FTY720 (S)-Phosphate ((S)-FTY720P)

FTY720 is a novel immune modulator that prolongs allograft transplant survival in numerous models by inhibiting lymphocyte emigration from lymphoid organs.¹ FTY720 is phosphorylated by sphingosine kinases in vivo, and then acts as a potent agonist at four of the five sphingosine-1-phosphate (S1P) receptors.² FTY720 (S)-phosphate is the single stereoisomer formed by phosphorylation of FTY720 in vivo, as determined in rats and humans.³ It exhibits K_i values of 2.1, 5.9, 23, and 2.2 nM for S1P₁,₃,₄,₅, respectively, whereas the R enantiomer binds with 5 to 130-fold lower affinity.⁴ FTY720 (S)-phosphate causes internalization of S1P₁ on lymphocytes, abrogating S1P-dependent egress of lymphocytes from lymphoid organs.⁵ It also enhances endothelial barrier function,⁵ stimulates the activity of the sphingosine transporter Abcb1 and the leukotriene C₄ transporter Abcc1⁶ and inhibits cytosolic phospholipase A₂ activity.⁷

1.Brinkmann, V., Pinschewer, D.D., Feng, L., et al.FTY720: Altered lymphocyte traffic results in allograft protectionTransplantation72(5)764-769(2001) 2.Brinkmann, V., Davis, M.D., Heise, C.E., et al.The immune modulator FTY720 targets sphingosine 1-phosphate receptorsJ. Biol. Chem.277(24)21453-21457(2002) 3.Albert, R., Hinterding, K., Brinkmann, V., et al.Novel immunomodulator FTY720 is phosphorylated in rats and humans to form a single stereoisomer. Identification, chemical proof, and biological characterization of the biologically active species and its enantiomerJ. Med. Chem.48(16)5373-5377(2005) 4.Kiuchi, M., Adachi, K., Tomatsu, A., et al.Asymmetric synthesis and biological evaluation of the enantiomeric isomers of the immunosuppressive FTY720-phosphateBioorg. Med. Chem.13(2)425-432(2005) 5.Brinkmann, V.FTY720: Mechanism of action and potential benefit in organ transplantationYonsei Med. J.45(6)991-997(2004) 6.Honig, S.M., Fu, S., Mao, X., et al.FTY720 stimulates multidrug transporter- and cysteinyl leukotriene-dependent T cell chemotaxis to lymph nodesJ. Clin. Invest.111(5)627-637(2003) 7.Payne, S.G., Oskeritizian, C.A., Griffiths, R., et al.The immunosuppressant drug FTY720 inhibits cytosolic phospholipase A2 independently of sphingosine-1-phosphate receptorsBlood109(3)1077-1085(2007)