Design of an orally efficacious hydroxyethylamine (HEA) BACE-1 inhibitor in a preclinical animal model

In this letter, we describe our efforts to design HEA BACE-1 inhibitors that are highly permeable coupled with negligible levels of permeability-glycoprotein activity. These efforts culminate in producing 16 which lowers Aβ by 28% and 32% in the cortex and CSF, respectively, in the wild type preclin...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2010-11, Vol.20 (21), p.6231-6236
Hauptverfasser:	Truong, Anh P., Tóth, Gergley, Probst, Gary D., Sealy, Jennifer M., Bowers, Simeon, Wone, David W.G., Dressen, Darren, Hom, Roy K., Konradi, Andrei W., Sham, Hing L., Wu, Jing, Peterson, Brian T., Ruslim, Lany, Bova, Michael P., Kholodenko, Dora, Motter, Ruth N., Bard, Frédérique, Santiago, Pamela, Ni, Huifang, Chian, David, Soriano, Ferdie, Cole, Tracy, Brigham, Elizabeth F., Wong, Karina, Zmolek, Wes, Goldbach, Erich, Samant, Bhushan, Chen, Linda, Zhang, Hongbing, Nakamura, David F., Quinn, Kevin P., Yednock, Ted A., Sauer, John-Michael
Format:	Artikel
Sprache:	eng
Schlagworte:	Alkylation Alzheimer Disease Alzheimer’s disease Amyloid Precursor Protein Secretases - antagonists & inhibitors Animals Aspartic Acid Endopeptidases - antagonists & inhibitors BACE-1 inhibitor Biological and medical sciences Brain - metabolism Cell Line Dogs Drug Design Ethylamines - chemical synthesis Ethylamines - pharmacology Fluorine Guinea Pigs Humans Hydroxyethylamine (HEA) Indicators and Reagents Medical sciences Neuropharmacology Pharmacology. Drug treatments Protease Inhibitors - chemical synthesis Protease Inhibitors - pharmacokinetics Protease Inhibitors - pharmacology Protein Binding Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease) Psychology. Psychoanalysis. Psychiatry Psychopharmacology Structure-Activity Relationship
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