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Research ArticleNeuropharmacology

The Orally Active Glutamate Carboxypeptidase II Inhibitor E2072 Exhibits Sustained Nerve Exposure and Attenuates Peripheral Neuropathy

Krystyna M. Wozniak, Ying Wu, James J. Vornov, Rena Lapidus, Rana Rais, Camilo Rojas, Takashi Tsukamoto and Barbara S. Slusher
Journal of Pharmacology and Experimental Therapeutics December 2012, 343 (3) 746-754; DOI: https://doi.org/10.1124/jpet.112.197665
Krystyna M. Wozniak
Brain Science Institute, NeuroTranslational Drug Discovery Program (K.M.W.,Y.W., C.R., T.T., B.S.S.), and Departments of Neurology (R.R., T.T., B.S.S.) and Psychiatry (B.S.S.), The Johns Hopkins School of Medicine, Baltimore, Maryland; Eisai Inc., Baltimore, Maryland (K.M.W., Y.W., R.L., C.R., T.T., B.S.S.); Parexel International, Waltham, Massachusetts (J.J.V.); and Greenbaum Cancer Center, University of Maryland, Baltimore, Maryland (R.L.)
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Ying Wu
Brain Science Institute, NeuroTranslational Drug Discovery Program (K.M.W.,Y.W., C.R., T.T., B.S.S.), and Departments of Neurology (R.R., T.T., B.S.S.) and Psychiatry (B.S.S.), The Johns Hopkins School of Medicine, Baltimore, Maryland; Eisai Inc., Baltimore, Maryland (K.M.W., Y.W., R.L., C.R., T.T., B.S.S.); Parexel International, Waltham, Massachusetts (J.J.V.); and Greenbaum Cancer Center, University of Maryland, Baltimore, Maryland (R.L.)
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James J. Vornov
Brain Science Institute, NeuroTranslational Drug Discovery Program (K.M.W.,Y.W., C.R., T.T., B.S.S.), and Departments of Neurology (R.R., T.T., B.S.S.) and Psychiatry (B.S.S.), The Johns Hopkins School of Medicine, Baltimore, Maryland; Eisai Inc., Baltimore, Maryland (K.M.W., Y.W., R.L., C.R., T.T., B.S.S.); Parexel International, Waltham, Massachusetts (J.J.V.); and Greenbaum Cancer Center, University of Maryland, Baltimore, Maryland (R.L.)
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Rena Lapidus
Brain Science Institute, NeuroTranslational Drug Discovery Program (K.M.W.,Y.W., C.R., T.T., B.S.S.), and Departments of Neurology (R.R., T.T., B.S.S.) and Psychiatry (B.S.S.), The Johns Hopkins School of Medicine, Baltimore, Maryland; Eisai Inc., Baltimore, Maryland (K.M.W., Y.W., R.L., C.R., T.T., B.S.S.); Parexel International, Waltham, Massachusetts (J.J.V.); and Greenbaum Cancer Center, University of Maryland, Baltimore, Maryland (R.L.)
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Rana Rais
Brain Science Institute, NeuroTranslational Drug Discovery Program (K.M.W.,Y.W., C.R., T.T., B.S.S.), and Departments of Neurology (R.R., T.T., B.S.S.) and Psychiatry (B.S.S.), The Johns Hopkins School of Medicine, Baltimore, Maryland; Eisai Inc., Baltimore, Maryland (K.M.W., Y.W., R.L., C.R., T.T., B.S.S.); Parexel International, Waltham, Massachusetts (J.J.V.); and Greenbaum Cancer Center, University of Maryland, Baltimore, Maryland (R.L.)
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Camilo Rojas
Brain Science Institute, NeuroTranslational Drug Discovery Program (K.M.W.,Y.W., C.R., T.T., B.S.S.), and Departments of Neurology (R.R., T.T., B.S.S.) and Psychiatry (B.S.S.), The Johns Hopkins School of Medicine, Baltimore, Maryland; Eisai Inc., Baltimore, Maryland (K.M.W., Y.W., R.L., C.R., T.T., B.S.S.); Parexel International, Waltham, Massachusetts (J.J.V.); and Greenbaum Cancer Center, University of Maryland, Baltimore, Maryland (R.L.)
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Takashi Tsukamoto
Brain Science Institute, NeuroTranslational Drug Discovery Program (K.M.W.,Y.W., C.R., T.T., B.S.S.), and Departments of Neurology (R.R., T.T., B.S.S.) and Psychiatry (B.S.S.), The Johns Hopkins School of Medicine, Baltimore, Maryland; Eisai Inc., Baltimore, Maryland (K.M.W., Y.W., R.L., C.R., T.T., B.S.S.); Parexel International, Waltham, Massachusetts (J.J.V.); and Greenbaum Cancer Center, University of Maryland, Baltimore, Maryland (R.L.)
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Barbara S. Slusher
Brain Science Institute, NeuroTranslational Drug Discovery Program (K.M.W.,Y.W., C.R., T.T., B.S.S.), and Departments of Neurology (R.R., T.T., B.S.S.) and Psychiatry (B.S.S.), The Johns Hopkins School of Medicine, Baltimore, Maryland; Eisai Inc., Baltimore, Maryland (K.M.W., Y.W., R.L., C.R., T.T., B.S.S.); Parexel International, Waltham, Massachusetts (J.J.V.); and Greenbaum Cancer Center, University of Maryland, Baltimore, Maryland (R.L.)
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Abstract

Peripheral neuropathy from nerve trauma is a significant problem in the human population and often constitutes a dose-limiting toxicity in patients receiving chemotherapy. (3–2-Mercaptoethyl)biphenyl-2,3-dicarboxylic acid (E2072) is a potent (Ki = 10 nM), selective, and orally available inhibitor of glutamate carboxypeptidase II (GCPII). Here, we report that E2072 attenuates hyperalgesia and nerve conduction velocity deficits in preclinical rodent models of neuropathic pain and oxaliplatin-induced neuropathy. In the chronic constrictive injury model, orally administered E2072 reversed pre-existing thermal hyperalgesia in rats in a dose-dependent fashion with a minimally effective dose of 0.1 mg/kg/day. It is noteworthy that multiple days of dosing of E2072 were required before analgesia was realized even though GCPII inhibitory exposures were achieved on the first day of dosing. In addition, analgesia was found to persist for up to 7 days after cessation of dosing, consistent with E2072's pharmacokinetic profile and sustained exposure. Furthermore, in a chronic oxaliplatin-induced neuropathy model (6 mg/kg i.p. oxaliplatin twice weekly for 4 weeks), female BALB/c mice receiving daily oral E2072 at 1.0 and 0.1 mg/kg displayed no deficits in either caudal or digital velocity compared with significant deficits observed in mice treated with oxaliplatin alone (12 ± 3 and 9 ± 2%, respectively). Similar findings were seen with oxaliplatin-induced digital and caudal amplitude deficits. It is noteworthy that E2072 showed no interference with the antineoplastic efficacy of oxaliplatin in mice bearing leukemia (L1210), even at doses 100 times its neuroprotective/analgesic dose, indicating a selective effect on neuropathy. These data support the therapeutic utility of GCPII inhibitors in neuropathy and neuropathic pain.

Footnotes

  • This work was supported by Eisai Inc. and the Johns Hopkins Brain Science Institute.

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

    http://dx.doi.org/10.1124/jpet.112.197665.

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

  • ABBREVIATIONS:

    GCPII
    glutamate carboxypeptidase II
    E2072
    (3–2-mercaptoethyl)biphenyl-2,3-dicarboxylic acid
    NAAG
    N-acetyl-aspartyl glutamate
    2-MPPA
    2-(3-mercaptopropyl)pentanedioic acid
    2-PMPA
    2-(phosphonomethyl pentanedioic acid)
    CCI
    chronic constrictive injury
    NCV
    nerve conduction velocity
    mGluR
    metabotropic glutamate receptor
    LC
    liquid chromatography
    MS/MS
    tandem mass spectrometry
    LY341495
    2-amino-2-(2-carboxycycloprop-1-yl)-3-(xanth-9-yl)propanoic acid
    APDC
    (2R,4R)-aminopyrrolidine 2,4-dicarboxylate
    ZJ17
    (S)-2-(3-((S)-1-carboxy-2-(4-hydroxyphenyl)ethyl)ureido)pentanedioic acid
    SLX-3095–1
    (±)-2-oxa-4-aminobicylco[3.1.0]hexane-4,6 dicarboxylic acid
    ZJ11
    (S)-2-(3-((S)-1-carboxy-3-(methylthio)propyl)ureido)pentanedioic acid
    ZJ43
    (S)-2-(3-((S)-1-carboxy-3-methylbutyl)ureido)pentanedioic acid
    Veh
    vehicle
    Oxali
    oxaliplatin.

  • Received June 25, 2012.
  • Accepted September 14, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 343 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 343, Issue 3
1 Dec 2012
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Research ArticleNeuropharmacology

GCPII Inhibitor E2072 Attenuates Neuropathy

Krystyna M. Wozniak, Ying Wu, James J. Vornov, Rena Lapidus, Rana Rais, Camilo Rojas, Takashi Tsukamoto and Barbara S. Slusher
Journal of Pharmacology and Experimental Therapeutics December 1, 2012, 343 (3) 746-754; DOI: https://doi.org/10.1124/jpet.112.197665

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Research ArticleNeuropharmacology

GCPII Inhibitor E2072 Attenuates Neuropathy

Krystyna M. Wozniak, Ying Wu, James J. Vornov, Rena Lapidus, Rana Rais, Camilo Rojas, Takashi Tsukamoto and Barbara S. Slusher
Journal of Pharmacology and Experimental Therapeutics December 1, 2012, 343 (3) 746-754; DOI: https://doi.org/10.1124/jpet.112.197665
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