Beacon Discovery Inc., San Diego, California (H.A.-S., K.L.-B., C.C.); Crown Bioscience, Inc., San Diego, California (M.S.); Arena Pharmaceuticals, Inc., San Diego, California (H.K.K., J.A.); and Institut National de la Santé et de la Recherche Médicale U954 and Department of Gastroenterology, Nancy University Hospital, Lorraine University, Nancy, France (L.P.-B.)
Beacon Discovery Inc., San Diego, California (H.A.-S., K.L.-B., C.C.); Crown Bioscience, Inc., San Diego, California (M.S.); Arena Pharmaceuticals, Inc., San Diego, California (H.K.K., J.A.); and Institut National de la Santé et de la Recherche Médicale U954 and Department of Gastroenterology, Nancy University Hospital, Lorraine University, Nancy, France (L.P.-B.).
J Pharmacol Exp Ther. 2019 Jun;369(3):311-317. doi: 10.1124/jpet.118.254268. Epub 2019 Mar 14.
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 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 EC), mouse (3.65 nM EC), dog (4.19 nM EC), and monkey (8.7 nM EC) S1P receptors, and a partial agonist of human S1P (147 nM EC) and S1P (24.4 nM EC), with relative efficacies of 63% and 73% of S1P response, respectively; whereas neither agonist nor antagonist activity was observed for human S1P or S1P A dose-dependent relationship was observed for etrasimod plasma concentration and lymphocyte count in mice, and chronic treatment with etrasimod resulted in attenuation of inflammation in a CD4CD45RB T-cell transfer mouse model of colitis.
淋巴细胞从次级淋巴器官的流出是受膜衍生的溶血磷脂信号分子 1-磷酸鞘氨醇（S1P）与 G 蛋白偶联受体之间浓度梯度依赖性相互作用调节的。埃特司莫单抗是一种新型的、下一代的小分子、口服 S1P 受体调节剂，目前正在开发用于治疗免疫介导的炎症性疾病，包括溃疡性结肠炎。在临床前药理学研究中，埃特司莫单抗是重组人（6.1 nM EC）、小鼠（3.65 nM EC）、狗（4.19 nM EC）和猴子（8.7 nM EC） S1P 受体的完全激动剂，对人 S1P（147 nM EC）和 S1P（24.4 nM EC）为部分激动剂，分别具有 S1P 反应的 63%和 73%的相对效力；而对人 S1P 或 S1P 则既没有激动剂也没有拮抗剂活性。在小鼠中，埃特司莫单抗的血浆浓度和淋巴细胞计数呈剂量依赖性关系，并且慢性治疗埃特司莫单抗可减轻结肠炎的 CD4CD45RB T 细胞转移小鼠模型中的炎症。
