The Selective Sphingosine 1-Phosphate Receptor Modulator Etrasimod Regulates Lymphocyte Trafficking and Alleviates Experimental Colitis.

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Al-Shamma H, Lehmann-Bruinsma K, Carroll C, Solomon M, Komori HK, Peyrin-Biroulet L, Adams J

The Selective Sphingosine 1-Phosphate Receptor Modulator Etrasimod Regulates Lymphocyte Trafficking and Alleviates Experimental Colitis.

J Pharmacol Exp Ther. 2019 Jun;369(3):311-317. doi: 10.1124/jpet.118.254268. Epub 2019 Mar 14.

PubMed ID
30872391 [ View in PubMed
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Abstract

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 EC(50)), mouse (3.65 nM EC(50)), dog (4.19 nM EC(50)), and monkey (8.7 nM EC(50)) S1P(1) receptors, and a partial agonist of human S1P(4) (147 nM EC(50)) and S1P(5) (24.4 nM EC(50)), with relative efficacies of 63% and 73% of S1P response, respectively; whereas neither agonist nor antagonist 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 treatment with etrasimod resulted in attenuation of inflammation in a CD4(+)CD45RB(high) T-cell transfer mouse model of colitis.

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