FINGOLIMOD – THE IMMUNOMODULATOR

by Selleckchem | Mar 19 2012

Introduction: Fingolimod and Multiple Sclerosis

One of the most widely used fungi in Chinese herbal medication is the ascomycete “Isaria sinclairii”. Known for its medical properties for centauries it was examined more closely after the immunosuppressant cyclosporin was discovered from a fungal source. From a screening of the extracts from this fungus came the molecule myriocin which demonstrated immunosuppressant properties as hope, however, it also killed the host in animal models. This molecule proved to be far too toxic for clinical use hence the molecule skeleton was used as a template to derive a series of derivatives in the effort to reduce the toxicity but preserve the immunosuppression potency. From this process came FTY720 which was researched pre-clinically in the area of transplant rejection [1], before being released in clinical trials as Fingolimod . Activity for Fingolimod was discovered to be against one the lipid mediator receptors (S1PR1) which is a G-protein-couple receptor located trans-membrane in mammalian cells. S1P is carried systemically in the blood and is thought to have a regulatory role in the immune system and the vascular system. Interaction with the S1PR1 receptor permits cell membrane to become more permeable. In various cancers and immune disease the S1P ligand is over-expressed to a significant degree, hence the inhibition of this receptor / ligand signaling pathway would seriously affect immune function. With Fingolimod preventing the movement of immune cells from the lymphatic system the over-expression of the immune system can be controlled. In transplant surgery this is a significant advantage but this is not where Fingolimond made a significant impact. Multiple sclerosis is a disease of inflammation in the spinal cord and brain stem destroying communication between nerve junctions. Fingolimond represents a significant advance in the treatment of multiple sclerosis raising a great deal of interest [2].

Fingolimond: Properties and availability

The discovery of Fingolimod Bcr-Abl Inhibitor was financed by the Yoshitomi Pharmaceuticals Ltd with lead scientist Prof. T. Fujita of Taito Co [3]. Acquired by Novartis, it was developed originally as a potential immunosuppresser for use after transplant surgery, but this molecule was found to highly active in the disorder known as multiple sclerosis [2]. Fingolimond is a derivative of the molecular skeleton 2-substitued-2-aminopropane-1,3-diol and is sold under the name Gilenya. Researched originally under the code name of FTY720 this molecule made a significant impact pre-clinically and was moved rapidly to the FDA fast track program. Research into the properties of this molecule is hampered by the simple fact that it is insoluble in water. Solutions of DMSO and ethanol can be made up to 100mg/ml but dilution to buffered solutions cannot give a concentration greater than 10 µM otherwise it will crystallize out of solution, amazingly this in not the case in pure water where 200 µM solutions can be prepared. Fingolimond is sold under license by several Fingolimond suppliers for research purposes as the hydrochloride salt. A 25 mg vial of Fingolimond can cost as little as $63 but also as high as $350 for compounds of similar purity.

Fingolimod: Preclinical investigations and Clinical status

Fingolimond proven action against S1PR1 as a agonist to the circulatory lipid ligand S1P inhibits the permeability of the cell membrane in the lymphatic system to the movement of immune cells into circulation. Hence in conditions where over-expression of immuno cells occurs; this molecule would prove to be a potential therapeutic. In ovarian cancer the S1P lipid is found to be significantly higher than normal physiological conditions, the mechanism of this in relation to ovarian cancer is unclear at the moment but xenograft models have demonstrated anti-tumor activity for Fingolimond. In the immune disorder multiple sclerosis Fingolimod ic50 has demonstrated surprising results, preventing relapse of the disease for significant periods of time, being a oral based medication this gives multiple sclerosis the freedom to self medicate on daily basis. This form of treatment seems to offer significant long term benefits, so much so that the FDA fast track procedure has taken this compound from initial animal models to approval in only 4-5 years.

REFERENCES:

1. Kunzendorf, U.e.a., FTY720-the first compound of a new promising class of immunosuppressive drugs. Nephrol. Dial. Transplant., 2004. 19: p. 1677-1681.

2. Budde, K.e.a., FTY720 (fingolimod) in renal transplantation. Clinical Transplantation, 2006. 20(17): p. 17-24.

3. Massberg, S.e.a., Fingolimod and Sphingosine-1-Phosphate - Modifiers of Lymphocyte Migration. N Engl J Med, 2006. 355: p. 1088-1091.

4. Chiba, K.e.a., Role of sphingosine 1-phosphate receptor type 1 in lymphocyte egress from secondary lymphoid tissues and thymus. Cell Mol. Immunol., 2006. 3: p. 11-19.

5. Dev, K.K.e.a., Brain sphingosine-1-phosphate receptors: implication for FTY720 in the treatment of multiple sclerosis. Pharmacol. Ther., 2008. 117: p. 77-93.

6. Berdyshev, E.V.e.a., FTY720 inhibits ceramide synthases and up-regulates dihydrosphingosine 1-phosphate formation in human lung endothelial cells. Journal of Biological Chemistry, 2009. 284(9): p. 5467-77.

7. Brinkmann, V.e.a., FTY720 (fingolimod) in Multiple Sclerosis: therapeutic effects in the immune and the central nervous system. British Journal of Pharmacology, 2009. 158(5): p. 1173-1182.

8. Zollinger, M.e.a., Absorption and Disposition of the Sphingosine 1-Phosphate Receptor Modulator Fingolimod (FTY720) in Healthy Volunteers: A Case of Xenobiotic Biotransformation Following Endogenous Metabolic Pathways. Drug Metabolism and Disposition 2011. 39(2): p. 199-207.

9. Lee, C.W.e.a., Neurological S1P signaling as an emerging mechanism of action of oral FTY720 (Fingolimod) in multiple sclerosis. Archives of Pharmacal Research, 2010. 33(10): p. 1567-1574.

10. Kiuchi, M.e.a., Synthesis and biological evaluation of 2,2-disubstituted 2-aminoethanols: analogues of FTY720. Bioorganic & Medicinal Chemistry Letters, 1998. 8(1): p. 101-6.

11. Kappos, L.e.a., Oral Fingolimod (FTY720) for Relapsing Multiple Sclerosis. N Engl J Med, 2006. 355: p. 1124-1140.

12. O'Connor, P.e.a., Oral fingolimod (FTY720) in multiple sclerosis: Two-year results of a phase II extension study. . Neurology, 2009. 72(1): p. 73-79.

13. Cohen, J.A.e.a., Oral Fingolimod or Intramuscular Interferon for Relapsing Multiple Sclerosis. N Engl J Med, 2010. 362: p. 402-415.

14. Brinkmann, V.e.a., Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis. Nature Reviews Drug Discovery, 2010. 9: p. 883-897.