Characterization of CCX282-B, an Orally Bioavailable Antagonist of the CCR9 Chemokine Receptor, for Treatment of Inflammatory Bowel Disease
Characterization of CCX282-B, an Orally Bioavailable Antagonist of the CCR9 Chemokine Receptor, for Treatment of Inflammatory Bowel Disease
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DOI：
10.1124/jpet.110.169714
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发表时间：
2010-10-10
影响因子：
3.5
通讯作者：
Schall, Thomas J.
中科院分区：
文献类型：
--
作者：
Walters, Matthew J.;Wang, Yu;Schall, Thomas J.
趋化因子系统代表了一组不同的G蛋白偶联受体，在稳态和炎症条件下负责协调细胞募集。趋化因子受体9 （CCR9）是一种已知的趋化因子受体，是免疫细胞迁移到肠道的中心。其唯一的配体CCL25在肠粘膜表面表达，已知在肠炎症中升高。到目前为止，还没有针对CCR9的小分子拮抗剂的报道。我们首次报道了一种小分子CCX282-B的发现，它是一种口服生物可利用的、选择性的、有效的人类CCR9拮抗剂。CCX282-B抑制ccr9介导的Ca2+动员和对Molt-4细胞的趋化作用，IC50值分别为5.4和3.4 nM。在100%人血清存在下，CCX282-B抑制ccr9介导的趋化作用，IC50为33 nM， α 1-酸性糖蛋白的添加不影响其效力。CCX282-B抑制原代ccr9表达细胞对CCL25的趋化作用，IC50为6.8 nM。CCX282-B是ccl25定向趋化CCR9剪接形式（CCR9A和CCR9B）的等效抑制剂，IC50值分别为2.8和2.6 nM。CCX282-B还抑制小鼠和大鼠ccr9介导的趋化性。用CCX282-B抑制CCR9导致克罗恩病的正常化，如与TNF δ ARE小鼠相关的组织病理学。分析与这种改善相关的血浆药物水平，有助于了解CCR9拮抗剂治疗肠道炎症的药代动力学/药效学关系。
The chemokine system represents a diverse group of G protein-coupled receptors responsible for orchestrating cell recruitment under both homeostatic and inflammatory conditions. Chemokine receptor 9 (CCR9) is a chemokine receptor known to be central for migration of immune cells into the intestine. Its only ligand, CCL25, is expressed at the mucosal surface of the intestine and is known to be elevated in intestinal inflammation. To date, there are no reports of small-molecule antagonists targeting CCR9. We report, for the first time, the discovery of a small molecule, CCX282-B, which is an orally bioavailable, selective, and potent antagonist of human CCR9. CCX282-B inhibited CCR9-mediated Ca2+ mobilization and chemotaxis on Molt-4 cells with IC50 values of 5.4 and 3.4 nM, respectively. In the presence of 100% human serum, CCX282-B inhibited CCR9-mediated chemotaxis with an IC50 of 33 nM, and the addition of alpha 1-acid glycoprotein did not affect its potency. CCX282-B inhibited chemotaxis of primary CCR9-expressing cells to CCL25 with an IC50 of 6.8 nM. CCX282-B was an equipotent inhibitor of CCL25-directed chemotaxis of both splice forms of CCR9 (CCR9A and CCR9B) with IC50 values of 2.8 and 2.6 nM, respectively. CCX282-B also inhibited mouse and rat CCR9-mediated chemotaxis. Inhibition of CCR9 with CCX282-B results in normalization of Crohn's disease such as histopathology associated with the TNF Delta ARE mice. Analysis of the plasma level of drug associated with this improvement provides an understanding of the pharmacokinetic/pharmacodynamic relationship for CCR9 antagonists in the treatment of intestinal inflammation.