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Research ArticleArticle

Pharmacological Characterization of MK-7246, a Potent and Selective CRTH2 (Chemoattractant Receptor-Homologous Molecule Expressed on T-Helper Type 2 Cells) Antagonist

Francois G. Gervais, Nicole Sawyer, Rino Stocco, Martine Hamel, Connie Krawczyk, Susan Sillaots, Danielle Denis, Elizabeth Wong, Zhaoyin Wang, Michel Gallant, William M. Abraham, Deborah Slipetz, Michael A. Crackower and Gary P. O'Neill
Molecular Pharmacology January 2011, 79 (1) 69-76; DOI: https://doi.org/10.1124/mol.110.068585
Francois G. Gervais
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Nicole Sawyer
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Rino Stocco
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Martine Hamel
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Connie Krawczyk
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Susan Sillaots
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Danielle Denis
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Elizabeth Wong
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Zhaoyin Wang
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Michel Gallant
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William M. Abraham
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Deborah Slipetz
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Michael A. Crackower
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Gary P. O'Neill
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Abstract

The chemoattractant receptor-homologous molecule expressed on T-helper type 2 cells (CRTH2) is a G protein-coupled receptor that has been reported to modulate inflammatory responses in various rodent models of asthma, allergic rhinitis and atopic dermatitis. In this study, we describe the biological and pharmacological properties of {(7R)-7-[[(4-fluorophenyl)sulfonyl](methyl)amino]-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl}acetic acid (MK-7246), a novel synthetic CRTH2 antagonist. We show that MK-7246 1) has high affinity for the human, monkey, dog, rat, and mouse CRTH2, 2) interacts with CRTH2 in a reversible manner, 3) exhibits high selectivity over all prostanoid receptors as well as 157 other receptors and enzymes, 4) acts as a full antagonist on recombinant and endogenously expressed CRTH2, 5) demonstrates good oral bioavailability and metabolic stability in various animal species, 6) yields ex vivo blockade of CRTH2 on eosinophils in monkeys and sheep, and 7) significantly blocks antigen-induced late-phase bronchoconstriction and airway hyper-responsiveness in sheep. MK-7246 represents a potent and selective tool to further investigate the in vivo function of CRTH2.

Footnotes

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

    doi:10.1124/mol.110.068585.

  • ABBREVIATIONS:

    PGD2
    prostaglandin D2
    CRTH2
    chemoattractant receptor-homologous molecule expressed on T-helper cells
    Th2
    T-helper cells type 2
    DK-PGD2
    13,14-dihydro-15-keto-prostaglandin D2
    MK-7246
    {(7R)-7-[[(4-fluorophenyl)sulfonyl](methyl)amino]-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl}acetic acid
    DP
    prostaglandin D2 receptor
    TP
    thromboxane A2
    HEK
    human embryonic kidney
    PBS
    phosphate-buffered saline
    PK
    pharmacokinetic
    PD
    pharmacodynamic
    AZ11805131
    2-[2-(4-ethylsulfonyl-2-methylphenyl)-4-(trifluoromethyl)phenoxy]acetic acid
    AZ11665362
    [2,5-dimethyl-3-(8-methylquinolin-4-yl)-1H-indole-1-yl]acetic acid
    AM156
    (2′-((cyclopropanecarbonylethylamino)methyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)acetic acid
    AM206
    (5-(2-((benzoyloxycarbonylethylamino)methyl)-4-trifluoromethylphenyl)pyridin-3-yl)acetic acid
    L-002245377
    (2S,3S,4S,5R,6S)-6-[({(7R)-7-[[(4-fluorophenyl)sulfonyl](methyl)amino]-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl}acetyl)oxy]-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid
    Amira's compound 23
    {8-[[(4-fluorophenyl)sulfonyl](methyl)amino]-6,7,8,9-tetrahydro-5H-pyrido[3,2-]indol-5-yl} acetic acid
    TM30089
    {(3)-3-[[(4-fluorophenyl)sulfonyl](methyl)amino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl} acetic acid.

  • Received September 2, 2010.
  • Accepted October 5, 2010.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 79 (1)
Molecular Pharmacology
Vol. 79, Issue 1
1 Jan 2011
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Research ArticleArticle

Pharmacological Characterization of MK-7246, a Potent and Selective CRTH2 (Chemoattractant Receptor-Homologous Molecule Expressed on T-Helper Type 2 Cells) Antagonist

Francois G. Gervais, Nicole Sawyer, Rino Stocco, Martine Hamel, Connie Krawczyk, Susan Sillaots, Danielle Denis, Elizabeth Wong, Zhaoyin Wang, Michel Gallant, William M. Abraham, Deborah Slipetz, Michael A. Crackower and Gary P. O'Neill
Molecular Pharmacology January 1, 2011, 79 (1) 69-76; DOI: https://doi.org/10.1124/mol.110.068585

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Research ArticleArticle

Pharmacological Characterization of MK-7246, a Potent and Selective CRTH2 (Chemoattractant Receptor-Homologous Molecule Expressed on T-Helper Type 2 Cells) Antagonist

Francois G. Gervais, Nicole Sawyer, Rino Stocco, Martine Hamel, Connie Krawczyk, Susan Sillaots, Danielle Denis, Elizabeth Wong, Zhaoyin Wang, Michel Gallant, William M. Abraham, Deborah Slipetz, Michael A. Crackower and Gary P. O'Neill
Molecular Pharmacology January 1, 2011, 79 (1) 69-76; DOI: https://doi.org/10.1124/mol.110.068585
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