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An Orally Available BACE1 Inhibitor That Affords Robust CNS Aß Reduction without Cardiovascular Liabilities.
Cheng, Yuan; Brown, James; Judd, Ted C; Lopez, Patricia; Qian, Wenyuan; Powers, Timothy S; Chen, Jian Jeffrey; Bartberger, Michael D; Chen, Kui; Dunn, Robert T; Epstein, Oleg; Fremeau, Robert T; Harried, Scott; Hickman, Dean; Hitchcock, Stephen A; Luo, Yi; Minatti, Ana Elena; Patel, Vinod F; Vargas, Hugo M; Wahl, Robert C; Weiss, Matthew M; Wen, Paul H; White, Ryan D; Whittington, Douglas A; Zheng, Xiao Mei; Wood, Stephen.
Afiliación
  • Cheng Y; 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, Califor
  • Brown J; 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, Califor
  • Judd TC; 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, Califor
  • Lopez P; 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, Califor
  • Qian W; 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, Califor
  • Powers TS; 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, Califor
  • Chen JJ; 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, Califor
  • Bartberger MD; 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, Califor
  • Chen K; 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, Califor
  • Dunn RT; 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, Califor
  • Epstein O; Department of Medicinal Chemistry and Department of Molecular Structure, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
  • Fremeau RT; 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, Califor
  • Harried S; 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, Califor
  • Hickman D; 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, Califor
  • Hitchcock SA; 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, Califor
  • Luo Y; 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, Califor
  • Minatti AE; 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, Califor
  • Patel VF; Department of Medicinal Chemistry and Department of Molecular Structure, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
  • Vargas HM; 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, Califor
  • Wahl RC; 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, Califor
  • Weiss MM; Department of Medicinal Chemistry and Department of Molecular Structure, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
  • Wen PH; 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, Califor
  • White RD; Department of Medicinal Chemistry and Department of Molecular Structure, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
  • Whittington DA; Department of Medicinal Chemistry and Department of Molecular Structure, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
  • Zheng XM; Department of Medicinal Chemistry and Department of Molecular Structure, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
  • Wood S; 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, Califor
ACS Med Chem Lett ; 6(2): 210-5, 2015 Feb 12.
Article en En | MEDLINE | ID: mdl-25699151
ABSTRACT
BACE1 inhibition to prevent Aß 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 Aß 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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: ACS Med Chem Lett Año: 2015 Tipo del documento: Article
Texto completo
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Imprimir
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PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: ACS Med Chem Lett Año: 2015 Tipo del documento: Article