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
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
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DOI：
10.1124/jpet.111.187203
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发表时间：
2012-02-01
影响因子：
3.5
通讯作者：
Hunter, Michael G.
中科院分区：
文献类型：
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作者：
Pettipher, Roy;Vinall, Shan L.;Hunter, Michael G.
D 前列腺素受体 2 (DP2) [也称为在 T 辅助细胞 2 (Th2) 细胞 (CRTH2) 上表达的趋化受体同源分子] 由 Th2 淋巴细胞、嗜酸性粒细胞和嗜碱性粒细胞选择性表达，并介导这些细胞类型响应前列腺素 D-2 (PGD(2)) 的募集和激活。 (5-Fluoro-2-methyl-3-quinolin-2-ylmethylindo-1-yl)-acetate (OC000459) 是一种吲哚-乙酸衍生物，可有效取代人重组 DP2 (K-i = 0.013 mu M)、大鼠重组 DP2 (K-i = 0.003 mu M) 和人天然 DP2 中的 [H-3]PGD(2) （Th2细胞膜；K-i=0.004μM）但不干扰其他前列腺素受体（前列腺素E1-4受体、D前列腺素受体1、血栓素受体、前列环素受体和前列腺素F受体）的配体结合特性或功能活性。 OC000459抑制人Th2淋巴细胞的趋化性(IC50 = 0.028μM)和人Th2淋巴细胞的细胞因子产生(IC50 = 0.019μM)。 OC000459 在分离的人白细胞 (pK(B) = 7.9) 和人全血 (pK(B) = 7.5) 中竞争性拮抗 PGD(2) 诱导的嗜酸性粒细胞形状变化反应，但不抑制对嗜酸细胞趋化因子、5-氧代-二十碳四烯酸或补体成分 C5a 的反应。 OC000459 还抑制 Th2 细胞和嗜酸性粒细胞响应 IgE/抗 IgE 激活的人肥大细胞上清液的激活。 OC000459 对 69 个受体和 19 种酶（包括环氧合酶 1 (COX1) 和 COX2）没有显着的抑制活性。 OC000459被发现在大鼠中具有口服生物利用度，并能有效抑制该物种中由13,14-二氢-15-酮-PGD(2) (DK-PGD(2))引起的血液嗜酸性粒细胞增多(ED50 = 0.04 mg/kg p.o.)和几内亚对DK-PGD(2)气溶胶反应引起的气道嗜酸性粒细胞增多猪 （ED50 = 0.01 毫克/千克，口服）。这些数据表明 OC000459 是一种有效的、选择性的、口服活性的 DP2 拮抗剂，在人全血中保留活性，并抑制人 Th2 淋巴细胞和嗜酸性粒细胞的肥大细胞依赖性激活。
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 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.