Lymphocyte trafficking is critically regulated by the Sphingosine 1-phosphate receptor-1 (S1P1), a G protein-coupled receptor that has been highlighted as a promising therapeutic target in autoimmunity. Fingolimod (FTY720, Gilenya) is a S1P1 receptor agonist that has recently been approved for the treatment of multiple sclerosis (MS). Here, we report the discovery of NIBR-0213, a potent and selective S1P1 antagonist that induces long-lasting reduction of peripheral blood lymphocyte counts after oral dosing. NIBR-0213 showed comparable therapeutic efficacy to fingolimod in experimental autoimmune encephalomyelitis (EAE), a model of human MS. These data provide convincing evidence that S1P1 antagonists are effective in EAE. In addition, the profile of NIBR-0213 makes it an attractive candidate to further study the consequences of S1P1 receptor antagonism and to differentiate the effects from those of S1P1 agonists. © 2012 Elsevier Ltd.
Quancard, J., Bollbuck, B., Janser, P., Angst, D., Berst, F., Buehlmayer, P., … Bigaud, M. (2012). A potent and selective S1P1 antagonist with efficacy in experimental autoimmune encephalomyelitis. Chemistry and Biology, 19(9), 1142–1151. https://doi.org/10.1016/j.chembiol.2012.07.016