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 (DP 2 ) [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 [ 3 H]PGD 2 from human recombinant DP 2 (K i ϭ 0.013 M), rat recombinant DP 2 (K i ϭ 0.003 M), and human native DP 2 (Th2 cell membranes; K i ϭ 0.004 M) but does not interfere with the ligand binding properties or functional activities of other prostanoid receptors (prostaglandin E 1-4 receptors, D prostanoid receptor 1, thromboxane receptor, prostacyclin receptor, and prostaglandin F receptor). OC000459 inhibited chemotaxis (IC 50 ϭ 0.028 M) of human Th2 lymphocytes and cytokine production (IC 50 ϭ 0.019 M) by human Th2 lymphocytes. OC000459 competitively antagonized eosinophil shape change responses induced by PGD 2 in both isolated human leukocytes (pK B ϭ 7.9) and human whole blood (pK B ϭ 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-PGD 2 (DK-PGD 2 ) in this species (ED 50 ϭ 0.04 mg/kg p.o.) and airway eosinophilia in response to an aerosol of DK-PGD 2 in guinea pigs (ED 50 ϭ 0.01 mg/kg p.o.). These data indicate that OC000459 is a potent, selective, and orally active DP 2 antagonist that retains activity in human whole blood and inhibits mast cell-dependent activation of both human Th2 lymphocytes and eosinophils.

Inhibition of the asthmatic allergen challenge response by the CRTH2 antagonist OC000459

“…The mean inhibitory concentration (IC50) of OC00459 for inhibition of PGD 2 -mediated activation of eosinophils in human whole blood is 35 ng?mL -1 (personal communication) and so the plasma levels of drug achieved in this study were well in excess of this level. We also showed that the systemic exposure caused functional antagonism of blood eosinophils ex vivo using a well established eosinophil shape change assay [10]. In phase II studies, blood pharmacokinetic and pharmacodynamic data can be used to help the overall interpretation of the results; for example, if plasma levels were low, and/or the shape change assay results were negative, it could be concluded that systemic exposure and/or activity was insufficient and so pulmonary effects would not be expected.…”

“…This assay was performed in all the subjects participating at one centre (n57), using the method described previously [10]. Blood samples (2 mL) were collected into heparinised Vacutainers for measurement of PGD 2 -induced eosinophil shape change predose and at 2, 4, 6 and 8 h after dosing on day 8.…”

Heightened response of eosinophilic asthmatic patients to the CRTH2 antagonist OC000459

“…CRTH2 plays a dominant role in mast cell-dependent activation of both Th2 lymphocytes and eosinophils (2)(3)(4), promoting both increased cell migration and elaboration of Th2 cytokines. Studies on CRTH2-deficient mice or on animals treated with small-molecule antagonists have highlighted the involvement of this receptor in effector responses to allergen including leucocyte accumulation, Th2 cytokine production, tissue swelling, airway hyperresponsiveness and production of IgE [reviewed in (5)].…”

Role of Prostaglandin D2 and DP1 Receptor on Japanese Cedar Pollen-Induced Allergic Rhinitis in Mice

“…MK-0524 (Takahashi et al, 2015) and OC000459 ((5-fluoro-2-methyl-3-quinolin-2-ylmethylindo-1-yl)-acetic acid) (Horak et al, 2012;Pettipher et al, 2012) were synthesized in our laboratories. Cetirizine dihydrochloride was purchased from the Tokyo Chemical Industry Co., Ltd. (Tokyo, Japan), fluticasone propionate (FP) was from Glaxo Smith Kline K.K.…”