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, Gary P. O'Neill

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39 Scopus citations

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 hyperresponsiveness in sheep. MK-7246 represents a potent and selective tool to further investigate the in vivo function of CRTH2.

Original languageEnglish (US)
Pages (from-to)69-76
Number of pages8
JournalMolecular Pharmacology
Volume79
Issue number1
DOIs
StatePublished - Jan 1 2011

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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    Gervais, F. G., Sawyer, N., Stocco, R., Hamel, M., Krawczyk, C., Sillaots, S., Denis, D., Wong, E., Wang, Z., Gallant, M., Abraham, W. M., Slipetz, D., Crackower, M. A., & O'Neill, G. P. (2011). Pharmacological characterization of MK-7246, a potent and selective CRTH2 (chemoattractant receptor-homologous molecule expressed on T-helper type 2 cells) antagonist. Molecular Pharmacology, 79(1), 69-76. https://doi.org/10.1124/mol.110.068585