Discovery of an Extremely Potent Thiazine-Based β-Secretase Inhibitor with Reduced Cardiovascular and Liver Toxicity at a Low Projected Human Dose

Abstract

Genetic evidence points to deposition of amyloid-β (Aβ) as a causal factor for Alzheimer's disease. Aβ generation is initiated when β-secretase (BACE1) cleaves the amyloid precursor protein. Starting with an oxazine lead <b>1</b>, we describe the discovery of a thiazine-based BACE1 inhibitor <b>5</b> with robust Aβ reduction in vivo at low concentrations, leading to a low projected human dose of 14 mg/day where <b>5</b> achieved sustained Aβ reduction of 80% at trough level.