title: Development of 2-aminooxazoline 3-azaxanthenes as orally efficacious β-secretase inhibitors for the potential treatment of Alzheimer's disease.
abstract: The β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is one of the most hotly pursued targets for the treatment of Alzheimer's disease. We used a structure- and property-based drug design approach to identify 2-aminooxazoline 3-azaxanthenes as potent BACE1 inhibitors which significantly reduced CSF and brain Aβ levels in a rat pharmacodynamic model. Compared to the initial lead 2, compound 28 exhibited reduced potential for QTc prolongation in a non-human primate cardiovascular safety model.
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA. Electronic address: jianc@amgen.com.
authors.forename: Jian Jeffrey
authors.initials: JJ
authors.lastname: Chen
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
authors.forename: Qingyian
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
authors.forename: Chester
authors.initials: C
authors.lastname: Yuan
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
authors.forename: Vijay
authors.initials: V
authors.lastname: Gore
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Lopez
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
authors.forename: Vu
authors.initials: V
authors.lastname: Ma
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
authors.forename: Albert
authors.initials: A
authors.lastname: Amegadzie
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
authors.forename: Wenyuan
authors.initials: W
authors.lastname: Qian
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
authors.forename: Ted C
authors.initials: TC
authors.lastname: Judd
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
authors.forename: Ana E
authors.initials: AE
authors.lastname: Minatti
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
authors.forename: James
authors.initials: J
authors.lastname: Brown
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
authors.forename: May
authors.initials: M
authors.lastname: Xue
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
authors.forename: Wenge
authors.initials: W
authors.lastname: Zhong
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., 360 Binney Street, Cambridge, MA 02142, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Dineen
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., 360 Binney Street, Cambridge, MA 02142, USA.
authors.forename: Oleg
authors.initials: O
authors.lastname: Epstein
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., 360 Binney Street, Cambridge, MA 02142, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Human
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., 360 Binney Street, Cambridge, MA 02142, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Kreiman
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., 360 Binney Street, Cambridge, MA 02142, USA.
authors.forename: Isaac
authors.initials: I
authors.lastname: Marx
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., 360 Binney Street, Cambridge, MA 02142, USA.
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Weiss
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Hitchcock
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Powers
authors.affiliation: Department of HTS and Molecular Pharmacology, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
authors.forename: Kui
authors.initials: K
authors.lastname: Chen
authors.affiliation: Department of Neuroscience, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
authors.forename: Paul H
authors.initials: PH
authors.lastname: Wen
authors.affiliation: Department of Molecular Structure, Amgen Inc., 360 Binney Street, Cambridge, MA 02142, USA.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Whittington
authors.affiliation: Department of Molecular Structure, Amgen Inc., 360 Binney Street, Cambridge, MA 02142, USA.
authors.forename: Alan C
authors.initials: AC
authors.lastname: Cheng
authors.affiliation: Department of Molecular Structure, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Bartberger
authors.affiliation: Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
authors.forename: Dean
authors.initials: D
authors.lastname: Hickman
authors.affiliation: Comparative Biology and Safety Sciences, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Werner
authors.affiliation: Comparative Biology and Safety Sciences, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
authors.forename: Hugo M
authors.initials: HM
authors.lastname: Vargas
authors.affiliation: Comparative Biology and Safety Sciences, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Everds
authors.affiliation: Comparative Biology and Safety Sciences, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Vonderfecht
authors.affiliation: Comparative Biology and Safety Sciences, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Dunn
authors.affiliation: Department of Neuroscience, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Wood
authors.affiliation: Department of Neuroscience, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Fremeau
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., 360 Binney Street, Cambridge, MA 02142, USA.
authors.forename: Ryan D
authors.initials: RD
authors.lastname: White
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., 360 Binney Street, Cambridge, MA 02142, USA.
authors.forename: Vinod F
authors.initials: VF
authors.lastname: Patel
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D002460:Cell Line; D057809:HEK293 Cells; D006801:Humans; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D014966:Xanthenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D011480:Protease Inhibitors; D014966:Xanthenes; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human
keywords: 3-Azaxanthene; Alzheimer’s disease (AD); Aminooxazoline; Amyloid; Aβ peptides; Xanthene; β-Secretase (BACE1)