RT Journal Article
SR Electronic
T1 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
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 473
OP 482
DO 10.1124/jpet.111.187203
VO 340
IS 2
A1 Roy Pettipher
A1 Shân L. Vinall
A1 Luzheng Xue
A1 Graham Speight
A1 Elizabeth R. Townsend
A1 Lucien Gazi
A1 Cliff J. Whelan
A1 Richard E. Armer
A1 Mark A. Payton
A1 Michael G. Hunter
YR 2012
UL http://jpet.aspetjournals.org/content/340/2/473.abstract
AB 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.