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Research ArticleNeuropharmacology

Establishing the Relationship between In Vitro Potency, Pharmacokinetic, and Pharmacodynamic Parameters in a Series of Orally Available, Hydroxyethylamine-Derived β-Secretase Inhibitors

Stephen Wood, Paul H. Wen, Jianhua Zhang, Li Zhu, Yi Luo, Safura Babu-Khan, Kui Chen, Roger Pham, Joel Esmay, Thomas A. Dineen, Matthew R. Kaller, Matthew M. Weiss, Stephen A. Hitchcock, Martin Citron, Wenge Zhong, Dean Hickman and Toni Williamson
Journal of Pharmacology and Experimental Therapeutics November 2012, 343 (2) 460-467; DOI: https://doi.org/10.1124/jpet.112.197954
Stephen Wood
Departments of Neuroscience (S.W., P.H.W., J.Z., L.Z., Y.L., S.B.-K., M.C., T.W.), Molecular Structure and Characterization (K.C.), Pharmacokinetics and Drug Metabolism (R.P., J.E., D.H.), and Medicinal Chemistry (M.R.K., S.A.H., W.Z.), Amgen, Inc., Thousand Oaks, California; and Department of Medicinal Chemistry, Amgen, Inc., Cambridge, Massachusetts (T.A.D., M.M.W.)
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Paul H. Wen
Departments of Neuroscience (S.W., P.H.W., J.Z., L.Z., Y.L., S.B.-K., M.C., T.W.), Molecular Structure and Characterization (K.C.), Pharmacokinetics and Drug Metabolism (R.P., J.E., D.H.), and Medicinal Chemistry (M.R.K., S.A.H., W.Z.), Amgen, Inc., Thousand Oaks, California; and Department of Medicinal Chemistry, Amgen, Inc., Cambridge, Massachusetts (T.A.D., M.M.W.)
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Jianhua Zhang
Departments of Neuroscience (S.W., P.H.W., J.Z., L.Z., Y.L., S.B.-K., M.C., T.W.), Molecular Structure and Characterization (K.C.), Pharmacokinetics and Drug Metabolism (R.P., J.E., D.H.), and Medicinal Chemistry (M.R.K., S.A.H., W.Z.), Amgen, Inc., Thousand Oaks, California; and Department of Medicinal Chemistry, Amgen, Inc., Cambridge, Massachusetts (T.A.D., M.M.W.)
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Li Zhu
Departments of Neuroscience (S.W., P.H.W., J.Z., L.Z., Y.L., S.B.-K., M.C., T.W.), Molecular Structure and Characterization (K.C.), Pharmacokinetics and Drug Metabolism (R.P., J.E., D.H.), and Medicinal Chemistry (M.R.K., S.A.H., W.Z.), Amgen, Inc., Thousand Oaks, California; and Department of Medicinal Chemistry, Amgen, Inc., Cambridge, Massachusetts (T.A.D., M.M.W.)
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Yi Luo
Departments of Neuroscience (S.W., P.H.W., J.Z., L.Z., Y.L., S.B.-K., M.C., T.W.), Molecular Structure and Characterization (K.C.), Pharmacokinetics and Drug Metabolism (R.P., J.E., D.H.), and Medicinal Chemistry (M.R.K., S.A.H., W.Z.), Amgen, Inc., Thousand Oaks, California; and Department of Medicinal Chemistry, Amgen, Inc., Cambridge, Massachusetts (T.A.D., M.M.W.)
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Safura Babu-Khan
Departments of Neuroscience (S.W., P.H.W., J.Z., L.Z., Y.L., S.B.-K., M.C., T.W.), Molecular Structure and Characterization (K.C.), Pharmacokinetics and Drug Metabolism (R.P., J.E., D.H.), and Medicinal Chemistry (M.R.K., S.A.H., W.Z.), Amgen, Inc., Thousand Oaks, California; and Department of Medicinal Chemistry, Amgen, Inc., Cambridge, Massachusetts (T.A.D., M.M.W.)
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Kui Chen
Departments of Neuroscience (S.W., P.H.W., J.Z., L.Z., Y.L., S.B.-K., M.C., T.W.), Molecular Structure and Characterization (K.C.), Pharmacokinetics and Drug Metabolism (R.P., J.E., D.H.), and Medicinal Chemistry (M.R.K., S.A.H., W.Z.), Amgen, Inc., Thousand Oaks, California; and Department of Medicinal Chemistry, Amgen, Inc., Cambridge, Massachusetts (T.A.D., M.M.W.)
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Roger Pham
Departments of Neuroscience (S.W., P.H.W., J.Z., L.Z., Y.L., S.B.-K., M.C., T.W.), Molecular Structure and Characterization (K.C.), Pharmacokinetics and Drug Metabolism (R.P., J.E., D.H.), and Medicinal Chemistry (M.R.K., S.A.H., W.Z.), Amgen, Inc., Thousand Oaks, California; and Department of Medicinal Chemistry, Amgen, Inc., Cambridge, Massachusetts (T.A.D., M.M.W.)
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Joel Esmay
Departments of Neuroscience (S.W., P.H.W., J.Z., L.Z., Y.L., S.B.-K., M.C., T.W.), Molecular Structure and Characterization (K.C.), Pharmacokinetics and Drug Metabolism (R.P., J.E., D.H.), and Medicinal Chemistry (M.R.K., S.A.H., W.Z.), Amgen, Inc., Thousand Oaks, California; and Department of Medicinal Chemistry, Amgen, Inc., Cambridge, Massachusetts (T.A.D., M.M.W.)
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Thomas A. Dineen
Departments of Neuroscience (S.W., P.H.W., J.Z., L.Z., Y.L., S.B.-K., M.C., T.W.), Molecular Structure and Characterization (K.C.), Pharmacokinetics and Drug Metabolism (R.P., J.E., D.H.), and Medicinal Chemistry (M.R.K., S.A.H., W.Z.), Amgen, Inc., Thousand Oaks, California; and Department of Medicinal Chemistry, Amgen, Inc., Cambridge, Massachusetts (T.A.D., M.M.W.)
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Matthew R. Kaller
Departments of Neuroscience (S.W., P.H.W., J.Z., L.Z., Y.L., S.B.-K., M.C., T.W.), Molecular Structure and Characterization (K.C.), Pharmacokinetics and Drug Metabolism (R.P., J.E., D.H.), and Medicinal Chemistry (M.R.K., S.A.H., W.Z.), Amgen, Inc., Thousand Oaks, California; and Department of Medicinal Chemistry, Amgen, Inc., Cambridge, Massachusetts (T.A.D., M.M.W.)
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Matthew M. Weiss
Departments of Neuroscience (S.W., P.H.W., J.Z., L.Z., Y.L., S.B.-K., M.C., T.W.), Molecular Structure and Characterization (K.C.), Pharmacokinetics and Drug Metabolism (R.P., J.E., D.H.), and Medicinal Chemistry (M.R.K., S.A.H., W.Z.), Amgen, Inc., Thousand Oaks, California; and Department of Medicinal Chemistry, Amgen, Inc., Cambridge, Massachusetts (T.A.D., M.M.W.)
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Stephen A. Hitchcock
Departments of Neuroscience (S.W., P.H.W., J.Z., L.Z., Y.L., S.B.-K., M.C., T.W.), Molecular Structure and Characterization (K.C.), Pharmacokinetics and Drug Metabolism (R.P., J.E., D.H.), and Medicinal Chemistry (M.R.K., S.A.H., W.Z.), Amgen, Inc., Thousand Oaks, California; and Department of Medicinal Chemistry, Amgen, Inc., Cambridge, Massachusetts (T.A.D., M.M.W.)
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Martin Citron
Departments of Neuroscience (S.W., P.H.W., J.Z., L.Z., Y.L., S.B.-K., M.C., T.W.), Molecular Structure and Characterization (K.C.), Pharmacokinetics and Drug Metabolism (R.P., J.E., D.H.), and Medicinal Chemistry (M.R.K., S.A.H., W.Z.), Amgen, Inc., Thousand Oaks, California; and Department of Medicinal Chemistry, Amgen, Inc., Cambridge, Massachusetts (T.A.D., M.M.W.)
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Wenge Zhong
Departments of Neuroscience (S.W., P.H.W., J.Z., L.Z., Y.L., S.B.-K., M.C., T.W.), Molecular Structure and Characterization (K.C.), Pharmacokinetics and Drug Metabolism (R.P., J.E., D.H.), and Medicinal Chemistry (M.R.K., S.A.H., W.Z.), Amgen, Inc., Thousand Oaks, California; and Department of Medicinal Chemistry, Amgen, Inc., Cambridge, Massachusetts (T.A.D., M.M.W.)
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Dean Hickman
Departments of Neuroscience (S.W., P.H.W., J.Z., L.Z., Y.L., S.B.-K., M.C., T.W.), Molecular Structure and Characterization (K.C.), Pharmacokinetics and Drug Metabolism (R.P., J.E., D.H.), and Medicinal Chemistry (M.R.K., S.A.H., W.Z.), Amgen, Inc., Thousand Oaks, California; and Department of Medicinal Chemistry, Amgen, Inc., Cambridge, Massachusetts (T.A.D., M.M.W.)
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Toni Williamson
Departments of Neuroscience (S.W., P.H.W., J.Z., L.Z., Y.L., S.B.-K., M.C., T.W.), Molecular Structure and Characterization (K.C.), Pharmacokinetics and Drug Metabolism (R.P., J.E., D.H.), and Medicinal Chemistry (M.R.K., S.A.H., W.Z.), Amgen, Inc., Thousand Oaks, California; and Department of Medicinal Chemistry, Amgen, Inc., Cambridge, Massachusetts (T.A.D., M.M.W.)
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Abstract

Sequential proteolytic cleavage of the amyloid precursor protein (APP) by β-site APP-cleaving enzyme 1 (BACE1) and the γ-secretase complex produces the amyloid-β peptide (Aβ), which is believed to play a critical role in the pathology of Alzheimer's disease (AD). The aspartyl protease BACE1 catalyzes the rate-limiting step in the production of Aβ, and as such it is considered to be an important target for drug development in AD. The development of a BACE1 inhibitor therapeutic has proven to be difficult. The active site of BACE1 is relatively large. Consequently, to achieve sufficient potency, many BACE1 inhibitors have required unfavorable physicochemical properties such as high molecular weight and polar surface area that are detrimental to efficient passage across the blood-brain barrier. Using a rational drug design approach we have designed and developed a new series of hydroxyethylamine-based inhibitors of BACE1 capable of lowering Aβ levels in the brains of rats after oral administration. Herein we describe the in vitro and in vivo characterization of two of these molecules and the overall relationship of compound properties [e.g., in vitro permeability, P-glycoprotein (P-gp) efflux, metabolic stability, and pharmacological potency] to the in vivo pharmacodynamic effect with more than 100 compounds across the chemical series. We demonstrate that high in vitro potency for BACE1 was not sufficient to provide central efficacy. A combination of potency, high permeability, low P-gp-mediated efflux, and low clearance was required for compounds to produce robust central Aβ reduction after oral dosing.

Footnotes

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.112.197954.

  • ↵Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    AD
    Alzheimer's disease
    Aβ
    amyloid-β peptide
    APP
    amyloid precursor protein
    BACE1
    β-site APP-cleaving enzyme 1
    CNS
    central nervous system
    CSF
    cerebrospinal fluid
    DMSO
    dimethyl sulfoxide
    ER
    efflux ratio
    FRET
    fluorescence resonance energy transfer
    HEA
    hydroxyethylamine
    HPMC
    hydroxypropyl methyl cellulose
    IS
    internal standard
    PD
    pharmacodynamic
    P-gp
    P-glycoprotein
    PK
    pharmacokinetic
    RLM
    rat liver microsome
    RLM CLint
    intrinsic clearance in RLMs
    QC
    quality control.

  • Received June 28, 2012.
  • Accepted August 20, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 343 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 343, Issue 2
1 Nov 2012
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Research ArticleNeuropharmacology

PK/PD Evaluation of HEA-Derived β-Secretase Inhibitors

Stephen Wood, Paul H. Wen, Jianhua Zhang, Li Zhu, Yi Luo, Safura Babu-Khan, Kui Chen, Roger Pham, Joel Esmay, Thomas A. Dineen, Matthew R. Kaller, Matthew M. Weiss, Stephen A. Hitchcock, Martin Citron, Wenge Zhong, Dean Hickman and Toni Williamson
Journal of Pharmacology and Experimental Therapeutics November 1, 2012, 343 (2) 460-467; DOI: https://doi.org/10.1124/jpet.112.197954

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Research ArticleNeuropharmacology

PK/PD Evaluation of HEA-Derived β-Secretase Inhibitors

Stephen Wood, Paul H. Wen, Jianhua Zhang, Li Zhu, Yi Luo, Safura Babu-Khan, Kui Chen, Roger Pham, Joel Esmay, Thomas A. Dineen, Matthew R. Kaller, Matthew M. Weiss, Stephen A. Hitchcock, Martin Citron, Wenge Zhong, Dean Hickman and Toni Williamson
Journal of Pharmacology and Experimental Therapeutics November 1, 2012, 343 (2) 460-467; DOI: https://doi.org/10.1124/jpet.112.197954
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