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Molecular Pharmacology

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Research ArticleArticle

Pharmacological Characterization of 1-(5-Chloro-6-(trifluoromethoxy)-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic Acid (JNJ-42041935), a Potent and Selective Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor

Terrance D. Barrett, Heather L. Palomino, Theresa I. Brondstetter, Kimon C. Kanelakis, Xiaodong Wu, Peter V. Haug, Wen Yan, Andrew Young, Hong Hua, Juliet C. Hart, Da-Thao Tran, Hariharan Venkatesan, Mark D. Rosen, Hillary M. Peltier, Kia Sepassi, Michele C. Rizzolio, Scott D. Bembenek, Tara Mirzadegan, Michael H. Rabinowitz and Nigel P. Shankley
Molecular Pharmacology June 2011, 79 (6) 910-920; DOI: https://doi.org/10.1124/mol.110.070508
Terrance D. Barrett
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Heather L. Palomino
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Theresa I. Brondstetter
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Kimon C. Kanelakis
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Xiaodong Wu
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Peter V. Haug
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Wen Yan
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Andrew Young
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Hong Hua
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Juliet C. Hart
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Da-Thao Tran
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Hariharan Venkatesan
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Abstract

The hypoxia-inducible factor (HIF) prolyl hydroxylase (PHD) enzymes represent novel targets for the treatment of anemia, ulcerative colitis, and ischemic and metabolic disease inter alia. We have identified a novel small-molecule inhibitor of PHD, 1-(5-chloro-6-(trifluoromethoxy)-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid (JNJ-42041935), through structure-based drug design methods. The pharmacology of JNJ-42041935 was investigated in enzyme, cellular, and whole-animal systems and was compared with other compounds described in the literature as PHD inhibitors. JNJ-42041935, was a potent (pKI = 7.3–7.9), 2-oxoglutarate competitive, reversible, and selective inhibitor of PHD enzymes. In addition, JNJ-42041935 was used to compare the effect of selective inhibition of PHD to intermittent, high doses (50 μg/kg i.p.) of an exogenous erythropoietin receptor agonist in an inflammation-induced anemia model in rats. JNJ-42041935 (100 μmol/kg, once a day for 14 days) was effective in reversing inflammation-induced anemia, whereas erythropoietin had no effect. The results demonstrate that JNJ-42041935 is a new pharmacological tool, which can be used to investigate PHD inhibition and demonstrate that PHD inhibitors offer great promise for the treatment of inflammation-induced anemia.

Footnotes

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

    doi:10.1124/mol.110.070508.

  • ABBREVIATIONS:

    HIF
    hypoxia-inducible factor
    PHD
    prolyl-4-hydroxylase
    2-OG
    2-oxoglutarate
    rhEPO
    recombinant human erythropoietin
    DMOG
    dimethyloxalylglycine
    3,4-EDHB
    ethyl-3,4-dihydroxybenzoate
    JNJ-42041935
    1-(5-chloro-6-(trifluoromethoxy)-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid
    FIH
    factor-inhibiting hypoxia-inducible factor
    PGPS
    peptidoglycan-polysaccharide polymers
    MCV
    mean corpuscular volume
    MCH
    mean cell hemoglobin.

  • Received December 10, 2010.
  • Accepted March 3, 2011.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 79 (6)
Molecular Pharmacology
Vol. 79, Issue 6
1 Jun 2011
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Pharmacological Characterization of 1-(5-Chloro-6-(trifluoromethoxy)-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic Acid (JNJ-42041935), a Potent and Selective Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor
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Research ArticleArticle

Pharmacological Characterization of 1-(5-Chloro-6-(trifluoromethoxy)-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic Acid (JNJ-42041935), a Potent and Selective Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor

Terrance D. Barrett, Heather L. Palomino, Theresa I. Brondstetter, Kimon C. Kanelakis, Xiaodong Wu, Peter V. Haug, Wen Yan, Andrew Young, Hong Hua, Juliet C. Hart, Da-Thao Tran, Hariharan Venkatesan, Mark D. Rosen, Hillary M. Peltier, Kia Sepassi, Michele C. Rizzolio, Scott D. Bembenek, Tara Mirzadegan, Michael H. Rabinowitz and Nigel P. Shankley
Molecular Pharmacology June 1, 2011, 79 (6) 910-920; DOI: https://doi.org/10.1124/mol.110.070508

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Research ArticleArticle

Pharmacological Characterization of 1-(5-Chloro-6-(trifluoromethoxy)-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic Acid (JNJ-42041935), a Potent and Selective Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor

Terrance D. Barrett, Heather L. Palomino, Theresa I. Brondstetter, Kimon C. Kanelakis, Xiaodong Wu, Peter V. Haug, Wen Yan, Andrew Young, Hong Hua, Juliet C. Hart, Da-Thao Tran, Hariharan Venkatesan, Mark D. Rosen, Hillary M. Peltier, Kia Sepassi, Michele C. Rizzolio, Scott D. Bembenek, Tara Mirzadegan, Michael H. Rabinowitz and Nigel P. Shankley
Molecular Pharmacology June 1, 2011, 79 (6) 910-920; DOI: https://doi.org/10.1124/mol.110.070508
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