In this Phase IIB SBIR project for Alzheimer’s disease (AD) drug development, Neurodon LLC proposes to conduct preclinical development and IND-enabling activities on our novel, orally available lead and backup compounds that, in our preceding Phase II project, showed neuroprotection and beneficial effects on learning and memory in a transgenic model of AD. Despite the enormity of AD as a national public health burden, the therapeutic options are very limited. The few approved drugs treat only symptoms, and there are no disease- modifying therapies available. All of the disease-modifying clinical trials have failed, with most drug targets being amyloid or amyloid-related. With this patient population set to almost triple over the next 30 years, there is an urgent need for disease-modifying therapies, specifically alternatives to amyloid-targeted drugs. Neuron loss is the only physiological phenomena that has been directly linked to the cognition and memory loss in patients, and a major cause of this brain cell loss in AD is endoplasmic reticulum (ER) stress-induced apoptosis caused by aberrant intracellular Ca2+ homeostasis. Neurodon’s patented, small molecule activators of the major ER Ca2+ handling protein, sarco/endoplasmic reticulum Ca2+-ATPase (SERCA), correct neuronal calcium handling, rescue brain cells in vitro and in vivo, improve learning and memory in the APP/PS1 double transgenic mouse model of AD, and reduce ER stress and apoptosis markers in vivo, enabling biomarker- driven drug discovery and an improved probability of clinical success. Our Phase II research met the milestones of nominating orally active lead and backup compounds that show efficacy in an animal model of AD. Our goal of delivering an IND for AD will be accomplished by pursuing the following Aims: 1) Chemistry scale-up, pre-formulation, ADME, and PK on our lead SERCA2b activator and 2 backup compounds. 2) To assess the effects of SERCA2b activators on cognition and profiling AD mechanism-specific biomarkers in vivo. 3) Perform necessary preclinical studies on a selected SERCA2b activator new chemical entity (NCE) and backup compound in preparation for IND filing. The results of these Aims will be the generation of efficacy, safety, and CMC information to complete a submission-ready FDA IND application for a new, disease- modifying therapeutic for AD.