RT Journal Article
SR Electronic
T1 The Selective Sphingosine 1-phosphate Receptor Modulator Etrasimod Regulates Lymphocyte Trafficking and Alleviates Experimental Colitis
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.118.254268
DO 10.1124/jpet.118.254268
A1 Hussien Al-Shamma
A1 Karin Lehmann-Bruinsma
A1 Chris Carroll
A1 Michelle Solomon
A1 H. Kiyomi Komori
A1 Laurent Peyrin-Biroulet
A1 John Adams
YR 2019
UL http://jpet.aspetjournals.org/content/early/2019/03/14/jpet.118.254268.abstract
AB 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.