FTY720 (Fingolimod) is a first-in-class sphingosine 1-phosphate (S1P) receptor modulator that inhibits S1P-dependent lymphocyte egress from secondary lymphoid organs. Oral administration of FTY720 shows a superior efficacy compared to interferon (IFN)-β in relapsing remitting multiple sclerosis (MS), the most common inflammatory disorder of the central nervous system (CNS) and in experimental autoimmune encephalomyelitis (EAE), a CD4 T cell-dependent animal model for MS. FTY720 is a structural

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... nalogue of sphingosine and is rapidly converted to the (S)-enantiomer of FTY720-phosphate [(S)-FTY720-P)] by sphingosine kinases. (S)-FTY720-P binds 4 types of S1P receptors (S1P 1 , S1P 3 , S1P 4 , and S1P 5 ), induces internalization and degradation of lymphocytic S1P 1 , and inhibits S1P responsiveness of lymphocytes. Consequently, (S)-FTY720-P acts as a functional antagonist at S1P 1 thereby inhibiting S1P-S1P 1 axis-mediated lymphocyte egress from secondary lymphoid organs. Based on this mechanism, FTY720 sequesters myelin antigen-specific CD4 T cells including interleukin 17-expressing helper T cells (Th17 cells) and IFN-γ-expressing type 1 helper T cells (Th1 cells) into the lymph nodes, and reduces the infiltration of these Th cells into the CNS in mouse EAE. Since FTY720 was approved by the United States Food and Drug Administration in September 2010 as a first-line treatment for relapsing remitting MS, it is presumed that oral FTY720 provides a new therapeutic approach for MS. Rec./Acc.