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

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 D-2 (PGD(2)). (5-Fluoro-2-methyl-3-quinolin-2-ylmethylindo-1-yl)-acetic acid (OC000459) is an indole-acetic acid derivative that potently displaces [H-3]PGD(2) from human recombinant DP2 (K-i = 0.013 mu M), rat recombinant DP2 (K-i = 0.003 mu M), and human native DP2 (Th2 cell membranes; K-i = 0.004 mu M) 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 mu M) of human Th2 lymphocytes and cytokine production (IC50 = 0.019 mu M) by human Th2 lymphocytes. OC000459 competitively antagonized eosinophil shape change responses induced by PGD(2) in both isolated human leukocytes (pK(B) = 7.9) and human whole blood (pK(B) = 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 bio-available in rats and effective in inhibiting blood eosinophilia induced by 13,14-dihydro-15-keto-PGD(2) (DK-PGD(2)) in this species (ED50 = 0.04 mg/kg p.o.) and airway eosinophilia in response to an aerosol of DK-PGD(2) 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.