Discovery of an Extremely Potent Thiazine-Based β-Secretase (BACE1) Inhibitor with Reduced Cardiovascular and Liver Toxicity at a Low Projected Human Dose
2019
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 1, we describe the discovery of a thiazine-based BACE1 inhibitor 5 with robust Aβ reduction in vivo at low concentrations, leading to a low projected human dose of 14 mg/day where 5 achieved sustained Aβ reduction of 80% at trough level.
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