Fingolimod

From Self-sufficiency
Jump to: navigation, search
Fingolimod
File:Fingolimod skeletal.svg
Systematic (IUPAC) name
2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol
Identifiers
CAS Number 162359-55-9
ATC code none
PubChem CID 107969
Chemical data
Formula C19H33NO2
Molar mass 307.471 g/mol[[Script error: No such module "String".]]
Script error: No such module "TemplatePar".Expression error: Unexpected < operator.

Fingolimod (rINN, codenamed FTY720) is an immunosuppressive drug. It is derived from the myriocin (ISP-1) metabolite of the fungus Isaria sinclairii. It is a structural analogue of sphingosine and gets phosphorylated by sphingosine kinases in the cell (most importantly sphingosine kinase 2).[1][2][3] The molecular biology of phospho-fingolimod is thought to lie in its activity at one of the five sphingosine-1-phosphate receptors, S1PR1[4]. It can sequester lymphocytes in lymph nodes, preventing them from moving to the central nervous system for auto-immune responses in multiple sclerosis and was originally proposed as a anti-rejection medication indicated post-transplantation. It has been reported to stimulate the repair process of glial cells and precursor cells after injury.[5] Fingolimod has also been reported to be a cannabinoid receptor antagonist[6], a cPLA2 inhibitor [7] and a ceramide synthase inhibitor[8].


History

First synthesized in 1992, fingolimod was derived from an immunosuppressive natural product, myriocin (ISP-I) through chemical modification. Myriocin was isolated from the culture broth a type of entomopathogenic fungi (Isaria sinclairii) that was an eternal youth nostrum in traditional Chinese medicine. [9] Showing postive results in both in vitro (mixed lymphocyte reaction) and in vivo screening (prolonging rat skin graft survival time), myriocin was modified through a series of steps to yield fingolimod, code named at the time FTY720. [10]

Structure activity relationship (SAR) studies on myriocin homologs and partially synthetic derivatives showed that the configuration at the carbon bearing the 3-hydroxy group or the 14-ketone, the 6-double bond, and the 4-hydroxy group were not important for its activity and simplification of the structure of ISP-I was done in an attempt to reduce toxicity and improve drugability [11]

Elimination of side chain functionalities and removal of chiral centers was part of the simplification process and an intermediate compound (ISP-I-28) with the carboxylic acid of myriocin transformed to a hydroxymethyl group was generated. ISP-I-28 was found to be less toxic and more effective at lenghtening rat skin allograft time than ISP-1.

Clinical trials

Organ transplant

In a previous phase III clinical trial of kidney transplantation, fingolimod was found to be no better than the existing standard of care.[citation needed]

Multiple sclerosis

In two Phase III clinical trials, fingolimod reduced the rate of relapses in relapsing-remitting multiple sclerosis by over half compared both to placebo and to the active comparator interferon beta-1-a. A double-blind randomized control trial comparing fingolimod to placebo found the drug reduced the annualized frequency of relapses to 0.18 relapses per year at 0.5 mg/day or 0.16 relapses per year at 1.25 mg/day, compared to 0.40 relapses per year for those patients taking the placebo. The probability of disease progression at 24 month followup was lower in the fingolimod groups compared to placebo (hazard ratio 0.70 at 0.5 mg and 0.68 at 1.25 mg). Fingolimod patients also had better results according to MRI imaging of new or enlarged lesions at 24 month followup. Side effects leading to discontinuation of the study drug were more common in the higher dose group (14.2% of patients) than at the lower dose (7.5%) or placebo (7.7%). Serious adverse events in the fingolimod group included bradycardia, relapse, and basal-cell carcinoma. Seven episodes of bradycardia occurred during the monitoring period after administration of the first dose, and were asymptomatic in six of these cases. There was a higher rate of lower respiratory tract infections (including bronchitis and pneumonia) in the fingolimod groups (9.6% at 0.5 mg, 11.4% at 1.5 mg) than the placebo group (6.0%). Other adverse events reported on the study drug included macular edema, malignant neoplasms, and laboratory abnormalities.[12][13]

Side effects

Fingolimod has been associated with potentially fatal infections, bradycardia, skin cancer and, recently, a case of haemorrhaging focal encephalitis, an inflammation of the brain with bleeding. Two subjects died: one due to brain herpes infection, second one due to zoster. It is unclear whether the drug was responsible for the events.[14]

The most common side effects of fingolimod have been head colds, headache, and fatigue. But there have also been a few cases of skin cancer, which has also been reported in patients taking natalizumab (Tysabri), an approved MS drug.[15]

Chemical synthesis

Several studies have described the synthesis of fingolimod and analogs.[16][17]

See also

References

Cite error: Invalid <references> tag; parameter "group" is allowed only.

Use <references />, or <references group="..." />
de:Fingolimod ja:フィンゴリモド
  1. ↑ Paugh SW, Payne SG, Barbour SE, Milstien S, Spiegel S (2003). "The immunosuppressant FTY720 is phosphorylated by sphingosine kinase type 2". FEBS Lett. 554 (1–2): 189–93. doi:10.1016/S0014-5793(03)01168-2. PMID 14596938. 
  2. ↑ Billich A, Bornancin F, Dévay P, Mechtcheriakova D, Urtz N, Baumruker T (2003). "Phosphorylation of the immunomodulatory drug FTY720 by sphingosine kinases". J Biol Chem. 278 (48): 47408–15. doi:10.1074/jbc.M307687200. PMID 13129923.  Free full text
  3. ↑ Sanchez, T; Estrada-Hernandez, T; Paik, JH; Wu, MT; Venkataraman, K; Brinkmann, V; Claffey, K; Hla, T (2003). "Phosphorylation and action of the immunomodulator FTY720 inhibits vascular endothelial cell growth factor-induced vascular permeability". The Journal of biological chemistry. 278 (47): 47281–90. doi:10.1074/jbc.M306896200. PMID 12954648. 
  4. ↑ Hla T, Lee MJ, Ancellin N, Paik JH, Kluk MJ (2001). "Lysophospholipids--receptor revelations". Science. 294 (5548): 1875–8. doi:10.1126/science.1065323. PMID 11729304. 
  5. ↑ FTY720 (Fingolimod) for Relapsing Multiple Sclerosis, Expert Review of Neurotherapeutics, Alejandro Horga; Xavier Montalban 06/04/2008; Expert Rev Neurother. 2008;8(5):699-714
  6. ↑ Paugh SW, Cassidy MP, He H, Milstien S, Sim-Selley LJ, Spiegel S, Selley DE (2006). "Sphingosine and its analog, the immunosuppressant 2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol, interact with the CB1 cannabinoid receptor". Mol Pharmacol. 70 (1): 41–50. doi:10.1124/mol.105.020552. PMID 16571654. 
  7. ↑ Payne SG, Oskeritzian CA, Griffiths R, Subramanian P, Barbour SE, Chalfant CE, Milstien S, Spiegel S. (2007). "The immunosuppressant drug FTY720 inhibits cytosolic phospholipase A2 independently of sphingosine-1-phosphate receptors". Blood. 109 (3): 1077–85. doi:10.1182/blood-2006-03-011437. PMC 1785128 Freely accessible. PMID 17008548. 
  8. ↑ Berdyshev EV, Gorshkova I, Skobeleva A, Bittman R, Lu X, Dudek SM, Mirzapoiazova T, Garcia JG, Natarajan V. (2009). "FTY720 inhibits ceramide synthases and up-regulates dihydrosphingosine 1-phosphate formation in human lung endothelial cells". Journal of Biological Chemistry. 284 (9): 5467–77. doi:10.1074/jbc.M805186200. PMC 2645812 Freely accessible. PMID 19119142. 
  9. ↑ Adachi, K; Chiba, K (2007). "FTY720 story. Its discovery and the following accelerated development of sphingosine 1-phosphate receptor agonists as immunomodulators based on reverse pharmacology". Perspectives in medicinal chemistry. 1: 11–23. PMC 2754916 Freely accessible. PMID 19812733. 
  10. ↑ Fujita, T., Yoneta, M., Hirose, R., Sasaki, S., Inoue, K., Kiuchi, M., Hirase, S., Adachi, K., Arita, M. and Chiba, K. (1995). "Simple compounds, 2-alkyl-2-amino-1,3-propanediols have potent immunosuppressive activity". Bioorg. Med. Chem. Lett. 5: 847–52. doi:10.1016/0960-894X(95)00126-E.  line feed character in |title= at position 18 (help)
  11. ↑ Adachi, K; Chiba, K (2007). "FTY720 story. Its discovery and the following accelerated development of sphingosine 1-phosphate receptor agonists as immunomodulators based on reverse pharmacology". Perspectives in medicinal chemistry. 1: 11–23. PMC 2754916 Freely accessible. PMID 19812733. 
  12. ↑ Kappos L, Radue E-W, O'Connor P, Polman C, Hohlfield R, Calabresi P, Selmaj K, Agoropoulou C, Leyk M, Zhang-Auberson L, Burtin P for the FREEDOMS Study Group (2010). "A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis". New England Journal of Medicine. 362 (5): epub ahead of print. doi:10.1056/NEJMoa0909494. PMID 20089952. 
  13. ↑ Efficacy and Safety of Fingolimod in Patients With Relapsing-Remitting Multiple Sclerosis. ClinicalTrials.gov
  14. ↑ http://www.msrc.co.uk/index.cfm/fuseaction/show/pageid/1309
  15. ↑ http://www.webmd.com/multiple-sclerosis/news/20080416/good-news-for-oral-ms-drug-fingolimod
  16. ↑ Kiuchi, M; Adachi, K; Kohara, T; Teshima, K; Masubuchi, Y; Mishina, T; Fujita, T (1998). "Synthesis and biological evaluation of 2,2-disubstituted 2-aminoethanols: analogues of FTY720". Bioorganic & medicinal chemistry letters. 8 (1): 101–6. doi:10.1016/S0960-894X(97)10188-3. PMID 9925439. 
  17. ↑ B.Sivaraman, A.Senthilmurugan, I.S.Aidhen (2007). "Weinreb Amide Based New Synthetic Equivalents for Convenient Access to Immunosuppressive Agent FTY720 and Analogues". Synletters. 2841. 
Retrieved from "http://ssf.f15ijp.com/wiki/index.php?title=Fingolimod&oldid=22900"