Pharmacological characterization of MK-7246, a potent and selective CRTH2 (chemoattractant receptor-homologous molecule expressed on T-helper type 2 cells) antagonist

• Published in: Molecular pharmacology Vol. 79; no. 1; p. 69
• Main Authors: Gervais, Francois G, Sawyer, Nicole, Stocco, Rino, Hamel, Martine, Krawczyk, Connie, Sillaots, Susan, Denis, Danielle, Wong, Elizabeth, Wang, Zhaoyin, Gallant, Michel, Abraham, William M, Slipetz, Deborah, Crackower, Michael A, O'Neill, Gary P
• Format: Journal Article
• Language: English
• Published: United States 01-01-2011
• Subjects: Animals; Carbolines - chemistry; Carbolines - pharmacology; Dogs; Gene Expression Regulation - drug effects; Gene Expression Regulation - immunology; HEK293 Cells; Humans; Macaca fascicularis; Mice; Platelet Aggregation Inhibitors - pharmacology; Protein Binding - immunology; Rats; Receptors, Immunologic - antagonists & inhibitors; Receptors, Immunologic - biosynthesis; Receptors, Immunologic - metabolism; Receptors, Immunologic - physiology; Receptors, Prostaglandin - antagonists & inhibitors; Receptors, Prostaglandin - biosynthesis; Receptors, Prostaglandin - metabolism; Receptors, Prostaglandin - physiology; Sheep; Species Specificity; Th2 Cells - drug effects; Th2 Cells - metabolism
• ISSN: 1521-0111
• DOI: 10.1124/mol.110.068585

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.