dc.contributor.author | Pettipher, Roy | |
dc.contributor.author | Vinall, Shan L. | |
dc.contributor.author | Xue, Luzheng | |
dc.contributor.author | Speight, Graham | |
dc.contributor.author | Townsend, Elizabeth R. | |
dc.contributor.author | Gazi, Lucien | |
dc.contributor.author | Whelan, C.J. | |
dc.contributor.author | Armer, Richard E. | |
dc.contributor.author | Payton, Mark A. | |
dc.contributor.author | Hunter, Michael G. | |
dc.date.accessioned | 2012-02-15T10:00:51Z | |
dc.date.available | 2012-02-15T10:00:51Z | |
dc.date.issued | 2012-02 | |
dc.identifier.citation | Pettipher , R , Vinall , S L , Xue , L , Speight , G , Townsend , E R , Gazi , L , Whelan , C J , Armer , R E , Payton , M A & Hunter , M G 2012 , ' 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 ' , Journal of Pharmacology and Experimental Therapeutics , vol. 340 , no. 2 , pp. 473-482 . https://doi.org/10.1124/jpet.111.187203 | |
dc.identifier.issn | 0022-3565 | |
dc.identifier.uri | http://hdl.handle.net/2299/7812 | |
dc.description.abstract | 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. | en |
dc.format.extent | 10 | |
dc.language.iso | eng | |
dc.relation.ispartof | Journal of Pharmacology and Experimental Therapeutics | |
dc.subject | PROSTAGLANDIN D-2 RECEPTOR | |
dc.subject | LATE ASTHMATIC REACTION | |
dc.subject | HELPER TYPE-2 CELLS | |
dc.subject | ALLERGIC INFLAMMATION | |
dc.subject | AIRWAY INFLAMMATION | |
dc.subject | TH2 CELLS | |
dc.subject | CYTOKINE PRODUCTION | |
dc.subject | CRTH2 RECEPTOR | |
dc.subject | CYCLOSPORINE-A | |
dc.subject | CHEMOATTRACTANT | |
dc.title | 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 | en |
dc.contributor.institution | Department of Human and Environmental Sciences | |
dc.contributor.institution | Health & Human Sciences Research Institute | |
dc.description.status | Peer reviewed | |
rioxxterms.versionofrecord | 10.1124/jpet.111.187203 | |
rioxxterms.type | Journal Article/Review | |
herts.preservation.rarelyaccessed | true | |