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 Jun 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 311--317
VI  - 369
IP  - 3
4099  - http://jpet.aspetjournals.org/content/369/3/311.short
4100  - http://jpet.aspetjournals.org/content/369/3/311.full
SO  - J Pharmacol Exp Ther2019 Jun 01; 369
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.