The Selective Sphingosine 1-Phosphate Receptor 1 Agonist Ponesimod Protects against Lymphocyte-Mediated Tissue Inflammation

Lymphocyte exit from lymph nodes and their re-circulation into blood is controlled by the sphingolipid sphingosine-1-phosphate (S1P). The cellular receptor mediating lymphocyte exit is S1P1, one of five S1P receptors. Non-selective agonists for S1P receptors lead to blood lymphocyte count reduction. The effects of selective S1P1 agonists on blood lymphocyte count and their impact in models of lymphocyte-mediated tissue inflammation have been less investigated. We describe here the general pharmacology of ponesimod, (Z,Z)-5-[3-chloro-4-((2R)-2,3-dihydroxy-propoxy)-benzylidene]-2-propylimino-3-o-tolyl-thiazolidin-4-one, a new, potent and orally active selective S1P1 agonist. Ponesimod activated S1P1-mediated signal transduction with high potency (EC50 of 5.7 nM) and selectivity. Oral administration of ponesimod to rats led to a dose-dependent decrease of blood lymphocyte count. After discontinuation of dosing, blood lymphocyte count returned to baseline within 48 hours. Ponesimod prevented edema formation, inflammatory cell accumulation and cytokine release in the skin of mice with delayed-type hypersensitivity. Ponesimod also prevented the increase in paw volume and joint inflammation in rats with adjuvant-induced arthritis. These data show that selective activation of S1P1 using ponesimod leads to blood lymphocyte count reduction and efficacy in models of lymphocyte-mediated tissue inflammation. Immunomodulation with a rapidly reversible S1P1 selective agonist may represent a new therapeutic approach in lymphocyte-mediated autoimmune diseases.