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Purity: ≥98%
Fingolimod (formerly FTY720; FTY-720; FTY 720; trade names Gilenia and Gilenya), an approved medication for treating Multiple sclerosis, is a potent S1P
(sphingosine 1-phosphate) antagonist with anticancer activity. It inhibits S1P with an IC50 of 0.033 nM in K562 and NK
cells. It is a folk medicine emerged from Fungi. Fingolimod was firstly
found to be a therapeutic agent in organ transplantation. It plays the
role in MS treatment through receptor-mediated actions both on the
immune system and in the CNS. Fingolimod is used to treat multiple
sclerosis, and has antineoplastic activity.
| Targets |
sphingosine 1-phosphate (S1P)(IC50 = 0.033 nM, in K562 and NK cells); PAK1
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|---|---|
| ln Vitro |
Before surviving with NK cells, monocyte-derived immature dendritic cells (iDCs) were exposed to various doses of S1P for variable amounts of time. In these dishes, autologous or allogeneic iDCs that were exposed to 0.2–20 μM S1P for four hours considerably shielded the NK cells. For autologous iDCs and allogeneic iDCs, the IC50 values for S1P were determined to be 160 nM and 34 nM, respectively. Subsequently, fingolimod or SEW2871 at varying doses were able to counteract the inhibitory effect of S1P, with IC50 values of 173 or 15 nM, respectively [1]. It has been observed that fungiolimod causes LPA to be synthesized by preventing lysophospholipase automobility in cells. An important component of axonal development, axonal cAMP concentration, showed a strong correlation with fingolim therapy. Furthermore, fingolimod dramatically lowered the nerve center's LPA levels. Myelin thickness improvements are linked to PF-8380 therapy [2].
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| ln Vivo |
Fourteen days after extrusion, fingolimod therapy led to a notable increase in nerves in wild-type C57BL/6 nozzles. On the other hand, T-deficient B-deleted Foxn1-/-nozzles treated with fingolimod demonstrated enhanced nerve regeneration. Though the average rate of nerve growth in Foxn1-/- nozzles treated with Fingolimod and control Foxn1-/- nozzles suggested that T deficit affects nerve regeneration. Possibility of a role, although only Foxn1-/-treated mice significantly outperformed C57BL/6 and fared better in functional examination [2]. Ex vivo radioactive autobinding was used to quantify the amount of 18F-GE180 tracer binding that occurred after animals treated with fingolimod for 28 days. The results showed that the binding potential of 18F-GE180 was significantly reduced (P<0.0001) after treatment with fingolimod.
|
| Enzyme Assay |
Detection of cytokines and chemokines release utilizing the ELISArray kits[1]
DCs or NK cells were incubated at a cell concentration of 1 × 106 cells/ml with either media or with 2 μM S1P, 10 nM SEW2871, 10 nM FTY720 or their combinations. DCs were also incubated with 1 μg/ml LPS. After 24 h incubation, the cells were harvested and the cell suspensions were centrifuged at 1,000 × g for 10 min before the supernatants were collected. Detection of the levels of various cytokines and chemokines was carried utilizing the Multi-Analyte ELISArray Kit as described by the manufacturers’ user manual. The kit analyzes the release of IL-1β, IL-4, IL-6, IL-10, IL-12, IL-17A, IFN-γ, TNF-α, TGF-β1, MCP-1, MIP-1α, and MIP-1β. Negative and positive controls supplied by the kits were also included[1]. |
| Cell Assay |
Immature DCs were left intact or were incubated with 2 μM S1P, 10 nM FTY720 , 10 nM SEW2871 or the combinations of S1P with these drugs for 4 h. As a control 1 μg/ml LPS was used. The cells were 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 were 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 were washed twice, and examined in the flow cytometer. Markers were set according to the isotype control FITC-conjugated mouse IgG.[1]
To stain NK cells with antibodies for various NK cell activating receptors, they were either left untreated or incubated with 2 μM S1P for 4 h, washed and stained with 1 μg/ml PE-conjugated mouse anti-human NKp30 (CD337), 1 μg/ml PE-conjugated mouse anti-human NKp44 (CD336), 1 μg/ml PE-conjugated mouse anti-human NKG2D (CD314), or as a control 1 μg/ml PE-conjugated mouse IgG1, for 45 min at 4°C. NK cells were also stained with 1 μg/ml FITC-conjugated anti-killer inhibitory receptor (KIR)/CD158 antibody which recognizes KIR2DL2, KIR2DL3, KIR2DS2 and KIR2DS4, and as a control with FITC-conjugated mouse IgG. The cells were washed twice, and examined in the flow cytometer. Markers were set according to the isotype control PE-conjugated or FITC-conjugated mouse IgG. |
| Animal Protocol |
Methods:[3]
Chronic focal experimental autoimmune encephalitis (EAE)-like lesions were induced in Lewis rats (n = 24) via stereotactic intrastriatal injection of heat-killed bacillus Calmette-Guérin (BCG) and subsequent activation using an intradermal injection of BCG in complete Freund adjuvant. This process resulted in a delayed-type hypersensitivity (DTH)-like EAE lesion. The extent of neuroinflammation surrounding the lesion was measured using (18)F-GE180 as a PET radioligand. The imaging was performed before and after treatment with fingolimod (0.3 mg/kg/d by mouth, 28 d) or vehicle as a control. In addition to imaging, autoradiography and immunohistochemistry experiments were performed to verify the in vivo results. Results: [3] The chronic DTH EAE lesion led to increased ligand binding in the ipsilateral, compared with contralateral, hemisphere when PET imaging was performed with the translocator protein-binding radioligand (18)F-GE180. Treatment with fingolimod led to a highly significant reduction in the binding potential, which could be demonstrated using both in vivo and ex vivo imaging (fingolimod vs. vehicle treatment, P < 0.0001). The area of increased (18)F-GE180 signal mapped closely to the area of activated microglial cells detected by immunohistochemistry. |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion
Fingolimod is slowly but efficiently absorbed in the gastrointestinal tract. AUC varies greatly, depending on the patient, and pharmacokinetic studies demonstrate a range of AUC values for fingolimod. The Tmax of fingolimod ranges between 12-16 hours and its bioavailability is 90-93%. Steady-state concentrations of fingolimod are achieved within 1-2 months after initiation when it is administered in a single daily dose. About 81% of an oral dose of fingolimod is excreted in the urine in the form of inactive metabolites. Intact fingolimod and its active metabolite account for less than 2.5% of the dose, and can be found excreted in the feces. The volume of distribution of fingolimod is about 1200±260 L. It is approximately 86% distributed in the red blood cells (RBC). Fingolimod blood clearance is 6.3±2.3 L/h, according to prescribing information. Another resource mentions it ranges from 6-8 L/h. Metabolism / Metabolites Sphingosine kinase metabolizes fingolimod to an active metabolite, fingolimod phosphate. Fingolimod metabolism occurs via 3 major metabolic pathways: firstly, phosphorylation of the (S)-enantiomer of fingolimod-phosphate (pharmacologically active), secondly, oxidation by cytochrome P450 4F2 (CYP4F2), and thirdly, fatty acid-like metabolism to various inactive metabolites. The formation of inactive non-polar ceramide analogs of fingolimod also occurs during its metabolism. Biological Half-Life The half-life of fingolimod and its active metabolite ranges from 6-9 days. |
| Toxicity/Toxicokinetics |
Hepatotoxicity
In large randomized controlled trials of fingolimod in patients with multiple sclerosis, serum ALT elevations above 3 times ULN were reported in 8% to 14% of fingolimod compared to 2% to 3% of placebo recipients. The enzyme elevations were usually transient and not associated with symptoms or jaundice and required drug discontinuation in less than 1% of cases. No instances of acute hepatitis or clinically apparent liver injury were reported in the preregistration trials of fingolimod. Subsequent to its approval and more wide scale use, however, instances of clinically apparent liver injury attributed to fingolimod were reported including cases of acute liver failure requiring emergency liver transplantation. The onset of liver injury was often within days or weeks of starting treatment and the pattern of liver enzyme elevations was usually hepatocellular. In addition, at least one instance of reactivation of hepatitis B in an inactive HBsAg carrier has been reported. Thus, mild-to-moderate and transient serum enzyme elevations during therapy are not uncommon, and clinically apparent liver injury with jaundice due to fingolimod can occur. Likelihood score: C (probable cause of clinically apparent liver injury as well as reactivation of hepatitis B in susceptible patients). Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation Although fingolimod and its active metabolite are highly bound in maternal plasma and unlikely to reach the breastmilk in large amounts, it is potentially toxic to the breastfed infant. Because there is no published experience with fingolimod during breastfeeding, expert opinion generally recommends that it should be avoided during breastfeeding, especially while nursing a newborn or preterm infant. However, the manufacturer's labeling does not recommend against its use in breastfeeding. ◉ Effects in Breastfed Infants Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. Protein Binding The protein binding of fingolimod and its active metabolite exceeds 99.7%. |
| References |
|
| Additional Infomation |
Pharmacodynamics
In multiple sclerosis, fingolimod binds to sphingosine receptors, reducing its associated neuroinflammation.In COVID-19, it may reduce lung inflammation and improve the clinical outcomes of patients with this disease. Fingolimod causes a transient reduction in heart rate and AV conduction during treatment initiation. It has the potential to prolong the QT interval. |
| Molecular Formula |
C19H33NO2
|
|---|---|
| Molecular Weight |
307.478
|
| Exact Mass |
307.251
|
| Elemental Analysis |
C, 74.22; H, 10.82; N, 4.56; O, 10.41
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| CAS # |
162359-55-9
|
| Related CAS # |
Fingolimod-d4;1346747-38-3;Fingolimod-d4 hydrochloride;1346604-90-7;Fingolimod hydrochloride;162359-56-0; 162359-55-9; 402615-91-2 (phosphate); 207113-62-0 (octanoic acid); 1242271-26-6 (palmitamide); 207113-64-2 (hexanoic acid)
|
| PubChem CID |
107970
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| Appearance |
White to off-white solid powder
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| Density |
1.0±0.1 g/cm3
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| Boiling Point |
479.5±45.0 °C at 760 mmHg
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| Melting Point |
102-107
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| Flash Point |
243.8±28.7 °C
|
| Vapour Pressure |
0.0±1.3 mmHg at 25°C
|
| Index of Refraction |
1.531
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| LogP |
5.25
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
12
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| Heavy Atom Count |
22
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| Complexity |
258
|
| Defined Atom Stereocenter Count |
0
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| InChi Key |
KKGQTZUTZRNORY-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C19H33NO2/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
|
| Chemical Name |
2-Amino-2-[2-(4-octylphenyl)ethyl]-1,3-propandiol
|
| Synonyms |
FTY720 (free base); FTY720; 162359-55-9; 2-Amino-2-(4-octylphenethyl)propane-1,3-diol; 2-Amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol; Fingolimod [INN]; 2-Amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol; Fty-720; fingolimodum; Fingolimod HCl; FTY-720; FTY 720; Trade name: Gilenia and Gilenya.
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| Solubility (In Vitro) |
Ethanol : ~7.69 mg/mL (~25.01 mM)
DMSO : ~2 mg/mL (~6.50 mM) |
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1 mg/mL (3.25 mM) (saturation unknown) in 10% EtOH + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 10.0 mg/mL clear EtOH stock solution to 400 μL of PEG300 and mix evenly; then add 50 μL of Tween-80 to the above solution and mix evenly; then add 450 μL of normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 1 mg/mL (3.25 mM) (saturation unknown) in 10% EtOH + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 10.0 mg/mL clear EtOH stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 1 mg/mL (3.25 mM) (saturation unknown) in 10% EtOH + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.2522 mL | 16.2612 mL | 32.5224 mL | |
| 5 mM | 0.6504 mL | 3.2522 mL | 6.5045 mL | |
| 10 mM | 0.3252 mL | 1.6261 mL | 3.2522 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT04667949 | Active Recruiting |
Drug: Fingolimod 0.5mg | Relapsing Multiple Sclerosis (RMS) |
Novartis Pharmaceuticals | February 20, 2021 | Phase 4 |
| NCT04088630 | Active Recruiting |
Drug: Fingolimod 0.5 mg Drug: Placebo |
Cerebral Edema Stroke Hemorrhagic |
Wake Forest University Health Sciences |
August 7, 2020 | Early Phase 1 |
| NCT05423769 | Active Recruiting |
Drug: Fingolimod | Relapsing-Remitting Multiple Sclerosis |
Hikma Pharmaceuticals LLC | January 19, 2022 | N/A |
| NCT04480853 | Recruiting | Drug: Fingolimod | Multiple Sclerosis | Novartis Pharmaceuticals | October 12, 2020 | Phase 4 |
| NCT01285479 | Completed | Drug: Fingolimod | Multiple Sclerosis | Novartis Pharmaceuticals | October 15, 2011 | N/A |
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