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.
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 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 (K(i) = 0.013 μM), rat recombinant DP₂ (K(i) = 0.003 μM), and human native DP₂ (Th2 cell membranes; K(i) = 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 (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 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.
authors: Oxagen Ltd, 91 Milton Park, Abingdon, Oxon, OX14 4RY, United Kingdom. r.pettipher@oxagen.co.uk
authors: Roy
authors: R
authors: Pettipher
authors: Shân L
authors: SL
authors: Vinall
authors: Luzheng
authors: L
authors: Xue
authors: Graham
authors: G
authors: Speight
authors: Elizabeth R
authors: ER
authors: Townsend
authors: Lucien
authors: L
authors: Gazi
authors: Cliff J
authors: CJ
authors: Whelan
authors: Richard E
authors: RE
authors: Armer
authors: Mark A
authors: MA
authors: Payton
authors: Michael G
authors: MG
authors: Hunter
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001095:Arachidonic Acids / Q000494:pharmacology; D001667:Binding, Competitive; D016466:CHO Cells; D020013:Calcium Signaling / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism; D048430:Cell Shape / Q000187:drug effects / Q000276:immunology; D054413:Chemokine CCL11 / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects / Q000276:immunology; D015936:Complement C5a / Q000494:pharmacology; D006224:Cricetinae; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004802:Eosinophilia / Q000139:chemically induced / Q000517:prevention & control; D004804:Eosinophils / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D006168:Guinea Pigs; D006801:Humans; D007210:Indoleacetic Acids / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D018793:Interleukin-13 / Q000378:metabolism; D015848:Interleukin-5 / Q000494:pharmacology; D007975:Leukotriene B4 / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D008407:Mast Cells / Q000276:immunology* / Q000378:metabolism; D011448:Prostaglandin Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D011657:Pulmonary Eosinophilia / Q000139:chemically induced / Q000517:prevention & control; D011804:Quinolines / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D011982:Receptors, Prostaglandin / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D018418:Th2 Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D014162:Transfection
chemical_list: C571151:(5-fluoro-2-methyl-3-quinolin-2-ylmethylindo-1-yl)acetic acid; D001095:Arachidonic Acids; D054413:Chemokine CCL11; D017077:Culture Media, Conditioned; D007210:Indoleacetic Acids; D018793:Interleukin-13; D015848:Interleukin-5; D011448:Prostaglandin Antagonists; D011804:Quinolines; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D011994:Recombinant Proteins; C080828:5-oxo-6,8,11,14-eicosatetraenoic acid; D007975:Leukotriene B4; C034832:13,14-dihydro-15-ketoprostaglandin D2; D015936:Complement C5a; D015230:Prostaglandin D2; C036293:prostaglandin D2 receptor