WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 100355
CAS#: 162359-56-0 (fingolimod HCl); 162359-55-9 (fingolimod free base)
Description: 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). The molecular biology of phospho-fingolimod is thought to lie in its activity at one of the five sphingosine-1-phosphate receptors, S1PR1. 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. Fingolimod has also been reported to be a cannabinoid receptor antagonist, a cPLA2 inhibitor and a ceramide synthase inhibitor. (source: http://en.wikipedia.org/wiki/Fingolimod).
MedKoo Cat#: 100355
Name: Fingolimod HCl
CAS#: 162359-56-0 (fingolimod HCl); 162359-55-9 (fingolimod free base)
Chemical Formula: C19H34ClNO2
Molecular Weight: 343.94
Elemental Analysis: C, 66.35; H, 9.96; Cl, 10.31; N, 4.07; O, 9.30
Synonym: FTY720; FTY-720; FTY 720. Fingolimod; AC1L332W; CHEMBL314854; CHEBI:63115; LS187221; CID107970; Band name: Gilenia and Gilenya.
IUPAC/Chemical Name: 2-amino-2-(4-octylphenethyl)propane-1,3-diol hydrochloride.
InChi Key: SWZTYAVBMYWFGS-UHFFFAOYSA-N
InChi Code: InChI=1S/C19H33NO2.ClH/c1-2-3-4-5-6-7-8-17-9-11-18(12-10-17)13-14-19(20,15-21)16-22;/h9-12,21-22H,2-8,13-16,20H2,1H3;1H
SMILES Code: OCC(CCC1=CC=C(CCCCCCCC)C=C1)(N)CO.[H]Cl
Status of FDA approval
June 11, 2010 Â— The US Food and Drug Administration's (FDA's) Peripheral and Central Nervous System Drugs Advisory Committee has recommended approval for the novel oral agent fingolimod in the treatment of patients with relapsing-remitting multiple sclerosis (MS). The highly anticipated drug is the first in a new class of disease-modifying agents called sphingosine 1 phosphate receptor modulators. Fingolimod's sponsor, Novartis, was seeking a new drug application for patients with MS to reduce the frequency of clinical exacerbations and to delay the accumulation of physical disability. Novartis plans to market fingolimod as Gilena. If approved by the FDA, it will be the first oral agent for patients with MS, giving them a welcome alternative to currently available injectable therapies. The committee spent hours discussing a long list of questions posed by the FDA but was unanimous in its decision to recommend fingolimod's approval.
History of research and development
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 vegetative wasp (Isaria sinclairii) that was an eternal youth nostrum in traditional Chinese medicine. 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. 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. 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. (source: http://en.wikipedia.org/wiki/Fingolimod).
1. 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.
2. 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.
Develope r of the product: Novartis.
1: Brunkhorst R, Vutukuri R, Pfeilschifter W. Fingolimod for the treatment of neurological diseases-state of play and future perspectives. Front Cell Neurosci. 2014 Sep 12;8:283. doi: 10.3389/fncel.2014.00283. eCollection 2014. Review. PubMed PMID: 25309325; PubMed Central PMCID: PMC4162362.
2: Harrison K. Fingolimod for multiple sclerosis: a review for the specialist nurse. Br J Nurs. 2014 Jun 12-25;23(11):582-9. Review. PubMed PMID: 24933548.
3: Thomas K, Ziemssen T. Management of fingolimod in clinical practice. Clin Neurol Neurosurg. 2013 Dec;115 Suppl 1:S60-4. doi: 10.1016/j.clineuro.2013.09.023. Review. PubMed PMID: 24321158.
4: Pilz G, Harrer A, Wipfler P, Oppermann K, Sellner J, Fazekas F, Trinka E, Kraus J. Tumefactive MS lesions under fingolimod: a case report and literature review. Neurology. 2013 Nov 5;81(19):1654-8. doi: 10.1212/01.wnl.0000435293.34351.11. Epub 2013 Oct 4. Review. Erratum in: Neurology. 2014 Apr 29;82(17):1569. PubMed PMID: 24097813.
5: Singer BA. Fingolimod for the treatment of relapsing multiple sclerosis. Expert Rev Neurother. 2013 Jun;13(6):589-602. doi: 10.1586/ern.13.52. Review. PubMed PMID: 23738997.
6: Willis MA, Cohen JA. Fingolimod therapy for multiple sclerosis. Semin Neurol. 2013 Feb;33(1):37-44. doi: 10.1055/s-0033-1343794. Epub 2013 May 25. Review. PubMed PMID: 23709211.
7: Groves A, Kihara Y, Chun J. Fingolimod: direct CNS effects of sphingosine 1-phosphate (S1P) receptor modulation and implications in multiple sclerosis therapy. J Neurol Sci. 2013 May 15;328(1-2):9-18. doi: 10.1016/j.jns.2013.02.011. Epub 2013 Mar 19. Review. PubMed PMID: 23518370; PubMed Central PMCID: PMC3640626.
8: SzÃ©plaki G, Merkely B. [Clinical significance of the cardiovascular effects of fingolimod treatment in multiple sclerosis]. Ideggyogy Sz. 2012 Nov 30;65(11-12):369-76. Review. Hungarian. PubMed PMID: 23289171.
9: Nikitin AV. [Molecular and cellular mechanisms of fingolimod action]. Antibiot Khimioter. 2013;58(11-12):38-42. Review. Russian. PubMed PMID: 24734428.
10: Liu J, Zhang C, Tao W, Liu M. Systematic review and meta-analysis of the efficacy of sphingosine-1-phosphate (S1P) receptor agonist FTY720 (fingolimod) in animal models of stroke. Int J Neurosci. 2013 Mar;123(3):163-9. doi: 10.3109/00207454.2012.749255. Epub 2012 Dec 21. Review. PubMed PMID: 23167788.