REVIEW OC000459 is a potent and selective D prostanoid receptor 2 (DP2) antagonist with IC50 of 13 nM. The D prostanoid receptor 2 (DP2) [also known as chemoattractant receptor-homologous molecule expressed on T helper 2 (Th2) cells (CRTH2)], G-protein-coupled receptor is selectively expressed by Th2 lymphocytes, eosinophils, and basophils and mediates recruitment and activation of these cell types in response to prostaglandin D2 (PGD2), and is involved in the pathogenesis of airway inflammation, limitation and dysfunction in asthma. OC000459 potently displaces [?H]PGD2 from human recombinant DP2 (K(i) = 0.013 uM), rat recombinant DP2 (K(i) = 0.003 uM), and human native DP2 (Th2 cell membranes; K(i) = 0.004 uM) 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 uM) of human Th2 lymphocytes and cytokine production (IC50 = 0.019 uM) 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-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. OC000459 has subsequently been shown that it can reduce airway inflammation and improve lung function in moderate persistent asthma.
REFERENCES
[1]
Barnes N, Pavord I, Chuchalin A, Bell J, Hunter M, Lewis T, Parker D, Payton M, Collins LP, Pettipher R, Steiner J, Perkins CM. A randomized, double-blind, placebo-controlled study of the CRTH2 antagonist OC000459 in moderate persistent asthma. Clin Exp Allergy. 2012 Jan;42(1):38-48.
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Straumann A, Hoesli S, Bussmann Ch, Stuck M, Perkins M, Collins LP, Payton M, Pettipher R, Hunter M, Steiner J, Simon HU. Anti-eosinophil activity and clinical efficacy of the CRTH2 antagonist OC000459 in eosinophilic esophagitis. Allergy. 2013 Mar;68(3):375-85.
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Singh D, Cadden P, Hunter M, Pearce Collins L, Perkins M, Pettipher R, Townsend E, Vinall S, O'Connor B. Inhibition of the asthmatic allergen challenge response by the CRTH2 antagonist OC000459. Eur Respir J. 2013 Jan;41(1):46-52.
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Pettipher R, Vinall SL, Xue L, Speight G, Townsend ER, Gazi L, Whelan CJ, Armer RE, Payton MA, Hunter MG. 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. J Pharmacol Exp Ther. 2012 Feb;340(2):473-82
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