Robust central reduction of amyloid-β in humans with an orally available, non-peptidic β-secretase inhibitor

• Published in: The Journal of neuroscience Vol. 31; no. 46; pp. 16507 - 16516
• Main Authors: May, Patrick C, Dean, Robert A, Lowe, Stephen L, Martenyi, Ferenc, Sheehan, Scott M, Boggs, Leonard N, Monk, Scott A, Mathes, Brian M, Mergott, Dustin J, Watson, Brian M, Stout, Stephanie L, Timm, David E, Smith Labell, Elizabeth, Gonzales, Celedon R, Nakano, Masako, Jhee, Stanford S, Yen, Mark, Ereshefsky, Larry, Lindstrom, Terry D, Calligaro, David O, Cocke, Patrick J, Greg Hall, D, Friedrich, Stuart, Citron, Martin, Audia, James E
• Format: Journal Article
• Language: English
• Published: United States Society for Neuroscience 16.11.2011
• Subjects: Adult; Alzheimer Disease - cerebrospinal fluid; Alzheimer Disease - drug therapy; Amyloid beta-Peptides - cerebrospinal fluid; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - cerebrospinal fluid; Amyloid beta-Protein Precursor - genetics; Amyloid Precursor Protein Secretases - analysis; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Analysis of Variance; Animals; Aspartic Acid Endopeptidases - analysis; Aspartic Acid Endopeptidases - antagonists & inhibitors; Cells, Cultured; Cerebral Cortex - cytology; Crystallography - methods; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Embryo, Mammalian; Enzyme Inhibitors - blood; Enzyme Inhibitors - pharmacology; Enzyme-Linked Immunosorbent Assay - methods; Female; Humans; Male; Mice; Mice, Transgenic; Middle Aged; Models, Chemical; Mutation - genetics; Neurons - drug effects; Peptide Fragments - cerebrospinal fluid; Pyrimidines - pharmacology; Pyrimidines - therapeutic use; Rats; Rats, Sprague-Dawley; Thiazines - pharmacology; Thiazines - therapeutic use; Time Factors; Young Adult

According to the amyloid cascade hypothesis, cerebral deposition of amyloid-β peptide (Aβ) is critical for Alzheimer's disease (AD) pathogenesis. Aβ generation is initiated when β-secretase (BACE1) cleaves the amyloid precursor protein. For more than a decade, BACE1 has been a prime target for...