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dc.contributor.authorPettipher, Roy
dc.contributor.authorVinall, Shan L.
dc.contributor.authorXue, Luzheng
dc.contributor.authorSpeight, Graham
dc.contributor.authorTownsend, Elizabeth R.
dc.contributor.authorGazi, Lucien
dc.contributor.authorWhelan, C.J.
dc.contributor.authorArmer, Richard E.
dc.contributor.authorPayton, Mark A.
dc.contributor.authorHunter, Michael G.
dc.date.accessioned2012-02-15T10:00:51Z
dc.date.available2012-02-15T10:00:51Z
dc.date.issued2012-02
dc.identifier.citationPettipher , 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.issn0022-3565
dc.identifier.otherPURE: 584478
dc.identifier.otherPURE UUID: 6339cfec-8f35-479a-bc75-2598c38e1d0b
dc.identifier.otherWOS: 000299323600025
dc.identifier.otherScopus: 84856006564
dc.identifier.urihttp://hdl.handle.net/2299/7812
dc.description.abstractD 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.extent10
dc.language.isoeng
dc.relation.ispartofJournal of Pharmacology and Experimental Therapeutics
dc.subjectPROSTAGLANDIN D-2 RECEPTOR
dc.subjectLATE ASTHMATIC REACTION
dc.subjectHELPER TYPE-2 CELLS
dc.subjectALLERGIC INFLAMMATION
dc.subjectAIRWAY INFLAMMATION
dc.subjectTH2 CELLS
dc.subjectCYTOKINE PRODUCTION
dc.subjectCRTH2 RECEPTOR
dc.subjectCYCLOSPORINE-A
dc.subjectCHEMOATTRACTANT
dc.titlePharmacologic 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 Eosinophilsen
dc.contributor.institutionDepartment of Human and Environmental Sciences
dc.contributor.institutionHealth & Human Sciences Research Institute
dc.description.statusPeer reviewed
rioxxterms.versionofrecordhttps://doi.org/10.1124/jpet.111.187203
rioxxterms.typeJournal Article/Review
herts.preservation.rarelyaccessedtrue
herts.rights.accesstyperestrictedAccess


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