PT  - JOURNAL ARTICLE
AU  - Hussien Al-Shamma
AU  - Karin Lehmann-Bruinsma
AU  - Chris Carroll
AU  - Michelle Solomon
AU  - H. Kiyomi Komori
AU  - Laurent Peyrin-Biroulet
AU  - John Adams
TI  - The Selective Sphingosine 1-phosphate Receptor Modulator Etrasimod Regulates Lymphocyte Trafficking and Alleviates Experimental Colitis
AID  - 10.1124/jpet.118.254268
DP  - 2019 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - jpet.118.254268
4099  - http://jpet.aspetjournals.org/content/early/2019/03/14/jpet.118.254268.short
4100  - http://jpet.aspetjournals.org/content/early/2019/03/14/jpet.118.254268.full
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.