The Selective Sphingosine 1-Phosphate Receptor Modulator Etrasimod Regulates Lymphocyte Trafficking and Alleviates Experimental Colitis.
Fiche publication
Date publication
juin 2019
Journal
The Journal of pharmacology and experimental therapeutics
Auteurs
Membres identifiés du Cancéropôle Est :
Pr PEYRIN-BIROULET Laurent
Tous les auteurs :
Al-Shamma H, Lehmann-Bruinsma K, Carroll C, Solomon M, Komori HK, Peyrin-Biroulet L, Adams J
Lien Pubmed
Résumé
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.
Référence
J. Pharmacol. Exp. Ther.. 2019 Jun;369(3):311-317