title: A Potent and Orally Efficacious, Hydroxyethylamine-Based Inhibitor of β-Secretase.
abstract: β-Secretase inhibitors are potentially disease-modifying treatments for Alzheimer's disease. Previous efforts in our laboratory have resulted in hydroxyethylamine-derived inhibitors such as 1 with low nanomolar potency against β-site amyloid precursor protein cleaving enzyme (BACE). When dosed intravenously, compound 1 was also shown to significantly reduce Aβ40 levels in plasma, brain, and cerebral spinal fluid. Herein, we report further optimizations that led to the discovery of inhibitor 16 as a novel, potent, and orally efficacious BACE inhibitor.
authors.affiliation: Chemistry Research and Discovery, Department of Molecular Structure, Department of Neuroscience, Department of HTS and Molecular Pharmacology, and Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Kaller
authors.affiliation: Chemistry Research and Discovery, Department of Molecular Structure, Department of Neuroscience, Department of HTS and Molecular Pharmacology, and Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Scott S
authors.initials: SS
authors.lastname: Harried
authors.affiliation: Chemistry Research and Discovery, Amgen Inc. , One Kendall Square Building 1000, Cambridge, Massachusetts 02139, United States.
authors.forename: Brian
authors.initials: B
authors.lastname: Albrecht
authors.affiliation: Chemistry Research and Discovery, Department of Molecular Structure, Department of Neuroscience, Department of HTS and Molecular Pharmacology, and Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Patricia
authors.initials: P
authors.lastname: Amarante
authors.affiliation: Chemistry Research and Discovery, Department of Molecular Structure, Department of Neuroscience, Department of HTS and Molecular Pharmacology, and Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Safura
authors.initials: S
authors.lastname: Babu-Khan
authors.affiliation: Chemistry Research and Discovery, Department of Molecular Structure, Department of Neuroscience, Department of HTS and Molecular Pharmacology, and Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Bartberger
authors.affiliation: Chemistry Research and Discovery, Department of Molecular Structure, Department of Neuroscience, Department of HTS and Molecular Pharmacology, and Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: James
authors.initials: J
authors.lastname: Brown
authors.affiliation: Chemistry Research and Discovery, Amgen Inc. , One Kendall Square Building 1000, Cambridge, Massachusetts 02139, United States.
authors.forename: Ryan
authors.initials: R
authors.lastname: Brown
authors.affiliation: Chemistry Research and Discovery, Department of Molecular Structure, Department of Neuroscience, Department of HTS and Molecular Pharmacology, and Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Kui
authors.initials: K
authors.lastname: Chen
authors.affiliation: Chemistry Research and Discovery, Department of Molecular Structure, Department of Neuroscience, Department of HTS and Molecular Pharmacology, and Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Chemistry Research and Discovery, Department of Molecular Structure, Department of Neuroscience, Department of HTS and Molecular Pharmacology, and Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Martin
authors.initials: M
authors.lastname: Citron
authors.affiliation: Chemistry Research and Discovery, Department of Molecular Structure, Department of Neuroscience, Department of HTS and Molecular Pharmacology, and Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Croghan
authors.affiliation: Chemistry Research and Discovery, Amgen Inc. , One Kendall Square Building 1000, Cambridge, Massachusetts 02139, United States.
authors.forename: Russell
authors.initials: R
authors.lastname: Graceffa
authors.affiliation: Chemistry Research and Discovery, Department of Molecular Structure, Department of Neuroscience, Department of HTS and Molecular Pharmacology, and Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Dean
authors.initials: D
authors.lastname: Hickman
authors.affiliation: Chemistry Research and Discovery, Department of Molecular Structure, Department of Neuroscience, Department of HTS and Molecular Pharmacology, and Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Ted
authors.initials: T
authors.lastname: Judd
authors.affiliation: Chemistry Research and Discovery, Amgen Inc. , One Kendall Square Building 1000, Cambridge, Massachusetts 02139, United States.
authors.forename: Chuck
authors.initials: C
authors.lastname: Kriemen
authors.affiliation: Chemistry Research and Discovery, Amgen Inc. , One Kendall Square Building 1000, Cambridge, Massachusetts 02139, United States.
authors.forename: Daniel
authors.initials: D
authors.lastname: La
authors.affiliation: Chemistry Research and Discovery, Department of Molecular Structure, Department of Neuroscience, Department of HTS and Molecular Pharmacology, and Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Vivian
authors.initials: V
authors.lastname: Li
authors.affiliation: Chemistry Research and Discovery, Department of Molecular Structure, Department of Neuroscience, Department of HTS and Molecular Pharmacology, and Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Patricia
authors.initials: P
authors.lastname: Lopez
authors.affiliation: Chemistry Research and Discovery, Department of Molecular Structure, Department of Neuroscience, Department of HTS and Molecular Pharmacology, and Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Yi
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Chemistry Research and Discovery, Amgen Inc. , One Kendall Square Building 1000, Cambridge, Massachusetts 02139, United States.
authors.forename: Craig
authors.initials: C
authors.lastname: Masse
authors.affiliation: Chemistry Research and Discovery, Department of Molecular Structure, Department of Neuroscience, Department of HTS and Molecular Pharmacology, and Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Holger
authors.initials: H
authors.lastname: Monenschein
authors.affiliation: Chemistry Research and Discovery, Department of Molecular Structure, Department of Neuroscience, Department of HTS and Molecular Pharmacology, and Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Thomas
authors.initials: T
authors.lastname: Nguyen
authors.affiliation: Chemistry Research and Discovery, Department of Molecular Structure, Department of Neuroscience, Department of HTS and Molecular Pharmacology, and Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Lewis D
authors.initials: LD
authors.lastname: Pennington
authors.affiliation: Chemistry Research and Discovery, Department of Molecular Structure, Department of Neuroscience, Department of HTS and Molecular Pharmacology, and Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Tisha San
authors.initials: TS
authors.lastname: Miguel
authors.affiliation: Chemistry Research and Discovery, Department of Molecular Structure, Department of Neuroscience, Department of HTS and Molecular Pharmacology, and Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: E Allen
authors.initials: EA
authors.lastname: Sickmier
authors.affiliation: Chemistry Research and Discovery, Department of Molecular Structure, Department of Neuroscience, Department of HTS and Molecular Pharmacology, and Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Wahl
authors.affiliation: Chemistry Research and Discovery, Amgen Inc. , One Kendall Square Building 1000, Cambridge, Massachusetts 02139, United States.
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Weiss
authors.affiliation: Chemistry Research and Discovery, Department of Molecular Structure, Department of Neuroscience, Department of HTS and Molecular Pharmacology, and Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Paul H
authors.initials: PH
authors.lastname: Wen
authors.affiliation: Chemistry Research and Discovery, Department of Molecular Structure, Department of Neuroscience, Department of HTS and Molecular Pharmacology, and Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Toni
authors.initials: T
authors.lastname: Williamson
authors.affiliation: Chemistry Research and Discovery, Department of Molecular Structure, Department of Neuroscience, Department of HTS and Molecular Pharmacology, and Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Stephen
authors.initials: S
authors.lastname: Wood
authors.affiliation: Chemistry Research and Discovery, Department of Molecular Structure, Department of Neuroscience, Department of HTS and Molecular Pharmacology, and Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: May
authors.initials: M
authors.lastname: Xue
authors.affiliation: Chemistry Research and Discovery, Department of Molecular Structure, Department of Neuroscience, Department of HTS and Molecular Pharmacology, and Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Bryant
authors.initials: B
authors.lastname: Yang
authors.affiliation: Chemistry Research and Discovery, Department of Molecular Structure, Department of Neuroscience, Department of HTS and Molecular Pharmacology, and Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Chemistry Research and Discovery, Amgen Inc. , One Kendall Square Building 1000, Cambridge, Massachusetts 02139, United States.
authors.forename: Vinod
authors.initials: V
authors.lastname: Patel
authors.affiliation: Chemistry Research and Discovery, Department of Molecular Structure, Department of Neuroscience, Department of HTS and Molecular Pharmacology, and Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Wenge
authors.initials: W
authors.lastname: Zhong
authors.affiliation: Chemistry Research and Discovery, Department of Molecular Structure, Department of Neuroscience, Department of HTS and Molecular Pharmacology, and Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Stephen
authors.initials: S
authors.lastname: Hitchcock
keywords: Alzheimer's disease (AD); hydroxyethylamine (HEA) isostere; β-site amyloid precursor protein cleaving enzyme (BACE)