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首页> 外文期刊>The Journal of Pharmacology and Experimental Therapeutics: Official Publication of the American Society for Pharmacology and Experimental Therapeutics >The Selective Sphingosine 1-Phosphate Receptor Modulator Etrasimod Regulates Lymphocyte Trafficking and Alleviates Experimental Colitis
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The Selective Sphingosine 1-Phosphate Receptor Modulator Etrasimod Regulates Lymphocyte Trafficking and Alleviates Experimental Colitis

机译：选择性鞘氨酸1-磷酸酯受体调节剂Etrasimod调节淋巴细胞贩运和减轻实验性结肠炎

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摘要

Lymphocyte trafficking out of secondary lymphoid organs is regulated by concentration gradient-dependent interactions between the membrane-derived lysophospholipid signaling molecule sphingosine 1-phosphate (S1P) and the G-protein-coupled receptor, S1P(1). Etrasimod is a novel, next-generation, small-molecule, oral S1P receptor modulator in clinical development for the treatment of immune-mediated inflammatory disorders, including ulcerative colitis. In preclinical pharmacology studies, etrasimod was a full agonist of recombinant human (6.1 nM EC50), mouse (3.65 nM EC50), dog (4.19 nM EC50), and monkey (8.7 nM EC50) S1P(1) receptors, and a partial agonist of human S1P(4) (147 nM EC50) and S1P5 (24.4 nM EC50), with relative efficacies of 63% and 73% of S1P response, respectively; whereas neither agonist nor ant(a)gonist activity was observed for human S1P(2) or S1P(3). A dose-dependent relationship was observed for etrasimod plasma concentration and lymphocyte count in mice, and chronic treatmentwith etrasimod resulted in attenuation of inflammation in a CD4(+)CD45RB(high) T-cell transfer mouse model of colitis.
机译：淋巴细胞次级淋巴器官的投放出由膜来源的溶血磷脂信号传导分子鞘氨醇-1-磷酸（S1P）和G-蛋白 - 偶联受体，S1P（1）之间的浓度梯度依赖性相互作用调节。 Etrasimod是一种新型的，下一代，小分子，口服S1P受体在临床开发用于免疫介导的炎性病症，包括溃疡性结肠炎的治疗调节剂。在临床前药理学研究，etrasimod是重组人（6.1 nM的EC 50），小鼠（3.65 nM的EC 50），狗（4.19 nM的EC 50），和猴（8.7 nM的EC 50）S1P（1）受体的完全激动剂和部分激动剂人S1P（4）（147 nM的EC 50）和S1P5（24.4 nM的EC 50），与63％和S1P响应，73％相对功效;而既不激动剂也不蚂蚁观察到人S1P（2）或S1P（3）的（a）gonist活性。观察到的剂量依赖关系为在小鼠etrasimod血浆浓度和淋巴细胞计数，以及慢性treatmentwith etrasimod导致在CD4（+）CD45RB（高）炎症的衰减结肠炎的T细胞转移小鼠模型。

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