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Discovery Of Fingolimod Based On The Chemical Modification Of A Natural Product From The Fungus, Isaria Sinclairii

K. Chiba
Published 2020 · Chemistry, Medicine

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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 paper references
10.1016/S0040-4020(01)93872-4
Isolation and structure determination of a new antifungal α-hydroxymethyl-α-amino acid
F. Aragozzini (1972)
10.7164/ANTIBIOTICS.25.109
Myriocin, a new antifungal antibiotic from Myriococcum albomyces.
D. Kluepfel (1972)
10.1021/JO00947A001
Elucidation of structure and stereochemistry of myriocin. A novel antifungal antibiotic.
M. St-Jacques (1973)
Cyclosporin A and C: new metabolites from Trichoderma polysporum (Link ex per.) Rifai
M Dreyfuss (1976)
History of cyclosporin A and its significance in immunology
JF Borel (1982)
Cyclosporin in marrow transplantation: concentration-dependent toxicity and immunosuppression in vivo
MS Kannedy (1983)
MS Kannedy (1983)
10.1056/NEJM198409133111103
Cyclosporine-associated chronic nephropathy.
B. Myers (1984)
New Medical College. Dictionary of Chinese crude drug
Chiang Su (1985)
New Medical College. Dictionary of Chinese crude drug. Shanghai: Shanghai Scientific Technologic Publisher
Chiang Su (1985)
10.7164/ANTIBIOTICS.40.1256
FK-506, a novel immunosuppressant isolated from a Streptomyces. I. Fermentation, isolation, and physico-chemical and biological characteristics.
T. Kino (1987)
10.7164/antibiotics.40.1256
FK-506, a novel immunosuppressant isolated from a Streptomyces. II. Immunosuppressive effect of FK-506 in vitro.
T. Kino (1987)
10.7164/ANTIBIOTICS.40.1249
FK-506, a novel immunosuppressant isolated from a Streptomyces. I. Fermentation, isolation, and physico-chemical and biological characteristics.
T. Kino (1987)
10.1021/JA00250A050
Structure of FK506, a novel immunosuppressant isolated from Streptomyces
Hirokazu Tanaka (1987)
T Kino (1987)
Kidney transplantation under FK 506 immunosuppression.
R. Shapiro (1991)
10.1126/SCIENCE.1702904
Chemistry and biology of the immunophilins and their immunosuppressive ligands.
S. L. Schreiber (1991)
10.1016/0092-8674(91)90124-H
Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes
J. Liu (1991)
R Shapiro (1991)
T Ochiai (1991)
Pharmacokinetics and clinical effects of FK506
T Ochiai (1991)
10.1146/ANNUREV.IY.10.040192.001101
Immunological aspects of demyelinating diseases.
R. Martin (1992)
10.1016/0092-8674(92)90158-9
Immunophilin-sensitive protein phosphatase action in cell signaling pathways
S. Schreiber (1992)
Inhibition of cytotoxic T lymphocytes induction by Isaria scinclairii-derived immunosuppressant ISP-I
K Chiba (1992)
K Chiba (1992)
10.7164/ANTIBIOTICS.47.208
Fungal metabolites. Part 11. A potent immunosuppressive activity found in Isaria sinclairii metabolite.
T. Fujita (1994)
10.7164/ANTIBIOTICS.47.216
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.
T. Fujita (1994)
10.7164/ANTIBIOTICS.47.420
Fungal metabolites. Part 14. Novel potent immunosuppressants, mycestericins, produced by Mycelia sterilia.
S. Sasaki (1994)
T Fujita (1994)
10.1016/0960-894X(95)00127-F
Design, synthesis, and structure-activity relationships of 2-substituted-2-amino-1,3-propanediols: Discovery of a novel immunosuppressant, FTY720
K. Adachi (1995)
10.1093/AJHP/52.14.1521
Tacrolimus: a new immunosuppressive agent.
P. Kelly (1995)
10.1016/0960-894X(95)00126-E
Simple compounds, 2-alkyl-2-amino-1,3-propanediols have potent immunosuppressive activity
T. Fujita (1995)
10.1006/BBRC.1995.1827
Serine palmitoyltransferase is the primary target of a sphingosine-like immunosuppressant, ISP-1/myriocin.
Y. Miyake (1995)
Tacrolimus: anew immunosuppressive agent
PA Kelly (1995)
10.1097/00007890-199601270-00006
A novel immunosuppressant, FTY720, with a unique mechanism of action, induces long-term graft acceptance in rat and dog allotransplantation.
S. Suzuki (1996)
10.1074/jbc.271.3.1255
Dual Roles of Sphingolipids in Signaling of the Escape from and Onset of Apoptosis in a Mouse Cytotoxic T-cell Line, CTLL-2 (*)
S. Nakamura (1996)
10.7164/ANTIBIOTICS.49.846
Determination of absolute configuration and biological activity of new immunosuppressants, mycestericins D, E, F and G.
T. Fujita (1996)
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.
Y. Hoshino (1996)
10.1021/JM960391L
Potent immunosuppressants, 2-alkyl-2-aminopropane-1,3-diols.
T. Fujita (1996)
FTY720, a novel immunosuppressant possessing unique mechanisms. III. Synergistic prolongation of canine renal allograft survival in combination with cyclosporine A.
T. Kawaguchi (1996)
10.1046/j.1365-2567.1996.d01-777.x
A new immunosuppressant, FTY720, induces bcl‐2‐associated apoptotic cell death in human lymphocytes
S. Suzuki (1996)
10.1074/JBC.271.19.11272
The Inducible G Protein-coupled Receptor edg-1 Signals via the G/Mitogen-activated Protein Kinase Pathway (*)
M. Lee (1996)
10.1212/WNL.46.4.907
Defining the clinical course of multiple sclerosis
F. Lublin (1996)
10.1212/wnl.46.4.907
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.
Lublin Fd (1996)
FTY720, a novel immunosuppressant possessing unique mechanisms. I. Prolongation of skin allograft survival and synergistic effect in combination with cyclosporine in rats.
K. Chiba (1996)
K Chiba (1996)
Y Hoshino (1996)
Potent immunosuppressants, 2alkyl-2-aminopropane- 1,3-diols
T Fujita (1996)
Determination of absolute configuration and biological activity of new immunosuppressants, mycestericines
T Fujita (1996)
T Kawaguchi (1996)
10.1074/jbc.273.42.27104
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*
H. Okamoto (1998)
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.
K. Chiba (1998)
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.
Y. Yanagawa (1998)
Y Yanagawa (1998)
K Chiba (1998)
10.1002/1531-8249(199907)46:1<132::AID-ANA22>3.0.CO;2-Z
Guidelines for clinical trials of new therapeutic agents in multiple sclerosis: Reporting extended results from phase III clinical trials
D. Goodkin (1999)
10.1021/JM000173Z
Synthesis and immunosuppressive activity of 2-substituted 2-aminopropane-1,3-diols and 2-aminoethanols.
M. Kiuchi (2000)
10.1016/S0165-6147(99)01419-4
FTY720: a novel transplantation drug that modulates lymphocyte traffic rather than activation.
V. Brinkmann (2000)
10.1007/s000110050608
Effect of FTY720, a novel immunosuppressant, on adjuvant-induced arthritis in rats
M. Matsuura (2000)
10.1016/S0002-9440(10)64537-3
Multiple sclerosis and chronic autoimmune encephalomyelitis: a comparative quantitative study of axonal injury in active, inactive, and remyelinated lesions.
B. Kornek (2000)
10.1111/j.1749-6632.2000.tb06537.x
Sphingosine 1‐Phosphate: A Ligand for the EDG‐1 Family of G‐Protein‐Coupled Receptors
S. Spiegel (2000)
10.1016/S0163-7258(00)00084-X
Sphingosine 1-phosphate signalling via the endothelial differentiation gene family of G-protein-coupled receptors.
S. Pyne (2000)
Sphingosine 1 phosphate signaling via the endothelial differentiation gene family of G-protein-coupled receptors
S Pyne (2000)
10.1126/SCIENCE.1065323
Lysophospholipids--Receptor Revelations
T. Hla (2001)
Lysophospholipidsreceptor revelations
T Hla (2001)
First human trial of FTY720, a novel immunomodulator, in stable renal transplant patients.
K. Budde (2002)
10.1126/SCIENCE.1070238
Alteration of Lymphocyte Trafficking by Sphingosine-1-Phosphate Receptor Agonists
S. Mandala (2002)
10.1074/JBC.C200176200
The Immune Modulator FTY720 Targets Sphingosine 1-Phosphate Receptors*
V. Brinkmann (2002)
Human first trail of FTY720, a novel immunomodulator, in stable renal transplant patients
K Budde (2002)
K Budde (2002)
10.1034/j.1600-6143.2003.00130.x
Pharmacodynamics of Single Doses of the Novel Immunosuppressant FTY720 in Stable Renal Transplant Patients
K. Budde (2003)
10.1097/01.TP.0000084822.01372.AC
Pharmacodynamics, pharmacokinetics, and safety of multiple doses of FTY720 in stable renal transplant patients: a multicenter, randomized, placebo-controlled, phase I study
B. Kahan (2003)
10.1016/S0014-5793(03)01168-2
The immunosuppressant FTY720 is phosphorylated by sphingosine kinase type 2
S. Paugh (2003)
10.1016/j.jneuroim.2004.04.015
Sphingosine 1-phosphate receptor agonists attenuate relapsing–remitting experimental autoimmune encephalitis in SJL mice
M. Webb (2004)
10.1007/BF00928431
Cyclosporin A and C
M. Dreyfuss (2004)
10.1038/nature02284
Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1
M. Matloubian (2004)
H Tedesco-Silva (2004)
10.1146/ANNUREV.IMMUNOL.23.021704.115628
Chemokines, sphingosine-1-phosphate, and cell migration in secondary lymphoid organs.
J. Cyster (2005)
10.1016/J.BMC.2004.10.008
Asymmetric synthesis and biological evaluation of the enantiomeric isomers of the immunosuppressive FTY720-phosphate.
M. Kiuchi (2005)
10.1084/jem.20041257
IL-23 drives a pathogenic T cell population that induces autoimmune inflammation
C. Langrish (2005)
10.1016/J.PHARMTHERA.2005.05.002
FTY720, a new class of immunomodulator, inhibits lymphocyte egress from secondary lymphoid tissues and thymus by agonistic activity at sphingosine 1-phosphate receptors.
K. Chiba (2005)
FTY720, sphingosine 1-phosphate receptor modulator, ameliorates experimental autoimmune encephalomyelitis by inhibition of T cell infiltration.
H. Kataoka (2005)
10.1097/01.TP.0000121761.02129.A6
FTY720, A Novel Immunomodulator: Efficacy and Safety Results from the First Phase 2A Study in de novo Renal Transplantation
H. Tedesco-Silva (2005)
10.1016/J.IMMUNI.2005.01.011
Phagocytosis of apoptotic neutrophils regulates granulopoiesis via IL-23 and IL-17.
M. Stark (2005)
10.1084/jem.20041509
Cyclical modulation of sphingosine-1-phosphate receptor 1 surface expression during lymphocyte recirculation and relationship to lymphoid organ transit
C. Lo (2005)
Cyclical modulation of sphingosine-1-phosphate receptor 1 surface expression during Discovery of fingolimod based on the chemical modification of a natural product from the fungus
CG Lo (2005)
H Kataoka (2005)
10.1056/NEJMOA052643
Oral fingolimod (FTY720) for relapsing multiple sclerosis.
L. Kappos (2006)
10.1111/j.1399-0012.2006.00596.x
FTY720 (fingolimod) in renal transplantation
K. Budde (2006)
10.1097/01.tp.0000251718.95622.b3
Randomized Controlled Trial of FTY720 Versus MMF in De Novo Renal Transplantation
H. Tedesco-Silva (2006)
Role of sphingosine 1-phosphate receptor type 1 in lymphocyte egress from secondary lymphoid tissues and thymus.
K. Chiba (2006)
Involvement of sphingosine 1-phosphate (S1P) receptor type 1 and type 4 in migratory response of mouse T cells toward S1P.
H. Matsuyuki (2006)
10.4049/jimmunol.177.1.566
IL-17 Plays an Important Role in the Development of Experimental Autoimmune Encephalomyelitis1
Y. Komiyama (2006)
H Matsuyuki (2006)
K Chiba (2006)
10.1126/SCIENCE.1139221
Promotion of Lymphocyte Egress into Blood and Lymph by Distinct Sources of Sphingosine-1-Phosphate
R. Pappu (2007)
10.1016/j.brainresbull.2007.06.023
FTY720 sustains and restores neuronal function in the DA rat model of MOG-induced experimental autoimmune encephalomyelitis
B. Balatoni (2007)
10.4049/jimmunol.178.6.3437
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
Y. Maeda (2007)
10.1124/jpet.107.127183
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
C. A. Foster (2007)
10.1016/J.PHARMTHERA.2007.04.006
Sphingosine 1-phosphate receptors in health and disease: mechanistic insights from gene deletion studies and reverse pharmacology.
V. Brinkmann (2007)
10.1016/j.immuni.2007.11.017
S1P1 receptor signaling overrides retention mediated by G alpha i-coupled receptors to promote T cell egress.
T. Pham (2008)
10.1038/nm1715
Differential regulation of central nervous system autoimmunity by TH1 and TH17 cells
Ingunn M. Stromnes (2008)
10.1016/j.immuni.2009.06.020
Interleukin-17-producing gammadelta T cells selectively expand in response to pathogen products and environmental signals.
Bruno Martin (2009)
10.1111/j.1476-5381.2009.00451.x
FTY720 (fingolimod) in Multiple Sclerosis: therapeutic effects in the immune and the central nervous system
V. Brinkmann (2009)
10.1016/j.immuni.2009.08.001
Interleukin-1 and IL-23 induce innate IL-17 production from gammadelta T cells, amplifying Th17 responses and autoimmunity.
C. Sutton (2009)
Interleukin-1 and IL-23 induce innate IL-17 production from γδ T cells, amplifying Th17 responses and autoimmunity
CE Sutton (2009)
10.2492/INFLAMMREGEN.30.451
Fingolimod (FTY720) ameliorates experimental autoimmune encephalomyelitis (EAE)
H. Kataoka (2010)
10.1073/pnas.1014154108
FTY720 (fingolimod) efficacy in an animal model of multiple sclerosis requires astrocyte sphingosine 1-phosphate receptor 1 (S1P1) modulation
Ji Woong Choi (2010)
10.1056/NEJMoa0907839
Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis.
Jeffrey A Cohen (2010)
10.1056/NEJMoa0909494
A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis.
L. Kappos (2010)
10.2492/INFLAMMREGEN.30.542
Fingolimod (FTY720) ameliorates experimental autoimmune encephalomyelitis (EAE) : II. FTY720 decreases infiltration of Th17 and Th1 cells into the central nervous system in EAE
N. Seki (2010)
10.1038/nri2974
The outs and the ins of sphingosine-1-phosphate in immunity
S. Spiegel (2011)
10.1016/j.intimp.2010.10.005
Fingolimod (FTY720), sphingosine 1-phosphate receptor modulator, shows superior efficacy as compared with interferon-β in mouse experimental autoimmune encephalomyelitis.
K. Chiba (2011)
10.1172/JCI45403
Engagement of S1P₁-degradative mechanisms leads to vascular leak in mice.
M. Oo (2011)
10.1146/annurev-immunol-020711-075011
Sphingosine-1-phosphate and lymphocyte egress from lymphoid organs.
J. Cyster (2012)
10.1177/1352458511435984
A randomized, controlled trial of fingolimod (FTY720) in Japanese patients with multiple sclerosis
T. Saida (2012)
10.4236/PP.2013.48089
Role of Sphingosine 1-Phosphate (S1P) Receptor 1 in Experimental Autoimmune Encephalomyelitis —I
N. Seki (2013)
N Seki (2013)
10.1111/bph.12678
Lysophospholipid receptor nomenclature review: IUPHAR Review 8
Y. Kihara (2014)
10.4049/jimmunol.1500599
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
Y. Maeda (2015)
10.3390/molecules22030344
Sphingosine 1-Phosphate Receptor 1 Signaling in Mammalian Cells
N. Pyne (2017)
Cyclosporin A and C: new metabolites from Trichoderma polysporum (Link ex per
M Dreyfuss



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