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 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.
MeSH terms
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Alzheimer Disease / metabolism
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Alzheimer Disease / pathology
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Amyloid Precursor Protein Secretases / antagonists & inhibitors*
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Amyloid Precursor Protein Secretases / metabolism
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Amyloid beta-Peptides / metabolism
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Animals
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Brain / drug effects
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Brain / metabolism
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Cytochrome P-450 CYP2C9 / chemistry
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Cytochrome P-450 CYP2C9 / metabolism
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Dogs
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Drug Evaluation, Preclinical
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Female
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Half-Life
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Haplorhini
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Heart / drug effects
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Humans
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Liver / drug effects
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Liver / metabolism
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Male
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Mice
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Protease Inhibitors / chemistry*
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Protease Inhibitors / pharmacokinetics
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Protease Inhibitors / pharmacology
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Rats
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Rats, Sprague-Dawley
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Thiazines / chemistry*
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Thiazines / metabolism
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Thiazines / pharmacology
Substances
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Amyloid beta-Peptides
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Protease Inhibitors
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Thiazines
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Cytochrome P-450 CYP2C9
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Amyloid Precursor Protein Secretases