title: An orally bioavailable small molecule antagonist of CRTH2, ramatroban (BAY u3405), inhibits prostaglandin D2-induced eosinophil migration in vitro.
abstract: Ramatroban (Baynas, BAY u3405), a thromboxane A(2) (TxA(2)) antagonist marketed for allergic rhinitis, has been shown to partially attenuate prostaglandin (PG)D(2)-induced bronchial hyperresponsiveness in humans, as well as reduce antigen-induced early- and late-phase inflammatory responses in mice, guinea pigs, and rats. PGD(2) is known to induce eosinophilia following intranasal administration, and to induce eosinophil activation in vitro. In addition to the TxA(2) receptor, PGD(2) is known as a ligand for the PGD(2) receptor, and the newly identified G-protein-coupled chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2). To fully characterize PGD(2)-mediated inflammatory responses relevant to eosinophil activation, further analysis of the mechanism of action of ramatroban has now been performed. PGD(2)-stimulated human eosinophil migration was shown to be mediated exclusively through activation of CRTH2, and surprisingly, these effects were completely inhibited by ramatroban. This is also the first report detailing an orally bioavailable small molecule CRTH2 antagonist. Our findings suggest that clinical efficacy of ramatroban may be in part mediated through its action on this Th2-, eosinophil-, and basophil-specific chemoattractant receptor.
authors.affiliation: Respiratory Diseases Research, and Medicinal Chemistry, Bayer Yakuhin, Ltd., Kyoto, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Sugimoto
authors.forename: Michitaka
authors.initials: M
authors.lastname: Shichijo
authors.forename: Takashi
authors.initials: T
authors.lastname: Iino
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Manabe
authors.forename: Akihiko
authors.initials: A
authors.lastname: Watanabe
authors.forename: Makoto
authors.initials: M
authors.lastname: Shimazaki
authors.forename: Florian
authors.initials: F
authors.lastname: Gantner
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Bacon
mesh_terms: D000284:Administration, Oral; D001682:Biological Availability; D002118:Calcium / Q000378:metabolism; D002227:Carbazoles / Q000494:pharmacology*; D002465:Cell Movement; D004347:Drug Interactions; D004804:Eosinophils / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D015230:Prostaglandin D2 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors; D011982:Receptors, Prostaglandin; D013449:Sulfonamides / Q000494:pharmacology*; D014162:Transfection
chemical_list: D002227:Carbazoles; D010975:Platelet Aggregation Inhibitors; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D013449:Sulfonamides; C063119:ramatroban; D015230:Prostaglandin D2; D002118:Calcium; C036293:prostaglandin D2 receptor