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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on January 21, 2003; DOI: 10.1124/jpet.102.046748

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Vol. 305, Issue 1, 347-352, April 2003

An Orally Bioavailable Small Molecule Antagonist of CRTH2, Ramatroban (BAY u3405), Inhibits Prostaglandin D2-Induced Eosinophil Migration in Vitro

Hiromi Sugimoto1, Michitaka Shichijo1, Takashi Iino, Yoshihisa Manabe, Akihiko Watanabe, Makoto Shimazaki, Florian Gantner and Kevin B. Bacon

Respiratory Diseases Research, and Medicinal Chemistry, Bayer Yakuhin, Ltd., Kyoto, Japan

Ramatroban (Baynas, BAY u3405), a thromboxane A2 (TxA2) antagonist marketed for allergic rhinitis, has been shown to partially attenuate prostaglandin (PG)D2-induced bronchial hyperresponsiveness in humans, as well as reduce antigen-induced early- and late-phase inflammatory responses in mice, guinea pigs, and rats. PGD2 is known to induce eosinophilia following intranasal administration, and to induce eosinophil activation in vitro. In addition to the TxA2 receptor, PGD2 is known as a ligand for the PGD2 receptor, and the newly identified G-protein-coupled chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2). To fully characterize PGD2-mediated inflammatory responses relevant to eosinophil activation, further analysis of the mechanism of action of ramatroban has now been performed. PGD2-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.

1 These authors contributed equally to this work.

0022-3565/03/3051-0347$07.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2003 by The American Society for Pharmacology and Experimental Therapeutics


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