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

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, S1P1 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) S1P1 receptors, and a partial agonist of human S1P4 (147 nM EC50) and S1P5 (24.4 nM EC50), with relative efficacies of 63% and 73% of S1P response, respectively; whereas neither agonist nor antagonist activity was observed for human S1P2 or S1P3 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+CD45RBhigh T-cell transfer mouse model of colitis.
AuthorsHussien Al-Shamma, Karin Lehmann-Bruinsma, Chris Carroll, Michelle Solomon, H Kiyomi Komori, Laurent Peyrin-Biroulet, John Adams
JournalThe Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 369 Issue 3 Pg. 311-317 (06 2019) ISSN: 1521-0103 [Electronic] United States
PMID30872391 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.
Chemical References
  • Acetates
  • Cyclopentanes
  • Heterocyclic Compounds, 3-Ring
  • Indoles
  • Sphingosine-1-Phosphate Receptors
  • etrasimod
Topics
  • Acetates (pharmacology, therapeutic use)
  • Animals
  • Biological Transport (drug effects)
  • Cell Count
  • Colitis (drug therapy, immunology, metabolism)
  • Cyclopentanes (pharmacology, therapeutic use)
  • Disease Models, Animal
  • Dogs
  • Heterocyclic Compounds, 3-Ring (pharmacology, therapeutic use)
  • Humans
  • Indoles (pharmacology, therapeutic use)
  • Lymphocytes (drug effects, metabolism)
  • Male
  • Mice
  • Sphingosine-1-Phosphate Receptors (metabolism)

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