title: Structure- and property-based design of aminooxazoline xanthenes as selective, orally efficacious, and CNS penetrable BACE inhibitors for the treatment of Alzheimer's disease.
abstract: A structure- and property-based drug design approach was employed to identify aminooxazoline xanthenes as potent and selective human β-secretase inhibitors. These compounds exhibited good isolated enzyme, cell potency, and selectivity against the structurally related aspartyl protease cathepsin D. Our efforts resulted in the identification of a potent, orally bioavailable CNS penetrant compound that exhibited in vivo efficacy. A single oral dose of compound 11a resulted in a significant reduction of CNS Aβ40 in naive rats.
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., 360 Binney Street, Cambridge, Massachusetts 02142, United States. hongbing.huang@amgen.com
authors.forename: Hongbing
authors.initials: H
authors.lastname: Huang
authors.forename: Daniel S
authors.initials: DS
authors.lastname: La
authors.forename: Alan C
authors.initials: AC
authors.lastname: Cheng
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Whittington
authors.forename: Vinod F
authors.initials: VF
authors.lastname: Patel
authors.forename: Kui
authors.initials: K
authors.lastname: Chen
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Dineen
authors.forename: Oleg
authors.initials: O
authors.lastname: Epstein
authors.forename: Russell
authors.initials: R
authors.lastname: Graceffa
authors.forename: Dean
authors.initials: D
authors.lastname: Hickman
authors.forename: Y-H
authors.initials: YH
authors.lastname: Kiang
authors.forename: Steven
authors.initials: S
authors.lastname: Louie
authors.forename: Yi
authors.initials: Y
authors.lastname: Luo
authors.forename: Robert C
authors.initials: RC
authors.lastname: Wahl
authors.forename: Paul H
authors.initials: PH
authors.lastname: Wen
authors.forename: Stephen
authors.initials: S
authors.lastname: Wood
authors.forename: Robert T
authors.initials: RT
authors.lastname: Fremeau
mesh_terms: D000284:Administration, Oral; D000544:Alzheimer Disease / Q000188:drug therapy*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D001921:Brain / Q000378:metabolism*; D002460:Cell Line; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010080:Oxazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D010446:Peptide Fragments / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014966:Xanthenes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D010080:Oxazoles; D010446:Peptide Fragments; D014966:Xanthenes; C078592:amyloid beta-protein (1-40); D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human