"目录号: HY-15342
GPCR/G Protein-
OC000459是D型前列腺素受体2（DP2）拮抗剂，IC50为13 nM。
Prostaglandin Receptor
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生物活性
Description
OC000459 is a potent and selective D prostanoid receptor 2 (DP2) antagonist with IC50 of 13 nM.IC50 Value: 13 nM( Ki for hrCRTH2); 3 nM( Ki for Rat rCRTH2);13 nM(Ki for human native CRTH2)Target: D prostanoid receptor 2CRTH2 (chemoattractant receptor expressed on T-helper (Th) type 2 cells) is a G-protein-coupled receptor expressed by Th2 lymphocytes and eosinophils that mediates prostaglandin (PG)D(2)-driven chemotaxis[1]. CRTH2 mediates activation of Th2 cells, eosinophils and basophils in response to prostaglandin D(2). The CRTH2 antagonist OC000459 has been demonstrated to reduce airway inflammation and improve lung function in moderate persistent asthma[2].in vitro: OC000459 is an indole-acetic acid derivative that potently displaces [3H]PGD2from 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[3] .in vivo: 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.) [3].Clinical trial: N/A.
Clinical Trial
NCT01056575
Oxagen Ltd
Healthy Volunteers
February 2010
Phase 1
NCT01056783
Oxagen Ltd
Eosinophilic Esophagitis
August 2010
Phase 2
NCT02560610
Atopix Therapeutics, Ltd.
Severe Eosinophilic Asthma
September 2016
Phase 2
NCT01448902
Oxagen Ltd
Allergic Rhinitis
March 2007
Phase 2
NCT02341521
Atopix Therapeutics, Ltd.-Simbec Research
Asthma
March 2015
Phase 1
NCT02002208
Atopix Therapeutics, Ltd.
Atopic Dermatitis
October 2013
Phase 2
NCT01057927
Oxagen Ltd
Asthma
January 2007
Phase 2
NCT01056692
Oxagen Ltd-Medicines Evaluation Unit, Manchester, UK-King's College Hospital NHS Trust
Bronchial Asthma
February 2006
Phase 2
NCT00890877
Oxagen Ltd
Mild to Moderate Persistent Asthma
April 2009
Phase 2
NCT00697281
Oxagen Ltd
Allergic Rhinitis
May 2008
Phase 2
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References
[1].Singh D, Cadden P, Hunter M, Inhibition of the asthmatic allergen challenge response by the CRTH2 antagonist OC000459. Eur Respir J. 2013 Jan;41(1):46-52.
[2].Horak F, Zieglmayer P, Zieglmayer R, The CRTH2 antagonist OC000459 reduces nasal and ocular symptoms in allergic subjects exposed to grass pollen, a randomised, placebo-controlled, double-blind trial. Allergy. 2012 Dec;67(12):1572-9.
[3].Pettipher R, Vinall SL, Xue L, 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