Fingolimod
(Synonyms: 芬戈莫德; FTY720 free base) 目录号 : GC43666
A fungal metabolite with immune modulating activities
Cas No.:162359-55-9
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Cell experiment: | Immature dendritic cells (DCs) are left intact or are incubated with 2 μM S1P, 10 nM Fingolimod, 10 nM SEW2871 or the combinations of S1P with these drugs for 4 h. As a control 1 μg/mL LPS is used. The cells are washed and incubated in a 96-well plate (v-bottom, 2×105 cells per well), washed again and resuspended in PBS buffer containing 0.1% sodium azide. They are labeled with 1 μg/mL FITC-conjugated mouse anti-human CD80, 1 μg/mL FITC-conjugated mouse anti-human CD83, 1 μg/mL FITC-conjugated mouse anti-human CD86, 1 μg/mL FITC-conjugated mouse anti-human HLA-class I, 1 μg/mL FITC-conjugated mouse anti-human HLA-DR, 1 μg/mL FITC-conjugated mouse anti-human HLA-E, or 1 μg/mL FITC-conjugated mouse IgG as a control. The cells are washed twice, and examined in the flow cytometer. Markers are set according to the isotype control FITC-conjugated mouse IgG[1]. |
Animal experiment: | Mice[2] Rag1-/- mice(B6.129S7-Rag1tm1Mom/J), Foxn1-/- mice (B6.Cg/NTac-Foxn1nu) mice, and control C57BL/6 mice are used. Mice receive non-phosphorylated Fingolimod via intraperitoneal injection at a concentration of 1 mg/kg once daily over the course of 16 days, starting 2 days before crush until 14 days post-crush. PF-8380 is dissolved in DMSO and administered at a concentration of 10 mg/kg via intraperitoneal injection once daily, as well starting 2 days before until 14 days post-crush. Controls receive an equal volume of solvent. Rats[3] Male Lewis rats (50-100 g, n=18) are used. After the peripheral activation of the lesion, the DTH EAE lesions are allowed to develop until day 127 to generate large chronic lesions and the animals are then treated for 28 d with either Fingolimod (n=7) or vehicle (n=7). The Fingolimod treatment is given daily (0.3 mg/kg in 0.5 mL of water). The control group is given water (0.5 mL) as a vehicle control. The animals are dosed via oral gavage to ensure accurate dosing. In this model, the acute inflammation subsides after day 20 of activation of the lesion, and the BBB damage subsides. Thus, at day 127 the lesion clearly represents a well-developed chronic MS lesion. PET imaging is performed immediately before initiation of treatment and at the end of the treatment period. |
References: [1]. Rolin J, et al. FTY720 and SEW2871 reverse the inhibitory effect of S1P on natural killer cell mediated lysis of K562 tumor cells and dendritic cells but not on cytokine release. Cancer Immunol Immunother. 2010, 59(4), 575-586. | |
Fingolimod is a sphingosine 1-phosphate (S1P) antagonist with IC50 of 0.033 nM in K562 and NK cells. Fingolimod also is a pak1 activator, a immunosuppressant.
The monocyte-derived immature dendritic cells (iDCs) are pretreated with various concentrations of S1P for various periods of time prior to their incubation with NK cells. Four hours incubation of autologous or allogeneic iDCs with 0.2-20 μM of S1P significantly protectes these cells from NK cell lysis. The IC50 values of S1P are calculated at 160 nM for autologous iDCs, and 34 nM for allogeneic iDCs. Next, the inhibitory effect of S1P is revered by various concentrations of Fingolimod or SEW2871, with an IC50 effect of 173 or 15 nM, respectively[1]. Fingolimod has been reported to reduce LPA synthesis via inhibition of the lysophospholipase autotaxin. Fingolimod treatment correlates with a significant elevation of axonal cAMP, a crucial factor for axonal outgrowth. Additionally, Fingolimod significantly reduces LPA levels in the injured nerve. PF-8380 treatment correlates with improved myelin thickness[2].
Fingolimod treatment results in significantly increased nerve conduction at 14 days post-crush in wildtype C57BL/6 mice. However, Foxn1-/- mice, which are devoid of T- but not B-lymphocytes, show an improvement of nerve regeneration under fingolimod treatment. Although the mean increase in nerve conduction velocity in both fingolimod-treated and controlFoxn1-/- mice implies a potentially positive role of T-lymphocyte deficiency on nerve regeneration, only fingolimod-treated Foxn1-/- mice show a significant improvement compared to C57BL/6 controls and performed better in the functional analysis[2]. Treatment of the animals with Fingolimod for 28 d results in a clear reduction in the binding of 18F-GE180 when compare with vehicle-treated animals and evaluated by ex vivo autoradiography. Quantification of the binding of the radiotracer revealed a significant reduction in the binding potential of 18F-GE180 (P<0.0001) after treatment with Fingolimod[3].
References:
[1]. Rolin J, et al. FTY720 and SEW2871 reverse the inhibitory effect of S1P on natural killer cell mediated lysis of K562 tumor cells and dendritic cells but not on cytokine release. Cancer Immunol Immunother. 2010, 59(4), 575-586.
[2]. Szepanowski F, et al. Fingolimod promotes peripheral nerve regeneration via modulation of lysophospholipid signaling. J Neuroinflammation. 2016 Jun 10;13(1):143.
[3]. Airas L, et al. In vivo PET imaging demonstrates diminished microglial activation after fingolimod treatment in an animal model of multiple sclerosis. J Nucl Med. 2015 Feb;56(2):305-10.
[4]. Shirakabe K, et al. Modification of lymphocyte migration to Peyer's patches by inhibition of sphingosine-1-phosphate lyase ameliorates murine colitis. J Gastroenterol Hepatol. 2018 Jan 15.
| Cas No. | 162359-55-9 | SDF | |
| 别名 | 芬戈莫德; FTY720 free base | ||
| Canonical SMILES | OCC(N)(CO)CCC1=CC=C(CCCCCCCC)C=C1 | ||
| 分子式 | C19H33NO2 | 分子量 | 307.5 |
| 溶解度 | DMF: 20 mg/ml,DMSO: 10 mg/ml,Ethanol: 5 mg/ml | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 3.252 mL | 16.2602 mL | 32.5203 mL |
| 5 mM | 0.6504 mL | 3.252 mL | 6.5041 mL |
| 10 mM | 0.3252 mL | 1.626 mL | 3.252 mL |
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Fingolimod: therapeutic mechanisms and ocular adverse effects
Eye (Lond) 2017 Feb;31(2):232-240.PMID:27886183DOI:10.1038/eye.2016.258.
Fingolimod is an oral immunomodulating drug used in the management of relapsing-remitting multiple sclerosis (RRMS). We aim to review the published literature on ocular manifestations of Fingolimod therapy and their possible underlying mechanisms. The therapeutic effects of Fingolimod are mediated via sphingosine receptors, which are found ubiquitously in various organs, including lymphoid cells, central nervous system, cardiac myocytes, and smooth muscle cells. Fingolimod-associated macular oedema (FAME) is the most common ocular side effect but retinal haemorrhages and retinal vein occlusion can occur. The visual consequences appear to be mild and, in cases of FAME, resolution is often attained with discontinuation of therapy. However, in cases of retinal vein occlusion, discontinuation of Fingolimod alone may not be sufficient and intra-vitreal therapy may be required. We also propose a pragmatic service pathway for monitoring patients on Fingolimod therapy, which includes stratifying them by risk and visual acuity.
Comparative safety and efficacy of ozanimod versus Fingolimod for relapsing multiple sclerosis
J Comp Eff Res 2020 Mar;9(4):275-285.PMID:31948278DOI:10.2217/cer-2019-0169.
Aim: Ozanimod and Fingolimod are sphingosine 1-phosphate receptor-modulating therapies for relapsing multiple sclerosis. Patients & methods: Comparative effectiveness was assessed by matching adjusted indirect comparisons of safety and efficacy trial outcomes at first-dose cardiac monitoring, 1 year and 2 years. Results: After adjustment, baseline characteristics were similar. Ozanimod was associated with a lower risk of extended first-dose monitoring, conduction abnormalities including atrioventricular block. One-year risks of any adverse event (AE), mean lymphocyte count reductions and abnormal liver enzymes were lower with ozanimod. Two-year risks of AEs leading to discontinuation, any AEs, herpetic infections, bradycardia and abnormal liver enzymes were lower with ozanimod. Analyses of efficacy outcomes were similar. Conclusion: Ozanimod appears to have a favorable benefit-risk profile versus Fingolimod.
Fingolimod: Lessons Learned and New Opportunities for Treating Multiple Sclerosis and Other Disorders
Annu Rev Pharmacol Toxicol 2019 Jan 6;59:149-170.PMID:30625282DOI:10.1146/annurev-pharmtox-010818-021358.
Fingolimod (FTY720, Gilenya) was the first US Food and Drug Administration-approved oral therapy for relapsing forms of multiple sclerosis (MS). Research on modified fungal metabolites converged with basic science studies that had identified lysophospholipid (LP) sphingosine 1-phosphate (S1P) receptors, providing mechanistic insights on Fingolimod while validating LP receptors as drug targets. Mechanism of action (MOA) studies identified receptor-mediated processes involving the immune system and the central nervous system (CNS). These dual actions represent a more general theme for S1P and likely other LP receptor modulators. Fingolimod's direct CNS activities likely contribute to its efficacy in MS, with particular relevance to treating progressive disease stages and forms that involve neurodegeneration. The evolving understanding of Fingolimod's MOA has provided strategies for developing next-generation compounds with superior attributes, suggesting new ways to target S1P as well as other LP receptor modulators for novel therapeutics in the CNS and other organ systems.
Fingolimod hydrochloride for the treatment of relapsing remitting multiple sclerosis
Expert Opin Pharmacother 2017 Oct;18(15):1649-1660.PMID:28844164DOI:10.1080/14656566.2017.1373093.
Fingolimod was the first oral and the first in class disease modifying treatment in multiple sclerosis that acts as sphingosine-1-phospathe receptor agonist. Since approval in 2010 there is a growing experience with Fingolimod use in clinical practice, but also next-generation sphingosin-1-receptor agonists in ongoing clinical trials. Growing evidence demonstrates additional effects beyond impact on lymphocyte circulation, highlighting further promising targets in multiple sclerosis therapy. Areas covered: Here we present a systematic review using PubMed database searching and expert opinion on Fingolimod use in clinical practice. Long-term data of initial clinical trials and post-marketing evaluations including long-term efficacy, safety, tolerability and management especially within growing disease modifying treatment options and pre-treatment constellation in multiple sclerosis patients are critically discussed. Furthermore novel findings in mechanism of actions and prospective on additional use in progressive forms in multiple sclerosis are presented. Expert opinion: There is an extensive long-term experience on Fingolimod use in clinical practice demonstrating the favorable benefit-risk of this drug. Using a defined risk management approach experienced MS clinicians should apply Fingolimod after critical choice of patients and review of clinical aspects. Further studies are essential to discuss additional benefit in progressive forms in multiple sclerosis.
The sphingosine 1-phosphate receptor modulator Fingolimod as a therapeutic agent: Recent findings and new perspectives
Pharmacol Ther 2018 May;185:34-49.PMID:29127024DOI:10.1016/j.pharmthera.2017.11.001.
The immunomodulatory drug Fingolimod (FTY720, GilenyaR) was approved for oral treatment of relapsing-remitting multiple sclerosis, due to its impressive efficacy and good tolerability. Pharmacologically, it acts as an unselective agonist of sphingosine 1-phosphate receptors (S1PR) and as a selective functional antagonist of the S1P1 subtype by induction of receptor downregulation. Since S1P1 is crucial for the regulation of lymphocyte trafficking, its downregulation causes redistribution of the immune cells to secondary lymphoid tissues, resulting in the depletion from the circulation and hence immunosuppression. Numerous preclinical studies have since been performed with the aim to increase the spectrum of potential indications for Fingolimod with emphasis on other autoimmune disorders and diseases associated with inflammation and uncontrolled cell proliferation, including cancer. As an alternative to Fingolimod, novel S1PR modulators with a more selective receptor activation profile and improved pharmacokinetic performance and tolerability have also been developed. Preclinical and clinical studies are ongoing to investigate their therapeutic potential. This review discusses the most relevant preclinical and clinical findings from S1PR-targeting and from less-well defined off-target effects reported in the literature, and reveals perspectives for using Fingolimod and functionally-related derivatives and new formulations in the management of an increasing number of diseases.