title: An Orally Available BACE1 Inhibitor That Affords Robust CNS Aβ Reduction without Cardiovascular Liabilities.
abstract: BACE1 inhibition to prevent Aβ peptide formation is considered to be a potential route to a disease-modifying treatment for Alzheimer's disease. Previous efforts in our laboratory using a combined structure- and property-based approach have resulted in the identification of aminooxazoline xanthenes as potent BACE1 inhibitors. Herein, we report further optimization leading to the discovery of inhibitor 15 as an orally available and highly efficacious BACE1 inhibitor that robustly reduces CSF and brain Aβ levels in both rats and nonhuman primates. In addition, compound 15 exhibited low activity on the hERG ion channel and was well tolerated in an integrated cardiovascular safety model.
authors.affiliation: Department of Medicinal Chemistry, Department of Molecular Structure, Department of Neuroscience, Department of HTS and Molecular Pharmacology, and Department of Pharmacokinetics and Drug Metabolism, Comparative Biology and Safety Sciences, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Department of Medicinal Chemistry, Department of Molecular Structure, Department of Neuroscience, Department of HTS and Molecular Pharmacology, and Department of Pharmacokinetics and Drug Metabolism, Comparative Biology and Safety Sciences, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: James
authors.initials: J
authors.lastname: Brown
authors.affiliation: Department of Medicinal Chemistry, Department of Molecular Structure, Department of Neuroscience, Department of HTS and Molecular Pharmacology, and Department of Pharmacokinetics and Drug Metabolism, Comparative Biology and Safety Sciences, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Ted C
authors.initials: TC
authors.lastname: Judd
authors.affiliation: Department of Medicinal Chemistry, Department of Molecular Structure, Department of Neuroscience, Department of HTS and Molecular Pharmacology, and Department of Pharmacokinetics and Drug Metabolism, Comparative Biology and Safety Sciences, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Patricia
authors.initials: P
authors.lastname: Lopez
authors.affiliation: Department of Medicinal Chemistry, Department of Molecular Structure, Department of Neuroscience, Department of HTS and Molecular Pharmacology, and Department of Pharmacokinetics and Drug Metabolism, Comparative Biology and Safety Sciences, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Wenyuan
authors.initials: W
authors.lastname: Qian
authors.affiliation: Department of Medicinal Chemistry, Department of Molecular Structure, Department of Neuroscience, Department of HTS and Molecular Pharmacology, and Department of Pharmacokinetics and Drug Metabolism, Comparative Biology and Safety Sciences, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Powers
authors.affiliation: Department of Medicinal Chemistry, Department of Molecular Structure, Department of Neuroscience, Department of HTS and Molecular Pharmacology, and Department of Pharmacokinetics and Drug Metabolism, Comparative Biology and Safety Sciences, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Jian Jeffrey
authors.initials: JJ
authors.lastname: Chen
authors.affiliation: Department of Medicinal Chemistry, Department of Molecular Structure, Department of Neuroscience, Department of HTS and Molecular Pharmacology, and Department of Pharmacokinetics and Drug Metabolism, Comparative Biology and Safety Sciences, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Bartberger
authors.affiliation: Department of Medicinal Chemistry, Department of Molecular Structure, Department of Neuroscience, Department of HTS and Molecular Pharmacology, and Department of Pharmacokinetics and Drug Metabolism, Comparative Biology and Safety Sciences, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Kui
authors.initials: K
authors.lastname: Chen
authors.affiliation: Department of Medicinal Chemistry, Department of Molecular Structure, Department of Neuroscience, Department of HTS and Molecular Pharmacology, and Department of Pharmacokinetics and Drug Metabolism, Comparative Biology and Safety Sciences, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Dunn
authors.affiliation: Department of Medicinal Chemistry and Department of Molecular Structure, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Oleg
authors.initials: O
authors.lastname: Epstein
authors.affiliation: Department of Medicinal Chemistry, Department of Molecular Structure, Department of Neuroscience, Department of HTS and Molecular Pharmacology, and Department of Pharmacokinetics and Drug Metabolism, Comparative Biology and Safety Sciences, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Fremeau
authors.affiliation: Department of Medicinal Chemistry, Department of Molecular Structure, Department of Neuroscience, Department of HTS and Molecular Pharmacology, and Department of Pharmacokinetics and Drug Metabolism, Comparative Biology and Safety Sciences, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Scott
authors.initials: S
authors.lastname: Harried
authors.affiliation: Department of Medicinal Chemistry, Department of Molecular Structure, Department of Neuroscience, Department of HTS and Molecular Pharmacology, and Department of Pharmacokinetics and Drug Metabolism, Comparative Biology and Safety Sciences, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Dean
authors.initials: D
authors.lastname: Hickman
authors.affiliation: Department of Medicinal Chemistry, Department of Molecular Structure, Department of Neuroscience, Department of HTS and Molecular Pharmacology, and Department of Pharmacokinetics and Drug Metabolism, Comparative Biology and Safety Sciences, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Hitchcock
authors.affiliation: Department of Medicinal Chemistry, Department of Molecular Structure, Department of Neuroscience, Department of HTS and Molecular Pharmacology, and Department of Pharmacokinetics and Drug Metabolism, Comparative Biology and Safety Sciences, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Yi
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Department of Medicinal Chemistry, Department of Molecular Structure, Department of Neuroscience, Department of HTS and Molecular Pharmacology, and Department of Pharmacokinetics and Drug Metabolism, Comparative Biology and Safety Sciences, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Ana Elena
authors.initials: AE
authors.lastname: Minatti
authors.affiliation: Department of Medicinal Chemistry and Department of Molecular Structure, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Vinod F
authors.initials: VF
authors.lastname: Patel
authors.affiliation: Department of Medicinal Chemistry, Department of Molecular Structure, Department of Neuroscience, Department of HTS and Molecular Pharmacology, and Department of Pharmacokinetics and Drug Metabolism, Comparative Biology and Safety Sciences, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Hugo M
authors.initials: HM
authors.lastname: Vargas
authors.affiliation: Department of Medicinal Chemistry, Department of Molecular Structure, Department of Neuroscience, Department of HTS and Molecular Pharmacology, and Department of Pharmacokinetics and Drug Metabolism, Comparative Biology and Safety Sciences, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Wahl
authors.affiliation: Department of Medicinal Chemistry and Department of Molecular Structure, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Weiss
authors.affiliation: Department of Medicinal Chemistry, Department of Molecular Structure, Department of Neuroscience, Department of HTS and Molecular Pharmacology, and Department of Pharmacokinetics and Drug Metabolism, Comparative Biology and Safety Sciences, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Paul H
authors.initials: PH
authors.lastname: Wen
authors.affiliation: Department of Medicinal Chemistry and Department of Molecular Structure, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Ryan D
authors.initials: RD
authors.lastname: White
authors.affiliation: Department of Medicinal Chemistry and Department of Molecular Structure, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Whittington
authors.affiliation: Department of Medicinal Chemistry and Department of Molecular Structure, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Xiao Mei
authors.initials: XM
authors.lastname: Zheng
authors.affiliation: Department of Medicinal Chemistry, Department of Molecular Structure, Department of Neuroscience, Department of HTS and Molecular Pharmacology, and Department of Pharmacokinetics and Drug Metabolism, Comparative Biology and Safety Sciences, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Stephen
authors.initials: S
authors.lastname: Wood
keywords: Alzheimer’s disease (AD); Aβ; aminooxazoline; xanthene; β-site amyloid precursor protein cleaving enzyme 1 (BACE1)