The objective for this work is to deliver an optimized, proprietary, first-in-class, clinically - enabled small molecule drug candidate partial inhibitor of Mitochondrial Complex I (MCI) as a disease-modifying therapeutic approach to treatment of Alzheimer's Disease. Extensive preclinical studies have demonstrated that application of lead compounds CP2 and C458 in multiple mouse models of AD using clinically relevant regimens (chronic dosing over 1 year period starting in utero or at pre- or symptomatic stages of the disease) provide cognitive protection and enhances health span without adverse side-effects. Investigation of the molecular mechanisms suggests that partial inhibition of MCI activates multiple canonical pathways involved in longevity and protection against oxidative stress, which overlap with the mechanisms involved in positive adaptation induced by exercise and caloric restriction (details will be investigated via an approved NIH R01 that is in the top 3% and will be activated in 04/2017). Within the previous funding period, we have: (a) developed a robust testing funnel that incorporates enzymatic assays, Biacore platform assays, and cellular assays to determine whether new compounds selectively and specifically bind MCI, and protect against Abeta toxicity; (b) extended studies with our lead compounds to demonstrate the translational potential of this approach by demonstrating that lead compounds protect human cells, including primary fibroblasts and iPSC-derived neuronal cells, against oxidative stress; (c) illustrated that the lead compounds possess promising pharmacokinetic (PK) profiles and brain penetration in rodents; (d) filed for patent protection (PCT application WO 2016/141188 published 09/09/2016, priority date 03/03/15); and (e) conducted extensive Structure-Activity Relationship (SAR) studies and identified several series of new compounds as MCI inhibitors. Based on the progress achieved to date, we are proposing a 22-month plan to drive forward the latter stages of Lead Optimization (LO), with the goal of identifying a Drug Candidate in 4Q 2018.