BACE-1 hydroxyethylamine inhibitors using novel edge-to-face interaction with Arg-296

Inhibition of the aspartyl protease BACE-1 has the potential to deliver a disease-modifying therapy for Alzheimer’s disease. Herein, is described a series of potent inhibitors based on an hydroxyethylamine (HEA) transition state mimetic template. These inhibitors interact with the non prime side of...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2010-08, Vol.20 (15), p.4639-4644
Hauptverfasser:	Clarke, Brian, Cutler, Leanne, Demont, Emmanuel, Dingwall, Colin, Dunsdon, Rachel, Hawkins, Julie, Howes, Colin, Hussain, Ishrut, Maile, Graham, Matico, Rosalie, Mosley, Julie, Naylor, Alan, O’Brien, Alistair, Redshaw, Sally, Rowland, Paul, Soleil, Virginie, Smith, Kathrine J., Sweitzer, Sharon, Theobald, Pam, Vesey, David, Walter, Daryl S., Wayne, Gareth
Format:	Artikel
Sprache:	eng
Schlagworte:	Alzheimer Alzheimer Disease - drug therapy Amyloid Precursor Protein Secretases - antagonists & inhibitors Amyloid Precursor Protein Secretases - chemistry Amyloid Precursor Protein Secretases - metabolism Animals Arginine - chemistry Aspartic protease BACE-1 Binding Sites Biological and medical sciences Computer Simulation Crystallography, X-Ray Edge-to-face Ethylamines - chemical synthesis Ethylamines - chemistry Ethylamines - therapeutic use Hydroxyethylamine Medical sciences Neuropharmacology Pharmacology. Drug treatments Protease Inhibitors - chemical synthesis Protease Inhibitors - chemistry Protease Inhibitors - therapeutic use Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease) Psychology. Psychoanalysis. Psychiatry Psychopharmacology Rats Structure-Activity Relationship
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Zusammenfassung:	Inhibition of the aspartyl protease BACE-1 has the potential to deliver a disease-modifying therapy for Alzheimer’s disease. Herein, is described a series of potent inhibitors based on an hydroxyethylamine (HEA) transition state mimetic template. These inhibitors interact with the non prime side of the enzyme using a novel edge-to-face interaction with Arg-296.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2010.05.111