzheimer's disease (AD) is a fatal protein misfolding disease that afflicts neurons and synapses in the brain. As no therapeutic avenue can currently delay or stop the progression of the disease, there is a need to develop therapeutics and drug targets that can inhibit pathogenesis in AD, a neurodegenerative diseases involving protein misfolding. A promising drug target for AD is protein disulfide isomerase (PDI), a thiol-oxidoreductase chaperone protein that is upregulated in mouse models of, and in brains of patients with, neurological protein folding diseases. One challenge in targeting PDI has been the lack of available drug-like inhibitors for in vivo evaluation in neurodegenerative disease models. Reported inhibitors of PDI that are irreversible inhibitors, have mechanism-based toxicity that is not likely well tolerated in neurons and may be cytotoxic in vivo. We hypothesized that reversible, non-covalent inhibitors of PDI might exhibit a therapeutic window upon PDI inhibition, and would have improved pharmaceutical properties. Enabled by initial funding from the ADDF in 2010 we discovered reversible modulator (LOC14) of PDI that is neuroprotective, has nanomolar potency, high in vitro stability metabolic, and is protective for neurons in a corticostriatal brain slice model for AD. LOC14 is orally bioavailable, blood-brain barrier penetrant, and tolerated at a high dose of 20 mg/kg in mice, making it an ideal scaffold upon which to develop clinical candidate molecules for evaluating the therapeutic potential of inhibiting PDI in AD. We will use the x-ray crystal structure of PDI and our LOC14/PDI binding structure determination in our iterative lead optimization pathway to design, synthesize and evaluate our analogs. A tau-mediated cortical neurodegeneration brain slice model will be a key phenotypic assay for testing and prioritizing the proposed optimized PDI lead candidates