RT Journal Article
SR Electronic
T1 Pharmacological Characterization of MK-7246, a Potent and Selective CRTH2 (Chemoattractant Receptor-Homologous Molecule Expressed on T-Helper Type 2 Cells) Antagonist
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 69
OP 76
DO 10.1124/mol.110.068585
VO 79
IS 1
A1 Gervais, Francois G.
A1 Sawyer, Nicole
A1 Stocco, Rino
A1 Hamel, Martine
A1 Krawczyk, Connie
A1 Sillaots, Susan
A1 Denis, Danielle
A1 Wong, Elizabeth
A1 Wang, Zhaoyin
A1 Gallant, Michel
A1 Abraham, William M.
A1 Slipetz, Deborah
A1 Crackower, Michael A.
A1 O'Neill, Gary P.
YR 2011
UL http://molpharm.aspetjournals.org/content/79/1/69.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 {(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.