Recently, research on the S1P/S1P1 system as a potential therapeutic target for the treatment of lymphocyte-mediated (autoimmune) diseases has resulted in the approval of fingolimod (FTY720), a nonselective S1P receptor agonist, for treatment of multiple sclerosis. Piali et al. describe the discovery of a potent, orally active and selective S1P1 receptor agonist, ponesimod [(Z,Z)-5-[3-chloro-4-((2R)-2,3-dihydroxy-propoxy)-benzylidene]-2-propylimino-3-O-tolyl-thiazolidin-4-one]. Ponesimod is a highly potent and selective agonist of the S1P1 receptor signaling system in cells. Treatment of animal models of delayed-type hypersensitivity and adjuvant-induced arthritis with ponesimod resulted in inhibition of edema, accumulation of inflammatory cells, and cytokine release at the sites of inflammation. Ponesimod, similar to other S1P agonists, decreased the number of circulating lymphocytes in the circulation of treated animals, consistent with the mechanism of S1P1 receptor activation to prevent egress of lymphocytes into the lymph vessels. Unlike fingolimod, ponesimod has a shorter terminal half-life that allows for rapid restoration of lymphocyte count in the peripheral blood upon treatment discontinuation. Immunomodulation with a rapidly reversible S1P1 selective agonist, such as ponesimod, may represent a new therapeutic approach in lymphocyte-mediated autoimmune diseases.
See article at J Pharmacol Exp Ther 2011, 337:547–556
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics