A Potent and Orally Efficacious, Hydroxyethylamine-Based Inhibitor of β-Secretase

β-Secretase inhibitors are potentially disease-modifying treatments for Alzheimer's disease. Previous efforts in our laboratory have resulted in hydroxyethylamine-derived inhibitors such as <b>1</b> with low nanomolar potency against β-site amyloid precursor protein cleaving enzyme (BACE). When dosed intravenously, compound <b>1</b> was also shown to significantly reduce Aβ₄₀ levels in plasma, brain, and cerebral spinal fluid. Herein, we report further optimizations that led to the discovery of inhibitor <b>16</b> as a novel, potent, and orally efficacious BACE inhibitor