Pharmacologic Profile of OC000459, a Potent, Selective, and Orally Active D Prostanoid Receptor 2 Antagonist That Inhibits Mast Cell-Dependent Activation of T Helper 2 Lymphocytes and Eosinophils

• Published in: The Journal of pharmacology and experimental therapeutics 2012-02, Vol.340 (2), p.473-482
• Main Authors: Pettipher, Roy, Vinall, Shân L., Xue, Luzheng, Speight, Graham, Townsend, Elizabeth R., Gazi, Lucien, Whelan, Cliff J., Armer, Richard E., Payton, Mark A., Hunter, Michael G.
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - drug effects; Arachidonic Acids - pharmacology; Binding, Competitive; Calcium Signaling - drug effects; Cell Membrane - metabolism; Cell Shape - drug effects; Cell Shape - immunology; Chemokine CCL11 - pharmacology; Chemotaxis - drug effects; Chemotaxis - immunology; CHO Cells; Complement C5a - pharmacology; Cricetinae; Culture Media, Conditioned - pharmacology; Eosinophilia - chemically induced; Eosinophilia - prevention & control; Eosinophils - cytology; Eosinophils - drug effects; Eosinophils - immunology; Guinea Pigs; Humans; Indoleacetic Acids - pharmacokinetics; Indoleacetic Acids - pharmacology; Indoleacetic Acids - therapeutic use; Interleukin-13 - metabolism; Interleukin-5 - pharmacology; Leukotriene B4 - pharmacology; Lymphocyte Activation - drug effects; Lymphocyte Activation - immunology; Mast Cells - immunology; Mast Cells - metabolism; Prostaglandin Antagonists - pharmacokinetics; Prostaglandin Antagonists - pharmacology; Prostaglandin Antagonists - therapeutic use; Prostaglandin D2 - analogs & derivatives; Prostaglandin D2 - metabolism; Prostaglandin D2 - pharmacology; Pulmonary Eosinophilia - chemically induced; Pulmonary Eosinophilia - prevention & control; Quinolines - pharmacokinetics; Quinolines - pharmacology; Quinolines - therapeutic use; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, Immunologic - genetics; Receptors, Immunologic - metabolism; Receptors, Prostaglandin - genetics; Receptors, Prostaglandin - metabolism; Recombinant Proteins - metabolism; Th2 Cells - cytology; Th2 Cells - drug effects; Th2 Cells - immunology; Th2 Cells - metabolism; Transfection
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.111.187203

D prostanoid receptor 2 (DP2) [also known as chemoattractant receptor-homologous molecule expressed on T helper 2 (Th2) cells (CRTH2)] is selectively expressed by Th2 lymphocytes, eosinophils, and basophils and mediates recruitment and activation of these cell types in response to prostaglandin D2 (PGD2). (5-Fluoro-2-methyl-3-quinolin-2-ylmethylindo-1-yl)-acetic acid (OC000459) is an indole-acetic acid derivative that potently displaces [3H]PGD2 from human recombinant DP2 (Ki = 0.013 μM), rat recombinant DP2 (Ki = 0.003 μM), and human native DP2 (Th2 cell membranes; Ki = 0.004 μM) but does not interfere with the ligand binding properties or functional activities of other prostanoid receptors (prostaglandin E1–4 receptors, D prostanoid receptor 1, thromboxane receptor, prostacyclin receptor, and prostaglandin F receptor). OC000459 inhibited chemotaxis (IC50 = 0.028 μM) of human Th2 lymphocytes and cytokine production (IC50 = 0.019 μM) by human Th2 lymphocytes. OC000459 competitively antagonized eosinophil shape change responses induced by PGD2 in both isolated human leukocytes (pKB = 7.9) and human whole blood (pKB = 7.5) but did not inhibit responses to eotaxin, 5-oxo-eicosatetraenoic acid, or complement component C5a. OC000459 also inhibited the activation of Th2 cells and eosinophils in response to supernatants from IgE/anti-IgE-activated human mast cells. OC000459 had no significant inhibitory activity on a battery of 69 receptors and 19 enzymes including cyclooxygenase 1 (COX1) and COX2. OC000459 was found to be orally bioavailable in rats and effective in inhibiting blood eosinophilia induced by 13,14-dihydro-15-keto-PGD2 (DK-PGD2) in this species (ED50 = 0.04 mg/kg p.o.) and airway eosinophilia in response to an aerosol of DK-PGD2 in guinea pigs (ED50 = 0.01 mg/kg p.o.). These data indicate that OC000459 is a potent, selective, and orally active DP2 antagonist that retains activity in human whole blood and inhibits mast cell-dependent activation of both human Th2 lymphocytes and eosinophils.