RT Journal Article
SR Electronic
T1 Pharmacological characterization of MK-7246, a potent and selective CRTH2 antagonist
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.110.068585
DO 10.1124/mol.110.068585
A1 Francois G Gervais
A1 Nicole Sawyer
A1 Rino Stocco
A1 Martine Hamel
A1 Connie Krawczyk
A1 Susan Sillaots
A1 Danielle Denis
A1 Elizabeth Wong
A1 Zhaoyin Wang
A1 Michel Gallant
A1 William M Abraham
A1 Deborah Slipetz
A1 Michael A Crackower
A1 Gary P O'Neill
YR 2010
UL http://molpharm.aspetjournals.org/content/early/2010/10/13/mol.110.068585.abstract
AB 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 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.