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FTY720 – THE IMMUNE CELLS’ TRAFFIC CONTROLLER

Introduction: Multiple Sclerosis

Multiple sclerosis is probably a condition that everybody has heard off but not many really understand the cause or nature of this destructive disease. Basically this disease is what is known as an inflammatory disease which affects area of the lining in the spinal cord or brain stem. The effect of this is the slow degradation of the functions of the spinal cord and brain stem. This means a loss of motor control, loss of communicative functions, loss of sight and digestive difficulties. Accompanying these debilitating symptoms are almost constant pain and fatigue, life quality of most suffers becomes very poor. There is currently no known cure for this disease, while treatment focuses on alleviating the symptoms or retarding the progression of the disease but always the end point is the same. Patients with this disease are known to try any form of treatment scientifically proven or not in the hope a remission can be triggered. Remission is the peculiar aspect of this disease in that it appears in phases with periods of relative peace in-between. However, relapses are usually progressively worse accumulating damage to essential functions that cannot be repaired. Triggers for relapses are unknown although stress or simple viral infections are thought to play some sort of role in the totally unpredictable nature of this disorder. While not thought to be hereditary this disorder does have genetic mutations at the heart of its occurrences although why it occurs mostly in young females is still unknown. New therapies for this disease that actually have clinical effect are very rare, so FTY720 has generated a great deal of interest since it is the first new treatment in a long time that might be able to alleviate this condition rather than just symptoms 1.

FTY720: Properties and Availability

Manufactured and developed by Novartis this molecule has demonstrated significant properties in the modulation of the immune system which has shown to be effective against Multiple sclerosis 2. Marketed under the formulation name Gilenya and the trade name Fingolimod this drug joins a total of 5 other compounds demonstrating some form of activity against multiple sclerosis; these include Interferon ß1 A & B, glatiramer acetate, mitoxantrone and a monoclonal antibody treatment called Natalizumab 3,3,4,4-7.

The FTY720 structure is relatively simple with a seven carbon aliphatic chain linked via a phenyl ring to an amide substituted propanediol8,9. The FTY720 solubility is poor in aqueous solutions but is soluble in DMSO and ethanol up 100 mg/ml. These solutions can be used to make aqueous solution of 200µM but this is dramatically reduced in cell culture buffers (5-10µM). FTY720 is freely available from FTY720 suppliers for the reasonable FTY720 price ranging from $63 - $350 for 25 mg vial of the hydrochloride salt.

FTY720: Preclinical investigation

Preclinical investigation has demonstrated that FTY720 is an agonist for the blood lipid ligand S1P of the S1PR1 cell membrane receptor with a FTY720 IC50 of 0.13 nM10,11. Investigation work is still ongoing but has demonstrated that the FTY720 S1P-1 receptor agonist prevents cell membranes from allowing immune cells to pass into the systemic circulation. This effectively reduces the immuno-systems capabilities to target toxins 8,9,12-16. However, in disorders where the immune system is over active and effectively attack the mammalian host this molecule provided significant benefits 3. Disorders where S1P is over expressed offer potential targets for this molecule; for example FTY720 in multiple sclerosis 8,9,12-18 and FTY720 in ovarian cancer. Extensive FTY720 clinical trials are ongoing in relation to multiple sclerosis and this molecule has been fast tracked to approval by both FDA and the European agencies. Much has been reported in relation to FTY720’s immunosuppression capabilities but recently work has established that this molecule also inhibits the Bcl-Abl fusion protein leading to a whole new area for research 19-22. The FTY720 BCR/ABL inhibitor could prove useful in positive advanced breast or ovarian cancers but it is too early to say at the moment.

Reference List

    1.    Chun, J.; Brinkmann, V. A mechanistically novel, first oral therapy for multiple sclerosis: the development of fingolimod (FTY720, Gilenya). Discov. Med. 2011, 12 (64), 213-228.

    2.    O'Connor, P.; Comi, G.; Montalban, X.; Antel, J.; Radue, E. W.; de, V. A.; Pohlmann, H.; Kappos, L. Oral fingolimod (FTY720) in multiple sclerosis: two-year results of a phase II extension study. Neurology 2009, 72 (1), 73-79.

    3.    Dev, K. K.; Mullershausen, F.; Mattes, H.; Kuhn, R. R.; Bilbe, G.; Hoyer, D.; Mir, A. Brain sphingosine-1-phosphate receptors: implication for FTY720 in the treatment of multiple sclerosis. Pharmacol. Ther. 2008, 117 (1), 77-93.

    4.    Kennedy, P. C.; Zhu, R.; Huang, T.; Tomsig, J. L.; Mathews, T. P.; David, M.; Peyruchaud, O.; Macdonald, T. L.; Lynch, K. R. Characterization of a sphingosine 1-phosphate receptor antagonist prodrug. J. Pharmacol. Exp. Ther. 2011, 338 (3), 879-889.

    5.    Koshiba, T.; Van, D. B.; Lu, Y.; Yan, Y.; Rutgeerts, O.; Overbergh, L.; Tanaka, K.; Waer, M.; Mathieu, C.; Pirenne, J. Combined use of FTY720 and cyclosporine A prevents chronic allograft vasculopathy. Transplant Proc. 2002, 34 (3), 748-749.

    6.    Martini, S.; Peters, H.; Bohler, T.; Budde, K. Current perspectives on FTY720. Expert Opin. Investig. Drugs 2007, 16 (4), 505-518.

    7.    Yeh, E. A. Current therapeutic options in pediatric multiple sclerosis. Curr. Treat. Options. Neurol. 2011, 13 (6), 544-559.

    8.    Demont, E. H.; Arpino, S.; Bit, R. A.; Campbell, C. A.; Deeks, N.; Desai, S.; Dowell, S. J.; Gaskin, P.; Gray, J. R.; Harrison, L. A.; Haynes, A.; Heightman, T. D.; Holmes, D. S.; Humphreys, P. G.; Kumar, U.; Morse, M. A.; Osborne, G. J.; Panchal, T.; Philpott, K. L.; Taylor, S.; Watson, R.; Willis, R.; Witherington, J. Discovery of a brain-penetrant S1P-sparing direct agonist of the S1P and S1P receptors efficacious at low oral dose. J. Med. Chem. 2011, 54 (19), 6724-6733.

    9.    Crosignani, S.; Bombrun, A.; Covini, D.; Maio, M.; Marin, D.; Quattropani, A.; Swinnen, D.; Simpson, D.; Sauer, W.; Francon, B.; Martin, T.; Cambet, Y.; Nichols, A.; Martinou, I.; Burgat-Charvillon, F.; Rivron, D.; Donini, C.; Schott, O.; Eligert, V.; Novo-Perez, L.; Vitte, P. A.; Arrighi, J. F. Discovery of a novel series of potent S1P1 agonists. Bioorg. Med. Chem. Lett. 2010, 20 (5), 1516-1519.

  10.    Muramatsu, K.; Doi, K.; Shigetomi, M.; Kido, K.; Kawai, S. A new immunosuppressant, FTY720, prolongs limb allograft survival in rats. Ann. Plast. Surg. 1998, 40 (2), 160-165.

  11.    Kappos, L.; Radue, E. W.; O'Connor, P.; Polman, C.; Hohlfeld, R.; Calabresi, P.; Selmaj, K.; Agoropoulou, C.; Leyk, M.; Zhang-Auberson, L.; Burtin, P. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N. Engl. J. Med. 2010, 362 (5), 387-401.

  12.    Sugito, K.; Koshinaga, T.; Inoue, M.; Ikeda, T.; Hagiwara, N.; Kusafuka, T.; Fukuzawa, M. Effect of FTY720 in rat small bowel transplantation: apoptosis of crypt cells and lymphocytes in gut-associated lymphoid tissues. Transplant Proc. 2006, 38 (9), 3058-3060.

  13.    Sugito, K.; Koshinaga, T.; Inoue, M.; Ikeda, T.; Hagiwara, N.; Fukuzawa, M. Effect of FTY720 in rat small bowel transplantation: expression of mucosal addressin cell adhesion molecule-1. Transplant Proc. 2005, 37 (10), 4472-4474.

  14.    Fujishiro, J.; Inoue, S.; Shimizu, H.; Yoshino, H.; Murakami, T.; Kobayashi, E. Effect of FTY720 on rat small bowel transplantation. Transplantation 2004, 77 (12), 1910-1911.

  15.    Matsuura, M.; Imayoshi, T.; Okumoto, T. Effect of FTY720, a novel immunosuppressant, on adjuvant- and collagen-induced arthritis in rats. Int. J. Immunopharmacol. 2000, 22 (4), 323-331.

  16.    Matsuura, M.; Imayoshi, T.; Chiba, K.; Okumoto, T. Effect of FTY720, a novel immunosuppressant, on adjuvant-induced arthritis in rats. Inflamm. Res. 2000, 49 (8), 404-410.

  17.    Rammohan, K. W.; Shoemaker, J. Emerging multiple sclerosis oral therapies. Neurology 2010, 74 Suppl 1, S47-S53.

  18.    Fox, E. J. Emerging oral agents for multiple sclerosis. Am. J. Manag. Care 2010, 16 (8 Suppl), S219-S226.

  19.    Fujino, M.; Li, X. K.; Kitazawa, Y.; Guo, L.; Kawasaki, M.; Funeshima, N.; Amano, T.; Suzuki, S. Distinct pathways of apoptosis triggered by FTY720, etoposide, and anti-Fas antibody in human T-lymphoma cell line (Jurkat cells). J. Pharmacol. Exp. Ther. 2002, 300 (3), 939-945.

  20.    Ubai, T.; Azuma, H.; Kotake, Y.; Inamoto, T.; Takahara, K.; Ito, Y.; Kiyama, S.; Sakamoto, T.; Horie, S.; Muto, S.; Takahara, S.; Otsuki, Y.; Katsuoka, Y. FTY720 induced Bcl-associated and Fas-independent apoptosis in human renal cancer cells in vitro and significantly reduced in vivo tumor growth in mouse xenograft. Anticancer Res. 2007, 27 (1A), 75-88.

  21.    Azuma, H.; Horie, S.; Muto, S.; Otsuki, Y.; Matsumoto, K.; Morimoto, J.; Gotoh, R.; Okuyama, A.; Suzuki, S.; Katsuoka, Y.; Takahara, S. Selective cancer cell apoptosis induced by FTY720; evidence for a Bcl-dependent pathway and impairment in ERK activity. Anticancer Res. 2003, 23 (4), 3183-3193.

  22.    Liao, A.; Broeg, K.; Fox, T.; Tan, S. F.; Watters, R.; Shah, M. V.; Zhang, L. Q.; Li, Y.; Ryland, L.; Yang, J.; Aliaga, C.; Dewey, A.; Rogers, A.; Loughran, K.; Hirsch, L.; Jarbadan, N. R.; Baab, K. T.; Liao, J.; Wang, H. G.; Kester, M.; Desai, D.; Amin, S.; Loughran, T. P., Jr.; Liu, X. Therapeutic efficacy of FTY720 in a rat model of NK-cell leukemia. Blood 2011, 118 (10), 2793-2800.