Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Discovery of fingolimod based on the chemical modification of a natural product from the fungus, Isaria sinclairii


Fingolimod is a first-in-class of sphingosine-1-phosphate (S1P) receptor modulator and is widely used a therapeutic drug for multiple sclerosis (MS), autoimmune disease in the central nervous system. About 25 year ago, a natural product, myriocin was isolated from culture broths of the fungus Isaria sinclairii. Myriocin, a rather complex amino acid having three successive asymmetric centers, was found to show a potent immunosuppressive activity in vitro; however, it induced a strong toxicity in vivo. To find out a less toxic immunosuppressive candidate, the chemical structure of myriocin was simplified to a nonchiral symmetric 2-substituted-2-aminoproane-1,3-diol framework. Finally, a highly potent immunosuppressant, fingolimod was found by the extensive chemical modification and pharmacological evaluation using skin allograft model in vivo. Throughout the analyses of the mechanism action of fingolimod, it is revealed that S1P receptor 1 (S1P1) plays an essential role in lymphocyte circulation and that the molecular target of fingolimod is S1P1. Phosphorylated fingolimod acts as a “functional” antagonist at S1P1, modulates lymphocyte circulation, and shows a potent immunosuppressive activity. Fingolimod significantly reduced the relapse rate of MS in the clinical studies and has been approved as a new therapeutic drug for MS in more than 80 countries.

This is a preview of subscription content

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6


  1. 1.

    Dreyfuss M, Harri E, Hoffman H, et al. Cyclosporin A and C: new metabolites from Trichoderma polysporum (Link ex per.) Rifai. Eur J Appl Microbiol. 1976;3:125–33.

    CAS  Google Scholar 

  2. 2.

    Borel JF, editor. History of cyclosporin A and its significance in immunology. In: Cyclosporin A. Amsterdam: Elsevier Biochemical Press; 1982. p. 5–17.

  3. 3.

    Tanaka H, Kuroda A, Marusawa H, et al. Structure of FK-506: a novel immunosuppressant isolated from Streptomyces. J Am Chem Soc. 1987;109:5031–3.

    CAS  Google Scholar 

  4. 4.

    Kino T, Hatanaka H, Hashimoto M, et al. FK-506, a novel immunosuppressant isolated from Streptomyces. I. Fermentation, isolation, and physico-chemical and biological characteristics. J Antibiot. 1987;40:1249–55.

    CAS  PubMed  Google Scholar 

  5. 5.

    Kino T, Hatanaka H, Miyata S, et al. FK-506, a novel immunosuppressant isolated from a Streptomyces. II. Immunosuppressive effect of FK506 in vitro. J Antibiot. 1987;40:1256–65.

    CAS  PubMed  Google Scholar 

  6. 6.

    Schreiber SL. Chemistry and Biology of the immunophilins and their immunosuppressive ligands. Science. 1991;251:283–7.

    CAS  PubMed  Google Scholar 

  7. 7.

    Liu J, Framer ID Jr, Lane WS, et al. Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell. 1991;66:807–15.

    CAS  PubMed  Google Scholar 

  8. 8.

    Schreiber SL. Immunophilin-sensitive protein phosphatase action in cell signaling pathways. Cell. 1992;70:365–8.

    CAS  PubMed  Google Scholar 

  9. 9.

    Kannedy MS, Deeg HJ, Storb R, Thomas ED. Cyclosporin in marrow transplantation: concentration-dependent toxicity and immunosuppression in vivo. Transplant Proc. 1983;15:471–3.

    Google Scholar 

  10. 10.

    Myers BD, Ross J, Newton L, Luetscher J, Perlroth M. Cyclosprin-associated chronic nephropathy. N Engl J Med. 1984;311:699–705.

    CAS  PubMed  Google Scholar 

  11. 11.

    Shapiro R, Jordan M, Fung J, et al. Kidney transplantation under FK506 immunosuppression. Transplant Proc. 1991;23:920–3.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Ochiai T, Isono K. Pharmacokinetics and clinical effects of FK506. Biotherapy. 1991;5:1531–6.

    Google Scholar 

  13. 13.

    Kelly PA, Burkart GJ, Venkataramanan R. Tacrolimus: anew immunosuppressive agent. Am J Health Syst Pharm. 1995;52:1521–35.

    CAS  PubMed  Google Scholar 

  14. 14.

    Fujita T, Inoue K, Yamamoto S, et al. Fungal metabolites. Part 11. A potent immunosuppressive activity found in Isaria sinclairii metabolite. J Antibiot. 1994;47:208–15.

    CAS  PubMed  Google Scholar 

  15. 15.

    Fujita T, Yoneta M, Hirose R, et al. Simple compounds, 2-alkyl-2-amino-1,3-propanediols have potent immunosuppressive activity. BioMed Chem Lett. 1995;5:847–52.

    CAS  Google Scholar 

  16. 16.

    Fujita T, Hirose R, Yoneta M, et al. Potent immunosuppressants, 2-alkyl-2-aminopropane- 1,3-diols. J Med Chem. 1996;39:4451–9.

    CAS  PubMed  Google Scholar 

  17. 17.

    Adachi K, Kohara T, Nakao N, et al. Design, synthesis, and structure-activity relationships of 2-substituted-2-amino-1.3-propanediols: discovery of a novel immunosuppressant, FTY720. BioMed Chem Lett. 1995;5:853–6.

    CAS  Google Scholar 

  18. 18.

    Kiuchi M, Adachi K, Kohara T, et al. Synthesis and immunosuppressive activity of 2-substituted 2-aminopropane- 1,3-diols and 2-aminoethanols. J Med Chem. 2000;43:2946–61.

    CAS  PubMed  Google Scholar 

  19. 19.

    Chiba K, Hoshino Y, Suzuki C, et al. FTY720, a novel immunosuppressant possessing unique mechanisms. I. Prolongation of skin allograft survival and synergistic effect in combination with cyclosporine in rats. Transplant Proc. 1996;28:1056–9.

    CAS  PubMed  Google Scholar 

  20. 20.

    Hoshino Y, Suzuki C, Ohtsuki M, Masubuchi Y, Amano Y, Chiba K. FTY720, a novel immunosuppressant possessing unique mechanisms. II. Long-term graft survival induction in rat heterotopic cardiac allografts and synergistic effect in combination with cyclosporine A. Transplant Proc. 1996;28:1060–1.

    CAS  PubMed  Google Scholar 

  21. 21.

    Kawaguchi T, Hoshino Y, Rahman F, et al. FTY720, a novel immunosuppressant possessing unique mechanisms. III. Synergistic prolongation of canine renal allograft survival in combination with cyclosporine A. Transplant Proc. 1996;28:1062–3.

    CAS  PubMed  Google Scholar 

  22. 22.

    Matsuura M, Imayoshi T, Chiba K, et al. Effect of FTY720, a novel immunosuppressant, on adjuvant-induced arthritis in rats. Inflamm Res. 2000;49:404–10.

    CAS  PubMed  Google Scholar 

  23. 23.

    Chiba K, Yanagawa Y, Masubuchi Y, et al. FTY720, a novel immunosuppressant, induces sequestration of circulating mature lymphocytes by acceleration of lymphocyte homing in rats. I. FTY720 selectively decreases the number of circulating mature lymphocytes by acceleration of lymphocyte homing. J Immunol. 1998;160:5037–44.

    CAS  PubMed  Google Scholar 

  24. 24.

    Yanagawa Y, Sugahara K, Kataoka H, Kawaguchi T, Masubuchi Y, Chiba K. FTY720, a novel immunosuppressant, induces sequestration of circulating mature lymphocytes by acceleration of lymphocyte homing in rats. II. FTY720 prolongs skin allograft survival by decreasing T cell infiltration into grafts but not cytokine production in vivo. J Immunol. 1998;160:5493–9.

    CAS  PubMed  Google Scholar 

  25. 25.

    Brinkmann V, Pinschewer D, Chiba K, Feng L. FTY720: a novel transplantation drug that modulates lymphocyte traffic rather than activation. Trends Pharm Sci. 2000;21:49–52.

    CAS  PubMed  Google Scholar 

  26. 26.

    Mandala S, Hajdu R, Bergstrom J, et al. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science. 2002;296:346–9.

    CAS  PubMed  Google Scholar 

  27. 27.

    Brinkmann V, Davis MD, Heise CE, et al. The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J Biol Chem. 2002;277:21453–7.

    CAS  PubMed  Google Scholar 

  28. 28.

    Matloubian M, Lo CG, Cinamon G, et al. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature. 2004;427:355–60.

    CAS  PubMed  Google Scholar 

  29. 29.

    Cyster JG. Chemokines, sphingosine-1-phosphate, and cell migration in secondary lymphoid organs. Annu Rev Immunol. 2005;23:127–59.

    CAS  PubMed  Google Scholar 

  30. 30.

    Chiba K. FTY720, a new class of immunomodulator, inhibits lymphocyte egress from secondary lymphoid tissues and thymus by agonistic activity at sphingosine 1-phosphate receptors. Pharm Ther. 2005;108:308–19.

    CAS  Google Scholar 

  31. 31.

    Chiba K, Matsuyuki H, Maeda Y, Sugahara K. Role of sphingosine 1-phosphate receptor type 1 in lymphocyte egress from secondary lymphoid tissues and thymus. Cell Mol Immunol. 2006;3:11–9.

    CAS  PubMed  Google Scholar 

  32. 32.

    Maeda Y, Matsuyuki H, Shimano K, Kataoka H, Sugahara K, Chiba K. Migration of CD4 T cells and dendritic cells toward sphingosine 1-phosphate (S1P) is mediated by different receptor subtypes: S1P regulates the functions of murine mature dendritic cells via S1P receptor type 3. J Immunol 2007;178:3437–46.

    CAS  PubMed  Google Scholar 

  33. 33.

    Paugh SW, Payne SG, Barbour SE, Milstien S, Spiegel S. The immunosuppressant FTY720 is phosphorylated by sphingosine kinase type 2. FEBS Lett. 2003;554:189–93.

    CAS  PubMed  Google Scholar 

  34. 34.

    Pham TH, Okada T, Matloubian M, Lo CG, Cyster JG. S1P1 receptor signaling overrides retention mediated by G alpha i-coupled receptors to promote T cell egress. Immunity. 2008;28:122–33.

    CAS  PubMed  Google Scholar 

  35. 35.

    Kappos L, Radue EW, O’Connor P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010;362:387–401.

    CAS  PubMed  Google Scholar 

  36. 36.

    Cohen JA, Barkhof F, Comi G, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010;362:402–15.

    CAS  PubMed  Google Scholar 

  37. 37.

    Chiang Su. New Medical College. Dictionary of Chinese crude drug. Shanghai: Shanghai Scientific Technologic Publisher; 1985. p. 767–8.

  38. 38.

    Kluepfel D, Bagli JF, Baker H, et al. Myriocin, a new antifungal antibiotic from Myriococcum albomyces. J Antibiot. 1972;25:109–15.

    CAS  PubMed  Google Scholar 

  39. 39.

    Bagli JF, Kluepfel D, St-Jacques M. Elucidation of structure and stereochemistry of myriocin. A novel antifungal antibiotic. J Org Chem. 1973;38:1253–60.

    Google Scholar 

  40. 40.

    Aragozzini F, Manachini PL, Caraveri R, Rindone B, Scolastico C. Isolatuon and structure determinatrion of a new antifungal α-hydroxymethyl-α-amino acid. Tetrahedron. 1972;28:5493–8.

    CAS  Google Scholar 

  41. 41.

    Chiba K, Hoshino Y, Fujita T. Inhibition of cytotoxic T lymphocytes induction by Isaria scinclairii-derived immunosuppressant ISP-I. Saibou. 1992;24:212–6.

    CAS  Google Scholar 

  42. 42.

    Sasaki S, Hashimoto R, Kiuchi M, et al. Fungal metabolites. Part 14. Novel potent immunosuppressants, mycestericins, produced by Mycelia sterilia. J Antibiot. 1994;47:420–33.

    CAS  PubMed  Google Scholar 

  43. 43.

    Fujita T, Hamamichi N, Kiuchi M, et al. Determination of absolute configuration and biological activity of new immunosuppressants, mycestericines D, E, F, and G. J Antibiot. 1996;49:846–53.

    CAS  PubMed  Google Scholar 

  44. 44.

    Fujita T, Inoue K, Yamamoto S, et al. Fungal metabolites. Part 12. Potent immunosuppressant, 14-deoxomyriocin, (2S,3R,4R)-(E)-2-amino-3,4-dihydroxy-2-hydroxymethyleicos- 6-enoic acid and structure-activity relationships of myriocin derivatives. J Antibiot. 1994;47:216–24.

    CAS  PubMed  Google Scholar 

  45. 45.

    Miyake Y, Kozutsumi Y, Nakamura S, Fujita T, Kawasaki T. Serine palmitoyltransferase is the primary target of a sphingosine-like immunosuppressant, ISP-I/Myriocin. Biochem BIophys Res Commun. 1995;211:396–403.

    CAS  PubMed  Google Scholar 

  46. 46.

    Nakamura S, Kozutsumi Y, Sun Y, et al. Dual roles of sphingolipids in signaling of the escape from and onset of apoptosis in a mouse cytotoxic T-cell line, CTLL-2. J Biol Chem. 1996;271:1255–7.

    CAS  PubMed  Google Scholar 

  47. 47.

    Suzuki S, Enosawa S, Kakefuda T, et al. A novel immunosuppressant, FTY720, having a unique mechanism of action induces long-term graft acceptance in rat and dog allotransplantation. Transplantation. 1996;61:200–5.

    CAS  PubMed  Google Scholar 

  48. 48.

    Suzuki S, Li XK, Enosawa S, Shinomiya T. A new immunosuppressant, FTY720 induces bcl-2-associated apoptotic cell death in human lymphocytes. Immunology. 1996;89:518–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Pyne S, Pyne N. Sphingosine 1 phosphate signaling via the endothelial differentiation gene family of G-protein-coupled receptors. Pharm Ther. 2000;88:115–31.

    CAS  Google Scholar 

  50. 50.

    Hla T, Lee MJ, Ancellin N, Paik JH, Kluk MJ. Lysophospholipids-receptor revelations. Science 2001;294:1875–8.

    CAS  PubMed  Google Scholar 

  51. 51.

    Lo CG, Xu Y, Proia RL, Cyster JG. Cyclical modulation of sphingosine-1-phosphate receptor 1 surface expression during lymphocyte recirculation and relationship to lymphoid organ transit. J Exp Med. 2005;201:291–301.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Pappu R, Schwab SR, Cornelissen I, et al. Promotion of lymphocyte egress into blood and lymph by distinct sources of sphingosine-1-phosphate. Science. 2007;316:295–8.

    CAS  PubMed  Google Scholar 

  53. 53.

    Spiegel S. Sphingosine 1-phosphate: a ligand for the EDG-1 family of G-protein-coupled receptors. Ann N Y Acad Sci. 2000;905:54–60.

    CAS  PubMed  Google Scholar 

  54. 54.

    Pyne NJ, Pyne S. Sphingosine 1-phosphate receptor 1 signaling in mammalian cells. Molecules. 2017;22:344.

    PubMed Central  Google Scholar 

  55. 55.

    Lee MJ, Evans M, Hla T. The inducible G protein-coupled receptor edg-1 signals via the G(i)/mitogen-activated protein kinase pathway. J Biol Chem. 1996;271:11272–9.

    CAS  PubMed  Google Scholar 

  56. 56.

    Okamoto H, Takuwa N, Gonda K, et al. EDG1 is a functional sphingosine-1-phosphate receptor that is linked via a Gi/o to multiple signaling pathways, including phospholipase C activation, Ca2+ mobilization, Ras-mitogen-activated protein kinase activation, and adenylate cyclase inhibition. J Biol Chem. 1998;273:27104–10.

    CAS  PubMed  Google Scholar 

  57. 57.

    Spiegel S, Milstien S. The outs and the ins of sphingosine-1-phosphate in immunity. Nat Rev Immunol. 2011;11:403–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Cyster JG, Schwab SR. Sphingosine-1-phosphate and lymphocyte egress from lymphoid organs. Annu Rev Immunol. 2012;30:69–94.

    CAS  PubMed  Google Scholar 

  59. 59.

    Kihara Y, Maceyka M, Spiegel S, Chun J. Lysophospholipid receptor nomenclature review: IUPHAR review 8. Br J Pharm. 2014;171:3575–94.

    CAS  Google Scholar 

  60. 60.

    Kiuchi M, Adachi K, Tomatsu A, et al. Asymmetric synthesis and biological evaluation of the enantiomeric isomers of the immunosuppressive FTY720-phosphate. Bioorg Med Chem. 2005;13:425–32.

    CAS  PubMed  Google Scholar 

  61. 61.

    Matsuyuki H, Maeda Y, Yano K, et al. Involvement of sphingosine 1-phosphate (S1P) receptor type 1 and type 4 in migratory response of mouse T cells toward S1P. Cell Mol Immunol. 2006;3:429–37.

    CAS  PubMed  Google Scholar 

  62. 62.

    Oo ML, Chang SH, Thangada S, et al. Engagement of S1P1-degradative mechanisms leads to vascular leak in mice. J Clin Invest. 2011;121:2290–300.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Webb M, Tham CS, Lin FF, et al. Sphingosine 1-phosphate receptor agonists attenuate relapsing-remitting experimental autoimmune encephalitis in SJL mice. J Neuroimmunol. 2004;153:108–21.

    CAS  PubMed  Google Scholar 

  64. 64.

    Kataoka H, Sugahara K, Shimano K, et al. FTY720, sphingosine 1-phosphate receptor modulator, ameliorates experimental autoimmune encephalomyelitis by inhibition of T cell infiltration. Cell Mol Immunol. 2005;2:439–48.

    CAS  PubMed  Google Scholar 

  65. 65.

    Balatoni B, Storch MK, Swoboda EM, et al. FTY720 sustains and restores neuronal function in the DA rat model of MOG-induced experimental autoimmune encephalomyelitis. Brain Res Bull. 2007;74:307–16.

    CAS  PubMed  Google Scholar 

  66. 66.

    Brinkmann V. Sphingosine 1-phosphate receptors in health and disease: mechanistic insights from gene deletion studies and reverse pharmacology. Pharm Ther. 2007;115:84–105.

    CAS  Google Scholar 

  67. 67.

    Foster CA, Howard LM, Schweitzer A, et al. Brain penetration of the oral immunomodulatory drug FTY720 and its phosphorylation in the central nervous system during experimental autoimmune encephalomyelitis: consequences for mode of action in multiple sclerosis. J Pharm Exp Ther. 2007;323:469–75.

    CAS  Google Scholar 

  68. 68.

    Chiba K, Kataoka H, Seki N, et al. Fingolimod (FTY720), sphingosine 1-phosphate receptor modulator, shows superior efficacy as compared with interferon-β in mouse experimental autoimmune encephalomyelitis. Int Immunopharmacol. 2011;11:366–72.

    CAS  PubMed  Google Scholar 

  69. 69.

    Langrish CL, Chen Y, Blumenschein WM, et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med. 2005;201:233–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Komiyama Y, Nakae S, Matsuki T, et al. IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J Immunol. 2006;177:566–73.

    CAS  PubMed  Google Scholar 

  71. 71.

    Stromnes IM, Cerretti LM, Liggitt D, Harris RA, Goverman JM. Differential regulation of central nervous system autoimmunity by TH1 and TH17 cells. Nat Med. 2008;14:337–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Kataoka H, Shimano K, Seki N, et al. Fingolimod (FTY720) ameliorates experimental autoimmune encephalomyelitis (EAE) I. Oral administration of FTY720 effectively inhibits relapse of EAE. Inflamm Regen. 2010;30:453–9.

    Google Scholar 

  73. 73.

    Seki N, Maeda Y, Kataoka H, Sugahara K, Sugita T, Chiba K. Fingolimod (FTY720) ameliorates experimental autoimmune encephalomyelitis (EAE) II. FTY720 decreases infiltration of Th17 and Th1 cells into the central nervous system in EAE. Inflamm Regen. 2010;30:545–51.

    Google Scholar 

  74. 74.

    Martin B, Hirota K, Cua DJ, Stockinger B, Veldhoen M. Interleukin-17-producing γδ T cells selectively expand in response to pathogen products and environmental signals. Immunity. 2009;31:321–30.

    CAS  PubMed  Google Scholar 

  75. 75.

    Sutton CE, Lalor SJ, Sweeney CM, et al. Interleukin-1 and IL-23 induce innate IL-17 production from γδ T cells, amplifying Th17 responses and autoimmunity. Immunity. 2009;31:331–41.

    CAS  PubMed  Google Scholar 

  76. 76.

    Stark MA, Huo Y, Burcin TL, et al. Phagocytosis of apoptotic neutrophils regulates granulopoiesis via IL-23 and IL-17. Immunity. 2005;22:285–94.

    CAS  PubMed  Google Scholar 

  77. 77.

    Maeda Y, Seki N, Kataoka H, et al. IL-17-producing Vγ4+ γδ T cells require sphingosine 1-phosphate receptor 1 for their egress from the lymph nodes under homeostatic and inflammatory conditions. J Immunol. 2015;195:1408–16.

    CAS  PubMed  Google Scholar 

  78. 78.

    Brinkmann V. FTY720 (fingolimod) in multiple sclerosis: therapeutic effects in the immune and the central nervous system. Br J Pharm. 2009;158:1173–82.

    CAS  Google Scholar 

  79. 79.

    Choi JW, Gardell SE, Herr DR, et al. FTY720 (fingolimod) efficacy in an animal model of multiple sclerosis requires astrocyte sphingosine 1-phosphate receptor 1 (S1P1) modulation. Proc Natl Acad Sci USA. 2011;108:751–6.

    CAS  PubMed  Google Scholar 

  80. 80.

    Seki N, Maeda Y, Kataoka H, Sugahara K, Chiba K. Role of sphingosine 1-phosphate (S1P) receptor 1 in experimental autoimmune encephalomyelitis I. S1P-S1P1 axis induces migration of Th1 and Th17 cells. Pharmacol Pharm. 2013;4:628–37.

    CAS  Google Scholar 

  81. 81.

    Seki N, Kataoka H, Sugahara K, Fukunari A, Chiba K. Role of sphingosine 1-phosphate (S1P) receptor 1 in experimental autoimmune encephalomyelitis II. S1P-S1P1 axis induces pro-inflammatory cytokine production in astrocytes. Pharmacol Pharm. 2013;4:638–46.

    CAS  Google Scholar 

  82. 82.

    Budde K, Schmouder RL, Brunkhorst R, et al. Human first trail of FTY720, a novel immunomodulator, in stable renal transplant patients. J Am Soc Nephrol. 2002;13:1073–83.

    CAS  PubMed  Google Scholar 

  83. 83.

    Budde K, Schmouder RL, Nashan B, et al. Pharmacodynamics of single doses of the novel immunosuppressant FTY720 in stable renal transplant patients. Am J Transpl. 2003;3:846–54.

    CAS  Google Scholar 

  84. 84.

    Kahan BD, Karlix JL, Ferguson RM, et al. Pharmacodynamics, pharmacokinetics, and safety of multiple doses of FTY720 in stable renal transplant patients: a multicenter, randomized, placebo-controlled, phase I study. Transplantation. 2003;76:1079–84.

    CAS  PubMed  Google Scholar 

  85. 85.

    Tedesco-Silva H, Mourad G, Kahan BD, et al. FTY720, a novel immunomodulator: efficacy and safety results from the first phase 2a study in de novo renal transplantation. Transplantation. 2004;77:1826–33.

    CAS  PubMed  Google Scholar 

  86. 86.

    Tedesco-Silva H, Pescovitz MD, Cibrik D, et al. Randomized controlled trial of FTY720 versus MMF in de novo renal transplantation. Transplantation. 2006;82:1689–97.

    CAS  PubMed  Google Scholar 

  87. 87.

    Budde K, Schütz M, Glander P, et al. FTY720 (fingolimod) in renal transplantation. Clin Transplant. 2006;20:17–24.

    PubMed  Google Scholar 

  88. 88.

    Martin R, McFarland HF, McFarlin DE. Immunological aspects of demyelinating diseases. Annu Rev Immunol. 1992;10:153–87.

    CAS  PubMed  Google Scholar 

  89. 89.

    Kornek B, Storch MK, Weissert R, et al. Multiple sclerosis and chronic autoimmune encephalomyelitis: a comparative quantitative study of axonal injury in active, inactive, and remyelinated lesions. Am J Pathol. 2000;157:267–76.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90.

    Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on clinical trials of new agents in multiple sclerosis. Neurology. 1996;46:907–11.

    CAS  PubMed  Google Scholar 

  91. 91.

    Goodkin DE, Reingold S, Sibley W, et al. Guidelines for clinical trials of new therapeutic agents in multiple sclerosis: reporting extended results from phase III clinical trials. National Multiple Sclerosis Society Advisory Committee on clinical trials of new agents in multiple sclerosis. Ann Neurol. 1999;46:132–4.

    CAS  PubMed  Google Scholar 

  92. 92.

    Kappos L, Antel J, Comi G, et al. Oral fingolimod (FTY720) for relapsing multiple sclerosis. N Engl J Med. 2006;355:1124–40.

    CAS  PubMed  Google Scholar 

  93. 93.

    Saida T, Kikuchi S, Itoyama Y, et al. A randomized, controlled trial of fingolimod (FTY720) in Japanese patients with multiple sclerosis. Mult Scler. 2012;18:1269–77.

    CAS  PubMed  Google Scholar 

Download references

Author information



Corresponding author

Correspondence to Kenji Chiba.

Ethics declarations

Conflict of interest

Fingolimod was developed and commercialized by Mitsubishi Tanabe Pharma Corporation. The author is an employee of this company.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Chiba, K. Discovery of fingolimod based on the chemical modification of a natural product from the fungus, Isaria sinclairii. J Antibiot 73, 666–678 (2020).

Download citation


Quick links