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.
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Authors | Hussien Al-Shamma, Karin Lehmann-Bruinsma, Chris Carroll, Michelle Solomon, H Kiyomi Komori, Laurent Peyrin-Biroulet, John Adams |
Journal | The 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 |
PMID | 30872391
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics. |
Chemical References |
- Acetates
- Cyclopentanes
- Heterocyclic Compounds, 3-Ring
- Indoles
- Sphingosine-1-Phosphate Receptors
- etrasimod
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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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