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Identification
- Summary
Fingolimod is a sphingosine 1-phosphate receptor modulator used to treat patients with the relapsing-remitting form of multiple sclerosis (MS) and studied to manage lung complications of COVID-19.
- Brand Names
- Gilenya, Tascenso
- Generic Name
- Fingolimod
- DrugBank Accession Number
- DB08868
- Background
Multiple sclerosis, or MS, is a devastating inflammatory disease that often progresses and causes severe neurological, physical, and cognitive effects.3 Fingolimod is a sphingosine 1-phosphate receptor modulator for the treatment of relapsing-remitting multiple sclerosis. It was developed by Novartis and initially approved by the FDA in 2010.12 Fingolimod was also studied for the treatment of COVID-19, the disease caused by infection with the SARS-CoV-2 virus.13,14
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Fingolimod (DB08868)
- Weight
- Average: 307.4708
Monoisotopic: 307.251129305 - Chemical Formula
- C19H33NO2
- Synonyms
- Fingolimod
- Fingolimodum
- External IDs
- FTY-720A
- FTY720
Pharmacology
- Indication
Fingolimod is indicated for the treatment of patients aged 10 and above with relapsing forms of multiple sclerosis, which may include clinically isolated syndrome, relapsing-remitting disease, as well as active secondary progressive disease.12,16
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Relapsing multiple sclerosis (rms) •••••••••••• Treatment of Relapsing multiple sclerosis (rms) •••••••••••• Treatment of Relapsing multiple sclerosis (rms) •••••••••••• Management of Relapsing multiple sclerosis (rms) •••••••••••• •••••• - Associated Therapies
- Contraindications & Blackbox Warnings
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In multiple sclerosis, fingolimod binds to sphingosine receptors, reducing its associated neuroinflammation.12In COVID-19, it may reduce lung inflammation and improve the clinical outcomes of patients with this disease.13
Fingolimod causes a transient reduction in heart rate and AV conduction during treatment initiation. It has the potential to prolong the QT interval.13
- Mechanism of action
Sphingosine‐1‐phosphate (S1P) is an important phospholipid that binds to various G‐protein‐coupled receptor subtypes, which can be identified as S1P1–5R. S1P and the receptors it binds to perform regular functions in the immune, cardiovascular, pulmonary, and nervous systems.10,11 S1P can be expressed ubiquitously, playing an important role in regulating inflammation. S1P1R, S1P2R, and S1P3R receptors can be found in the cardiovascular, immune, and central nervous systems. S1P4R is found on lymphocytic and hematopoietic cells, while S1P5R expression is found only on the spleen (on natural killer cells) or in the central nervous system.6
The active form of the drug, fingolimod phosphate, is a sphingosine 1-phosphate receptor modulator that exerts its mechanism of action in MS by binding to various sphingosine 1-phosphate receptors (1, 3, 4, and 5). It suppresses the exit of lymphocytes from lymph nodes, leading to a lower level of lymphocytes circulating in the peripheral circulation. This reduces the inflammation that is associated with MS. The mechanism of action of fingolimod is not fully understood but may be related to reduced lymphocyte circulation into the central nervous system.3,12
Immune modulating treatment such as fingolimod is not typically employed for SARS-CoV-2 pneumonia. Despite this, with the tissue findings of pulmonary edema and hyaline membrane formation, the timely use of immune modulators such as fingolimod can be considered to prevent acute respiratory distress syndrome (ARDS) associated with COVID-19.13
Target Actions Organism AD(3) dopamine receptor antagonistHumans ASphingosine kinase 1 inhibitorHumans ASphingosine 1-phosphate receptor 5 modulatorHumans ASphingosine 1-phosphate receptor 1 modulatorHumans ASphingosine 1-phosphate receptor 3 modulatorHumans UHistone deacetylase 1 inhibitorHumans USphingosine 1-phosphate receptor 4 modulatorHumans - Absorption
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.5 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.5,12
- Volume of distribution
The volume of distribution of fingolimod is about 1200±260 L. It is approximately 86% distributed in the red blood cells (RBC).5,12
- Protein binding
The protein binding of fingolimod and its active metabolite exceeds 99.7%.5,12
- Metabolism
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.5,12
Hover over products below to view reaction partners
- Route of elimination
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.12
- Half-life
The half-life of fingolimod and its active metabolite ranges from 6-9 days.5,12
- Clearance
Fingolimod blood clearance is 6.3±2.3 L/h,12 according to prescribing information. Another resource mentions it ranges from 6-8 L/h.5
- Adverse Effects
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The LD50 of fingolimod in rats ranges from 300-600 mg/kg.7
Prescribing information for fingolimod does not mention symptoms or management of an overdose 12, however, a case report of an intentional overdose with 14mg of fingolimod and 2g phenoxymethylpenicillin resulted in hypotension in bradycardia, resolved by administering atropine.8 Since fingolimod has been associated with cardiotoxicity, it would be reasonable to expect cardiac effects such as bradycardia and heart block in the case of an overdose.9,12
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAbatacept Abatacept may increase the immunosuppressive activities of Fingolimod. Acebutolol Acebutolol may increase the bradycardic activities of Fingolimod. Acetaminophen Fingolimod may increase the hepatotoxic activities of Acetaminophen. Adalimumab Adalimumab may increase the immunosuppressive activities of Fingolimod. Ademetionine The metabolism of Fingolimod can be decreased when combined with Ademetionine. - Food Interactions
- Take with or without food.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Product Ingredients
Ingredient UNII CAS InChI Key Fingolimod hydrochloride G926EC510T 162359-56-0 SWZTYAVBMYWFGS-UHFFFAOYSA-N Fingolimod lauryl sulfate J3HZQ9BE2S 1967800-35-6 XTLZVNMZICNQBB-UHFFFAOYSA-N - International/Other Brands
- Gilenia
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Asn-fingolimod Capsule 0.5 mg Oral Ascend Laboratories Ltd Not applicable Not applicable Canada 
Fingolimod Accord Capsule 0.5 mg Oral Accord Healthcare S.L.U. 2021-01-12 Not applicable EU 
Fingolimod Accord Capsule 0.5 mg Oral Accord Healthcare S.L.U. 2021-01-12 Not applicable EU Fingolimod Accord Capsule 0.5 mg Oral Accord Healthcare S.L.U. 2021-01-12 Not applicable EU Fingolimod Accord Capsule 0.5 mg Oral Accord Healthcare S.L.U. 2021-01-12 Not applicable EU - Generic Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Ach-fingolimod Capsule 0.5 mg Oral Accord Healthcare Inc 2019-12-11 Not applicable Canada Apo-fingolimod Capsule 0.5 mg Oral Apotex Corporation 2019-11-01 Not applicable Canada Fingolimod Capsule 0.5 mg/1 Oral Aurobindo Pharma Limited 2024-02-28 Not applicable US 
Fingolimod Capsule 0.5 mg/1 Oral Glenmark Pharmaceuticals Inc., USA 2022-09-28 Not applicable US Fingolimod Capsule 0.5 mg/1 Oral Solco Healthcare US, LLC 2020-02-17 Not applicable US
Categories
- ATC Codes
- L04AE01 — Fingolimod
- Drug Categories
- Alcohols
- Amines
- Amino Alcohols
- Antineoplastic and Immunomodulating Agents
- Bradycardia-Causing Agents
- Cytochrome P-450 CYP2E1 Substrates
- Cytochrome P-450 Substrates
- Experimental Unapproved Treatments for COVID-19
- Glycols
- Immunologic Factors
- Immunomodulatory Agents
- Immunosuppressive Agents
- P-glycoprotein inducers
- P-glycoprotein inhibitors
- Propylene Glycols
- Selective Immunosuppressants
- Sphingosine 1 Phosphate Receptor Modulators
- Sphingosine 1-phosphate Receptor Modulator
- Sphingosine-1-phosphate (S1P) receptor modulators
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as aralkylamines. These are alkylamines in which the alkyl group is substituted at one carbon atom by an aromatic hydrocarbyl group.
- Kingdom
- Organic compounds
- Super Class
- Organic nitrogen compounds
- Class
- Organonitrogen compounds
- Sub Class
- Amines
- Direct Parent
- Aralkylamines
- Alternative Parents
- Benzene and substituted derivatives / 1,2-aminoalcohols / Primary alcohols / Organopnictogen compounds / Monoalkylamines / Hydrocarbon derivatives
- Substituents
- 1,2-aminoalcohol / Alcohol / Aralkylamine / Aromatic homomonocyclic compound / Benzenoid / Hydrocarbon derivative / Monocyclic benzene moiety / Organic oxygen compound / Organooxygen compound / Organopnictogen compound
- Molecular Framework
- Aromatic homomonocyclic compounds
- External Descriptors
- primary amino compound, aminodiol (CHEBI:63115)
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- 3QN8BYN5QF
- CAS number
- 162359-55-9
- InChI Key
- KKGQTZUTZRNORY-UHFFFAOYSA-N
- InChI
- 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
- IUPAC Name
- 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol
- SMILES
- CCCCCCCCC1=CC=C(CCC(N)(CO)CO)C=C1
References
- Synthesis Reference
Ramesh Matioram Gidwani, Channaveerayya Hiremath, "PROCESS FOR PRODUCING FINGOLIMOD SALTS." U.S. Patent US20120184617, issued July 19, 2012.
US20120184617- General References
- An X, Kezuka T, Usui Y, Matsunaga Y, Matsuda R, Yamakawa N, Goto H: Suppression of experimental autoimmune optic neuritis by the novel agent fingolimod. J Neuroophthalmol. 2013 Jun;33(2):143-8. doi: 10.1097/WNO.0b013e31828ea2fc. [Article]
- Ali R, Nicholas RS, Muraro PA: Drugs in development for relapsing multiple sclerosis. Drugs. 2013 May;73(7):625-50. doi: 10.1007/s40265-013-0030-6. [Article]
- Ghasemi N, Razavi S, Nikzad E: Multiple Sclerosis: Pathogenesis, Symptoms, Diagnoses and Cell-Based Therapy. Cell J. 2017 Apr-Jun;19(1):1-10. Epub 2016 Dec 21. [Article]
- Fakhoury M, Negrulj R, Mooranian A, Al-Salami H: Inflammatory bowel disease: clinical aspects and treatments. J Inflamm Res. 2014 Jun 23;7:113-20. doi: 10.2147/JIR.S65979. eCollection 2014. [Article]
- David OJ, Kovarik JM, Schmouder RL: Clinical pharmacokinetics of fingolimod. Clin Pharmacokinet. 2012 Jan 1;51(1):15-28. doi: 10.2165/11596550-000000000-00000. [Article]
- Tran JQ, Hartung JP, Tompkins CA, Frohna PA: Effects of High- and Low-Fat Meals on the Pharmacokinetics of Ozanimod, a Novel Sphingosine-1-Phosphate Receptor Modulator. Clin Pharmacol Drug Dev. 2018 Aug;7(6):634-640. doi: 10.1002/cpdd.409. Epub 2017 Nov 10. [Article]
- Dumont FJ: Fingolimod. Mitsubishi Pharma/Novartis. IDrugs. 2005 Mar;8(3):236-53. [Article]
- Stephenson M, Wong A, Rotella JA, Crump N, Kerr F, Greene SL: Deliberate fingolimod overdose presenting with delayed hypotension and bradycardia responsive to atropine. J Med Toxicol. 2014 Jun;10(2):215-8. doi: 10.1007/s13181-013-0354-3. [Article]
- Enjeti AK, D'Crus A, Melville K, Verrills NM, Rowlings P: A systematic evaluation of the safety and toxicity of fingolimod for its potential use in the treatment of acute myeloid leukaemia. Anticancer Drugs. 2016 Jul;27(6):560-8. doi: 10.1097/CAD.0000000000000358. [Article]
- Tran JQ, Hartung JP, Peach RJ, Boehm MF, Rosen H, Smith H, Brooks JL, Timony GA, Olson AD, Gujrathi S, Frohna PA: Results From the First-in-Human Study With Ozanimod, a Novel, Selective Sphingosine-1-Phosphate Receptor Modulator. J Clin Pharmacol. 2017 Aug;57(8):988-996. doi: 10.1002/jcph.887. Epub 2017 Apr 11. [Article]
- Chaudhry BZ, Cohen JA, Conway DS: Sphingosine 1-Phosphate Receptor Modulators for the Treatment of Multiple Sclerosis. Neurotherapeutics. 2017 Oct;14(4):859-873. doi: 10.1007/s13311-017-0565-4. [Article]
- FDA Approved Products: Gilenya (fingolimod) oral capsules [Link]
- Clinicaltrials.gov: Fingolimod in COVID-19 [Link]
- Clinical trials on drug repositioning for COVID-19 treatment [Link]
- European Medicines Agency Public Assessment Report: Gilenya (fingolimod) [Link]
- FDA Approved Drug Products: TASCENSO ODT (fingolimod) orally disintegrating tablets [Link]
- External Links
- Human Metabolome Database
- HMDB0252262
- KEGG Drug
- D10001
- PubChem Compound
- 107970
- PubChem Substance
- 175427125
- ChemSpider
- 97087
- BindingDB
- 50158336
- 1012892
- ChEBI
- 63115
- ChEMBL
- CHEMBL314854
- ZINC
- ZINC000001542002
- RxList
- RxList Drug Page
- Drugs.com
- Drugs.com Drug Page
- Wikipedia
- Fingolimod
- MSDS
- Download (351 KB)
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample dataNot Available Completed Not Available Relapsing Remitting Multiple Sclerosis (RRMS) 1 somestatus stop reason just information to hide 4 Active Not Recruiting Treatment Relapsing Multiple Sclerosis (RMS) 1 somestatus stop reason just information to hide 4 Active Not Recruiting Treatment Relapsing Remitting Multiple Sclerosis (RRMS) 1 somestatus stop reason just information to hide 4 Completed Basic Science Disorders of the Autonomic Nervous System / Multiple Sclerosis 1 somestatus stop reason just information to hide 4 Completed Basic Science Relapsing Multiple Sclerosis (RMS) 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet Oral 0.5 mg Capsule Oral 0.5 mg/1 Capsule Oral Capsule Oral 0.25 mg/1 Capsule Oral 0.25 mg Capsule Oral 0.560 mg Capsule Oral 0.5 mg Capsule, coated Oral 0.56 mg Capsule, coated Oral 0.5 mg Tablet, orally disintegrating Oral 0.25 mg/1 Tablet, orally disintegrating Oral 0.5 mg/1 - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US9187405 Yes 2015-11-17 2027-12-25 US US6004565 No 1999-12-21 2017-09-23 US US5604229 Yes 1997-02-18 2019-08-18 US US8324283 Yes 2012-12-04 2026-09-29 US US9592208 Yes 2017-03-14 2032-09-30 US US10543179 No 2020-01-28 2027-12-25 US US10555902 No 2020-02-11 2036-01-19 US US10925829 No 2021-02-23 2036-01-19 US US9925138 No 2018-03-27 2036-01-19 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) 102-107 https://www.chemicalbook.com/ChemicalProductProperty_US_CB4244536.aspx boiling point (°C) 479.5 https://www.lookchem.com/Fingolimod-hydrochloride/ water solubility Soluble https://www.chemicalbook.com/ChemicalProductProperty_US_CB4244536.aspx logP 5.5 https://www.ema.europa.eu/en/documents/variation-report/gilenya-h-c-2202-ii-0034-epar-assessment-report-variation_en.pdf pKa 8.0 https://www.ema.europa.eu/en/documents/variation-report/gilenya-h-c-2202-ii-0034-epar-assessment-report-variation_en.pdf - Predicted Properties
Property Value Source Water Solubility 0.0069 mg/mL ALOGPS logP 4 ALOGPS logP 4.06 Chemaxon logS -4.6 ALOGPS pKa (Strongest Acidic) 14.41 Chemaxon pKa (Strongest Basic) 9.38 Chemaxon Physiological Charge 1 Chemaxon Hydrogen Acceptor Count 3 Chemaxon Hydrogen Donor Count 3 Chemaxon Polar Surface Area 66.48 Å2 Chemaxon Rotatable Bond Count 12 Chemaxon Refractivity 93.28 m3·mol-1 Chemaxon Polarizability 38.81 Å3 Chemaxon Number of Rings 1 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
Property Value Probability Human Intestinal Absorption + 0.9884 Blood Brain Barrier + 0.5779 Caco-2 permeable - 0.5055 P-glycoprotein substrate Substrate 0.6975 P-glycoprotein inhibitor I Non-inhibitor 0.9505 P-glycoprotein inhibitor II Non-inhibitor 0.9391 Renal organic cation transporter Non-inhibitor 0.823 CYP450 2C9 substrate Non-substrate 0.8251 CYP450 2D6 substrate Non-substrate 0.6702 CYP450 3A4 substrate Non-substrate 0.7685 CYP450 1A2 substrate Inhibitor 0.5519 CYP450 2C9 inhibitor Non-inhibitor 0.8526 CYP450 2D6 inhibitor Inhibitor 0.6567 CYP450 2C19 inhibitor Non-inhibitor 0.8152 CYP450 3A4 inhibitor Non-inhibitor 0.7348 CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.8945 Ames test Non AMES toxic 0.8647 Carcinogenicity Non-carcinogens 0.8562 Biodegradation Not ready biodegradable 0.9062 Rat acute toxicity 1.9996 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.933 hERG inhibition (predictor II) Non-inhibitor 0.7302
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted GC-MS Spectrum - GC-MS Predicted GC-MS splash10-0006-9150000000-3d6345487f899f4e1abf Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-08ml-0191000000-9c6ffa7b8ae24dff9967 Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-0a4i-0019000000-28cd66a75d73e6802a1b Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-0a4i-1097000000-e3bea79fce7049db5fd6 Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-03k9-3190000000-d0e6692fbad5e14425e0 Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-0api-0290000000-0cf53114702ae7513701 Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-0le9-6910000000-f0013e3ba7363587cc3d Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 180.8063 predictedDeepCCS 1.0 (2019) [M+H]+ 183.16432 predictedDeepCCS 1.0 (2019) [M+Na]+ 189.32646 predictedDeepCCS 1.0 (2019)
Targets
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- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Antagonist
- General Function
- Dopamine receptor whose activity is mediated by G proteins which inhibit adenylyl cyclase. Promotes cell proliferation
- Specific Function
- Dopamine neurotransmitter receptor activity, coupled via gi/go
- Gene Name
- DRD3
- Uniprot ID
- P35462
- Uniprot Name
- D(3) dopamine receptor
- Molecular Weight
- 44194.315 Da
References
- Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Catalyzes the phosphorylation of sphingosine to form sphingosine 1-phosphate (SPP), a lipid mediator with both intra- and extracellular functions. Also acts on D-erythro-sphingosine and to a lesser extent sphinganine, but not other lipids, such as D,L-threo-dihydrosphingosine, N,N-dimethylsphingosine, diacylglycerol, ceramide, or phosphatidylinositol (PubMed:11923095, PubMed:20577214, PubMed:23602659, PubMed:24929359, PubMed:29662056). In contrast to proapoptotic SPHK2, has a negative effect on intracellular ceramide levels, enhances cell growth and inhibits apoptosis (PubMed:16118219). Involved in the regulation of inflammatory response and neuroinflammation. Via the product sphingosine 1-phosphate, stimulates TRAF2 E3 ubiquitin ligase activity, and promotes activation of NF-kappa-B in response to TNF signaling leading to IL17 secretion (PubMed:20577214). In response to TNF and in parallel to NF-kappa-B activation, negatively regulates RANTES induction through p38 MAPK signaling pathway (PubMed:23935096). Involved in endocytic membrane trafficking induced by sphingosine, recruited to dilate endosomes, also plays a role on later stages of endosomal maturation and membrane fusion independently of its kinase activity (PubMed:24929359, PubMed:28049734). In Purkinje cells, seems to be also involved in the regulation of autophagosome-lysosome fusion upon VEGFA (PubMed:25417698)
- Specific Function
- Acetyltransferase activity
- Gene Name
- SPHK1
- Uniprot ID
- Q9NYA1
- Uniprot Name
- Sphingosine kinase 1
- Molecular Weight
- 42517.245 Da
References
- Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Modulator
- General Function
- Receptor for the lysosphingolipid sphingosine 1-phosphate (S1P). S1P is a bioactive lysophospholipid that elicits diverse physiological effect on most types of cells and tissues. Is coupled to both the G(i/0)alpha and G(12) subclass of heteromeric G-proteins (By similarity). May play a regulatory role in the transformation of radial glial cells into astrocytes and may affect proliferative activity of these cells
- Specific Function
- G protein-coupled receptor activity
- Gene Name
- S1PR5
- Uniprot ID
- Q9H228
- Uniprot Name
- Sphingosine 1-phosphate receptor 5
- Molecular Weight
- 41774.515 Da
References
- Zu Heringdorf DM, Ihlefeld K, Pfeilschifter J: Pharmacology of the sphingosine-1-phosphate signalling system. Handb Exp Pharmacol. 2013;(215):239-53. doi: 10.1007/978-3-7091-1368-4_13. [Article]
- Bhabak KP, Arenz C: Novel drugs targeting sphingolipid metabolism. Handb Exp Pharmacol. 2013;(215):187-96. doi: 10.1007/978-3-7091-1368-4_10. [Article]
- FDA Approved Products: Gilenya (fingolimod) oral capsules [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Modulator
- General Function
- G-protein coupled receptor for the bioactive lysosphingolipid sphingosine 1-phosphate (S1P) that seems to be coupled to the G(i) subclass of heteromeric G proteins. Signaling leads to the activation of RAC1, SRC, PTK2/FAK1 and MAP kinases. Plays an important role in cell migration, probably via its role in the reorganization of the actin cytoskeleton and the formation of lamellipodia in response to stimuli that increase the activity of the sphingosine kinase SPHK1. Required for normal chemotaxis toward sphingosine 1-phosphate. Required for normal embryonic heart development and normal cardiac morphogenesis. Plays an important role in the regulation of sprouting angiogenesis and vascular maturation. Inhibits sprouting angiogenesis to prevent excessive sprouting during blood vessel development. Required for normal egress of mature T-cells from the thymus into the blood stream and into peripheral lymphoid organs. Plays a role in the migration of osteoclast precursor cells, the regulation of bone mineralization and bone homeostasis (By similarity). Plays a role in responses to oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine by pulmonary endothelial cells and in the protection against ventilator-induced lung injury
- Specific Function
- G protein-coupled receptor activity
- Gene Name
- S1PR1
- Uniprot ID
- P21453
- Uniprot Name
- Sphingosine 1-phosphate receptor 1
- Molecular Weight
- 42810.195 Da
References
- David OJ, Kovarik JM, Schmouder RL: Clinical pharmacokinetics of fingolimod. Clin Pharmacokinet. 2012 Jan 1;51(1):15-28. doi: 10.2165/11596550-000000000-00000. [Article]
- Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]
- FDA Approved Products: Gilenya (fingolimod) oral capsules [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Modulator
- General Function
- Receptor for the lysosphingolipid sphingosine 1-phosphate (S1P). S1P is a bioactive lysophospholipid that elicits diverse physiological effect on most types of cells and tissues. When expressed in rat HTC4 hepatoma cells, is capable of mediating S1P-induced cell proliferation and suppression of apoptosis
- Specific Function
- G protein-coupled receptor activity
- Gene Name
- S1PR3
- Uniprot ID
- Q99500
- Uniprot Name
- Sphingosine 1-phosphate receptor 3
- Molecular Weight
- 42249.805 Da
References
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Histone deacetylase that catalyzes the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4) (PubMed:16762839, PubMed:17704056, PubMed:28497810). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events (PubMed:16762839, PubMed:17704056). Histone deacetylases act via the formation of large multiprotein complexes (PubMed:16762839, PubMed:17704056). Acts as a component of the histone deacetylase NuRD complex which participates in the remodeling of chromatin (PubMed:16428440, PubMed:28977666). As part of the SIN3B complex is recruited downstream of the constitutively active genes transcriptional start sites through interaction with histones and mitigates histone acetylation and RNA polymerase II progression within transcribed regions contributing to the regulation of transcription (PubMed:21041482). Also functions as a deacetylase for non-histone targets, such as NR1D2, RELA, SP1, SP3, STAT3 and TSHZ3 (PubMed:12837748, PubMed:16285960, PubMed:16478997, PubMed:17996965, PubMed:19343227). Deacetylates SP proteins, SP1 and SP3, and regulates their function (PubMed:12837748, PubMed:16478997). Component of the BRG1-RB1-HDAC1 complex, which negatively regulates the CREST-mediated transcription in resting neurons (PubMed:19081374). Upon calcium stimulation, HDAC1 is released from the complex and CREBBP is recruited, which facilitates transcriptional activation (PubMed:19081374). Deacetylates TSHZ3 and regulates its transcriptional repressor activity (PubMed:19343227). Deacetylates 'Lys-310' in RELA and thereby inhibits the transcriptional activity of NF-kappa-B (PubMed:17000776). Deacetylates NR1D2 and abrogates the effect of KAT5-mediated relieving of NR1D2 transcription repression activity (PubMed:17996965). Component of a RCOR/GFI/KDM1A/HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development (By similarity). Involved in CIART-mediated transcriptional repression of the circadian transcriptional activator: CLOCK-BMAL1 heterodimer (By similarity). Required for the transcriptional repression of circadian target genes, such as PER1, mediated by the large PER complex or CRY1 through histone deacetylation (By similarity). In addition to protein deacetylase activity, also has protein-lysine deacylase activity: acts as a protein decrotonylase by mediating decrotonylation ((2E)-butenoyl) of histones (PubMed:28497810)
- Specific Function
- Core promoter sequence-specific dna binding
- Gene Name
- HDAC1
- Uniprot ID
- Q13547
- Uniprot Name
- Histone deacetylase 1
- Molecular Weight
- 55102.615 Da
References
- Hait NC, Wise LE, Allegood JC, O'Brien M, Avni D, Reeves TM, Knapp PE, Lu J, Luo C, Miles MF, Milstien S, Lichtman AH, Spiegel S: Active, phosphorylated fingolimod inhibits histone deacetylases and facilitates fear extinction memory. Nat Neurosci. 2014 Jul;17(7):971-80. doi: 10.1038/nn.3728. Epub 2014 May 25. [Article]
- Hait NC, Avni D, Yamada A, Nagahashi M, Aoyagi T, Aoki H, Dumur CI, Zelenko Z, Gallagher EJ, Leroith D, Milstien S, Takabe K, Spiegel S: The phosphorylated prodrug FTY720 is a histone deacetylase inhibitor that reactivates ERalpha expression and enhances hormonal therapy for breast cancer. Oncogenesis. 2015 Jun 8;4:e156. doi: 10.1038/oncsis.2015.16. [Article]
- Perla AS, Fratini L, Cardoso PS, de Farias CB, da Cunha Jaeger M, Roesler R: Fingolimod (FTY720) reduces viability and survival and increases histone H3 acetylation in medulloblastoma cells. Pediatr Hematol Oncol. 2020 Mar;37(2):170-175. doi: 10.1080/08880018.2019.1699213. Epub 2019 Dec 11. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Modulator
- General Function
- Receptor for the lysosphingolipid sphingosine 1-phosphate (S1P). S1P is a bioactive lysophospholipid that elicits diverse physiological effect on most types of cells and tissues. May be involved in cell migration processes that are specific for lymphocytes
- Specific Function
- G protein-coupled receptor activity
- Gene Name
- S1PR4
- Uniprot ID
- O95977
- Uniprot Name
- Sphingosine 1-phosphate receptor 4
- Molecular Weight
- 41622.525 Da
References
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInhibitor
- General Function
- Catalyzes the phosphorylation of sphingosine to form sphingosine 1-phosphate (SPP), a lipid mediator with both intra- and extracellular functions. Also acts on D-erythro-sphingosine and to a lesser extent sphinganine, but not other lipids, such as D,L-threo-dihydrosphingosine, N,N-dimethylsphingosine, diacylglycerol, ceramide, or phosphatidylinositol (PubMed:11923095, PubMed:20577214, PubMed:23602659, PubMed:24929359, PubMed:29662056). In contrast to proapoptotic SPHK2, has a negative effect on intracellular ceramide levels, enhances cell growth and inhibits apoptosis (PubMed:16118219). Involved in the regulation of inflammatory response and neuroinflammation. Via the product sphingosine 1-phosphate, stimulates TRAF2 E3 ubiquitin ligase activity, and promotes activation of NF-kappa-B in response to TNF signaling leading to IL17 secretion (PubMed:20577214). In response to TNF and in parallel to NF-kappa-B activation, negatively regulates RANTES induction through p38 MAPK signaling pathway (PubMed:23935096). Involved in endocytic membrane trafficking induced by sphingosine, recruited to dilate endosomes, also plays a role on later stages of endosomal maturation and membrane fusion independently of its kinase activity (PubMed:24929359, PubMed:28049734). In Purkinje cells, seems to be also involved in the regulation of autophagosome-lysosome fusion upon VEGFA (PubMed:25417698)
- Specific Function
- Acetyltransferase activity
- Gene Name
- SPHK1
- Uniprot ID
- Q9NYA1
- Uniprot Name
- Sphingosine kinase 1
- Molecular Weight
- 42517.245 Da
References
- Pchejetski D, Bohler T, Brizuela L, Sauer L, Doumerc N, Golzio M, Salunkhe V, Teissie J, Malavaud B, Waxman J, Cuvillier O: FTY720 (fingolimod) sensitizes prostate cancer cells to radiotherapy by inhibition of sphingosine kinase-1. Cancer Res. 2010 Nov 1;70(21):8651-61. doi: 10.1158/0008-5472.CAN-10-1388. Epub 2010 Oct 19. [Article]
- Paugh SW, Payne SG, Barbour SE, Milstien S, Spiegel S: The immunosuppressant FTY720 is phosphorylated by sphingosine kinase type 2. FEBS Lett. 2003 Nov 6;554(1-2):189-93. doi: 10.1016/s0014-5793(03)01168-2. [Article]
- Spijkers LJ, Alewijnse AE, Peters SL: FTY720 (fingolimod) increases vascular tone and blood pressure in spontaneously hypertensive rats via inhibition of sphingosine kinase. Br J Pharmacol. 2012 Jun;166(4):1411-8. doi: 10.1111/j.1476-5381.2012.01865.x. [Article]
- FDA Approved Products: Gilenya (fingolimod) oral capsules [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of fatty acids (PubMed:10553002, PubMed:18577768). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:10553002, PubMed:18577768). Catalyzes the hydroxylation of carbon-hydrogen bonds. Hydroxylates fatty acids specifically at the omega-1 position displaying the highest catalytic activity for saturated fatty acids (PubMed:10553002, PubMed:18577768). May be involved in the oxidative metabolism of xenobiotics (Probable)
- Specific Function
- 4-nitrophenol 2-monooxygenase activity
- Gene Name
- CYP2E1
- Uniprot ID
- P05181
- Uniprot Name
- Cytochrome P450 2E1
- Molecular Weight
- 56848.42 Da
References
- Jin Y, Zollinger M, Borell H, Zimmerlin A, Patten CJ: CYP4F enzymes are responsible for the elimination of fingolimod (FTY720), a novel treatment of relapsing multiple sclerosis. Drug Metab Dispos. 2011 Feb;39(2):191-8. doi: 10.1124/dmd.110.035378. Epub 2010 Nov 2. [Article]
- European Medicines Agency Public Assessment Report: Gilenya (fingolimod) [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInducer
- Curator comments
- Therapeutic doses of fingolimod are not expected to have significant induction effects on this enzyme.
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, eicosanoids and vitamins (PubMed:10660572, PubMed:10833273, PubMed:11997390, PubMed:17341693, PubMed:18574070, PubMed:18577768). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (CPR; NADPH-ferrihemoprotein reductase). Catalyzes predominantly the oxidation of the terminal carbon (omega-oxidation) of long- and very long-chain fatty acids. Displays high omega-hydroxylase activity toward polyunsaturated fatty acids (PUFAs) (PubMed:18577768). Participates in the conversion of arachidonic acid to omega-hydroxyeicosatetraenoic acid (20-HETE), a signaling molecule acting both as vasoconstrictive and natriuretic with overall effect on arterial blood pressure (PubMed:10660572, PubMed:17341693, PubMed:18574070). Plays a role in the oxidative inactivation of eicosanoids, including both pro-inflammatory and anti-inflammatory mediators such as leukotriene B4 (LTB4), lipoxin A4 (LXA4), and several HETEs (PubMed:10660572, PubMed:10833273, PubMed:17341693, PubMed:18574070, PubMed:18577768, PubMed:8026587, PubMed:9799565). Catalyzes omega-hydroxylation of 3-hydroxy fatty acids (PubMed:18065749). Converts monoepoxides of linoleic acid leukotoxin and isoleukotoxin to omega-hydroxylated metabolites (PubMed:15145985). Contributes to the degradation of very long-chain fatty acids (VLCFAs) by catalyzing successive omega-oxidations and chain shortening (PubMed:16547005, PubMed:18182499). Plays an important role in vitamin metabolism by chain shortening. Catalyzes omega-hydroxylation of the phytyl chain of tocopherols (forms of vitamin E), with preference for gamma-tocopherols over alpha-tocopherols, thus promoting retention of alpha-tocopherols in tissues (PubMed:11997390). Omega-hydroxylates and inactivates phylloquinone (vitamin K1), and menaquinone-4 (MK-4, a form of vitamin K2), both acting as cofactors in blood coagulation (PubMed:19297519, PubMed:24138531)
- Specific Function
- 20-aldehyde-leukotriene b4 20-monooxygenase activity
- Gene Name
- CYP4F2
- Uniprot ID
- P78329
- Uniprot Name
- Cytochrome P450 4F2
- Molecular Weight
- 59852.825 Da
References
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inducer
- Curator comments
- There are limited data in the literature regarding this transporter action.
- General Function
- Sodium-dependent, high-affinity amino acid transporter that mediates the uptake of L-glutamate and also L-aspartate and D-aspartate (PubMed:14506254, PubMed:15265858, PubMed:26690923, PubMed:7521911). Functions as a symporter that transports one amino acid molecule together with two or three Na(+) ions and one proton, in parallel with the counter-transport of one K(+) ion (PubMed:14506254). Mediates Cl(-) flux that is not coupled to amino acid transport; this avoids the accumulation of negative charges due to aspartate and Na(+) symport (PubMed:14506254). Essential for the rapid removal of released glutamate from the synaptic cleft, and for terminating the postsynaptic action of glutamate (By similarity)
- Specific Function
- Cysteine transmembrane transporter activity
- Gene Name
- SLC1A2
- Uniprot ID
- P43004
- Uniprot Name
- Excitatory amino acid transporter 2
- Molecular Weight
- 62103.665 Da
References
- Lee DH, Seubert S, Huhn K, Brecht L, Rotger C, Waschbisch A, Schlachetzki J, Klausmeyer A, Melms A, Wiese S, Winkler J, Linker RA: Fingolimod effects in neuroinflammation: Regulation of astroglial glutamate transporters? PLoS One. 2017 Mar 8;12(3):e0171552. doi: 10.1371/journal.pone.0171552. eCollection 2017. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inducer
- Curator comments
- There are limited data in the literature regarding this transporter action.
- General Function
- Sodium-dependent, high-affinity amino acid transporter that mediates the uptake of L-glutamate and also L-aspartate and D-aspartate (PubMed:20477940, PubMed:26690923, PubMed:28032905, PubMed:28424515, PubMed:7521911, PubMed:8123008). Functions as a symporter that transports one amino acid molecule together with two or three Na(+) ions and one proton, in parallel with the counter-transport of one K(+) ion (PubMed:20477940). Mediates Cl(-) flux that is not coupled to amino acid transport; this avoids the accumulation of negative charges due to aspartate and Na(+) symport (PubMed:20477940). Plays a redundant role in the rapid removal of released glutamate from the synaptic cleft, which is essential for terminating the postsynaptic action of glutamate (By similarity)
- Specific Function
- Glutamate binding
- Gene Name
- SLC1A3
- Uniprot ID
- P43003
- Uniprot Name
- Excitatory amino acid transporter 1
- Molecular Weight
- 59571.855 Da
References
- Lee DH, Seubert S, Huhn K, Brecht L, Rotger C, Waschbisch A, Schlachetzki J, Klausmeyer A, Melms A, Wiese S, Winkler J, Linker RA: Fingolimod effects in neuroinflammation: Regulation of astroglial glutamate transporters? PLoS One. 2017 Mar 8;12(3):e0171552. doi: 10.1371/journal.pone.0171552. eCollection 2017. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- General Function
- Translocates drugs and phospholipids across the membrane (PubMed:2897240, PubMed:35970996, PubMed:8898203, PubMed:9038218). Catalyzes the flop of phospholipids from the cytoplasmic to the exoplasmic leaflet of the apical membrane. Participates mainly to the flop of phosphatidylcholine, phosphatidylethanolamine, beta-D-glucosylceramides and sphingomyelins (PubMed:8898203). Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells (PubMed:2897240, PubMed:35970996, PubMed:9038218)
- Specific Function
- Abc-type xenobiotic transporter activity
- Gene Name
- ABCB1
- Uniprot ID
- P08183
- Uniprot Name
- ATP-dependent translocase ABCB1
- Molecular Weight
- 141477.255 Da
References
- di Nuzzo L, Orlando R, Nasca C, Nicoletti F: Molecular pharmacodynamics of new oral drugs used in the treatment of multiple sclerosis. Drug Des Devel Ther. 2014 May 19;8:555-68. doi: 10.2147/DDDT.S52428. eCollection 2014. [Article]
- Xing Y, Wang ZH, Ma DH, Han Y: FTY720 enhances chemosensitivity of colon cancer cells to doxorubicin and etoposide via the modulation of P-glycoprotein and multidrug resistance protein 1. J Dig Dis. 2014 May;15(5):246-59. doi: 10.1111/1751-2980.12131. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- InhibitorInducer
- Curator comments
- Data regarding this transporter action are conflicting in the literature.
- General Function
- Mediates export of organic anions and drugs from the cytoplasm (PubMed:10064732, PubMed:11114332, PubMed:16230346, PubMed:7961706, PubMed:9281595). Mediates ATP-dependent transport of glutathione and glutathione conjugates, leukotriene C4, estradiol-17-beta-o-glucuronide, methotrexate, antiviral drugs and other xenobiotics (PubMed:10064732, PubMed:11114332, PubMed:16230346, PubMed:7961706, PubMed:9281595). Confers resistance to anticancer drugs by decreasing accumulation of drug in cells, and by mediating ATP- and GSH-dependent drug export (PubMed:9281595). Hydrolyzes ATP with low efficiency (PubMed:16230346). Catalyzes the export of sphingosine 1-phosphate from mast cells independently of their degranulation (PubMed:17050692). Participates in inflammatory response by allowing export of leukotriene C4 from leukotriene C4-synthezing cells (By similarity). Mediates ATP-dependent, GSH-independent cyclic GMP-AMP (cGAMP) export (PubMed:36070769). Thus, by limiting intracellular cGAMP concentrations negatively regulates the cGAS-STING pathway (PubMed:36070769)
- Specific Function
- Abc-type glutathione s-conjugate transporter activity
- Gene Name
- ABCC1
- Uniprot ID
- P33527
- Uniprot Name
- Multidrug resistance-associated protein 1
- Molecular Weight
- 171589.5 Da
References
- Honig SM, Fu S, Mao X, Yopp A, Gunn MD, Randolph GJ, Bromberg JS: FTY720 stimulates multidrug transporter- and cysteinyl leukotriene-dependent T cell chemotaxis to lymph nodes. J Clin Invest. 2003 Mar;111(5):627-37. doi: 10.1172/JCI16200. [Article]
- Xing Y, Wang ZH, Ma DH, Han Y: FTY720 enhances chemosensitivity of colon cancer cells to doxorubicin and etoposide via the modulation of P-glycoprotein and multidrug resistance protein 1. J Dig Dis. 2014 May;15(5):246-59. doi: 10.1111/1751-2980.12131. [Article]
Drug created at April 28, 2013 20:17 / Updated at September 10, 2024 07:06