Identification

Name
Fingolimod
Accession Number
DB08868
Type
Small Molecule
Groups
Approved, Investigational
Description

Fingolimod is a sphingosine 1-phosphate receptor modulator indicated and approved for the treatment of relapsing-remitting multiple sclerosis.

Structure
Thumb
Synonyms
  • fingolimod
  • Fingolimodum
External IDs
FTY-720A / FTY720
Product Ingredients
IngredientUNIICASInChI Key
Fingolimod hydrochlorideG926EC510T162359-56-0SWZTYAVBMYWFGS-UHFFFAOYSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
GilenyaCapsule0.5 mgOralNovartis2011-03-28Not applicableCanada
GilenyaCapsule0.5 mgOralNovartis Europharm Limited2011-03-17Not applicableEu
GilenyaCapsule0.25 mg/1OralNovartis Pharmaceuticals Corporation2010-09-21Not applicableUs
GilenyaCapsule0.5 mgOralNovartis Europharm Limited2011-03-17Not applicableEu
GilenyaCapsule0.5 mgOralNovartis Europharm Limited2011-03-17Not applicableEu
GilenyaCapsule0.5 mgOralNovartis Europharm Limited2011-03-17Not applicableEu
GilenyaCapsule0.5 mg/1OralNovartis Pharmaceuticals Corporation2010-09-21Not applicableUs
GilenyaCapsule0.5 mgOralNovartis Europharm Limited2011-03-17Not applicableEu
GilenyaCapsule0.5 mgOralNovartis Europharm Limited2011-03-17Not applicableEu
International/Other Brands
Gilenia
Categories
UNII
3QN8BYN5QF
CAS number
162359-55-9
Weight
Average: 307.4708
Monoisotopic: 307.251129305
Chemical Formula
C19H33NO2
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

Pharmacology

Indication

Fingolimod is a sphingosine 1-phosphate receptor modulator indicated for the treatment of patients with relapsing forms of multiple sclerosis to reduce the frequency of clinical exacerbations and to delay the accumulation of physical disability.

Associated Conditions
Pharmacodynamics

Fingolimod causes a transient reduction in heart rate and AV conduction at treatment initiation. Potential to prolong the QT interval. Effects on immune cell numbers in the blood- decreased lymphocyte counts. Mild decrease in the neutrophil count- about 80% of original pre-therapy count. Compared to placebo, antigen-specific IgM titers were decreased by 91% and 25% in response to KLH and PPV, respectively. IgG titers were decreased by 45% and 50%, in response to KLH and PPV. The capacity to mount a skin delayed-type hypersensitivity reaction to Candida and tetanus toxoid was decreased by approximately 30% in subjects on fingolimod 0.5 mg daily, compared to placebo. Immunologic responses were further decreased with fingolimod 1.25 mg (a dose higher than recommended for MS). Single fingolimod doses ≥5 mg (10-fold the recommended dose) are associated with a dose-dependent increase in airway resistance.

Mechanism of action

Fingolimod is metabolized by sphingosine kinase to the active metabolite, fingolimod-phosphate. Fingolimod-phosphate is a sphingosine 1-phosphate receptor modulator, and binds with high affinity to sphingosine 1-phosphate receptors 1, 3, 4, and 5. Fingolimod-phosphate blocks the capacity of lymphocytes to egress from lymph nodes, reducing the number of lymphocytes in peripheral blood. The mechanism by which fingolimod exerts therapeutic effects in multiple sclerosis is unknown, but may involve reduction of lymphocyte migration into the central nervous system.

TargetActionsOrganism
ASphingosine 1-phosphate receptor 5
modulator
Human
UHistone deacetylase 1
inhibitor
Human
Absorption

The Tmax of fingolimod is 12-16 hours. Bioavailability: 93%

Volume of distribution

about 1200±260 L.

Protein binding

>99.7%

Metabolism

3 main pathways: -reversible stereoselective phosphorylation to the pharmacologically active (S)-enantiomer of fingolimod-phosphate. -oxidative biotransformation mainly via the cytochrome P450 4F2 isoenzyme and subsequent fatty acid-like degradation to inactive metabolites. -by formation of pharmacologically inactive non-polar ceramide analogs of fingolimod.

Route of elimination
Not Available
Half life

6-9 days

Clearance

Fingolimod blood clearance is 6.3±2.3 L/h.

Toxicity

Bradyarrhythmia and Atrioventricular Blocks Risk of infections Macular Edema Respiratory Effects Hepatic Effects
Fetal Risk Blood Pressure Effects Immune System Effects Following Fingolimod Discontinuation

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
2-MethoxyethanolThe risk or severity of adverse effects can be increased when 2-Methoxyethanol is combined with Fingolimod.
9-(N-methyl-L-isoleucine)-cyclosporin AThe risk or severity of adverse effects can be increased when Fingolimod is combined with 9-(N-methyl-L-isoleucine)-cyclosporin A.
AbataceptThe risk or severity of adverse effects can be increased when Abatacept is combined with Fingolimod.
AbetimusThe risk or severity of adverse effects can be increased when Abetimus is combined with Fingolimod.
AbexinostatThe risk or severity of QTc prolongation can be increased when Fingolimod is combined with Abexinostat.
AcebutololAcebutolol may increase the bradycardic activities of Fingolimod.
AceprometazineThe risk or severity of QTc prolongation can be increased when Fingolimod is combined with Aceprometazine.
AcetyldigoxinThe risk or severity of QTc prolongation can be increased when Fingolimod is combined with Acetyldigoxin.
AcrivastineThe risk or severity of QTc prolongation can be increased when Fingolimod is combined with Acrivastine.
ActeosideThe risk or severity of adverse effects can be increased when Fingolimod is combined with Acteoside.
Food Interactions
Not Available

References

Synthesis Reference

Ramesh Matioram Gidwani, Channaveerayya Hiremath, "PROCESS FOR PRODUCING FINGOLIMOD SALTS." U.S. Patent US20120184617, issued July 19, 2012.

US20120184617
General References
  1. 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. [PubMed:23609767]
  2. 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. [PubMed:23609782]
External Links
KEGG Drug
D10001
PubChem Compound
107970
PubChem Substance
175427125
ChemSpider
97087
BindingDB
50158336
ChEBI
63115
ChEMBL
CHEMBL314854
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Fingolimod
ATC Codes
L04AA27 — Fingolimod
AHFS Codes
  • 92:44.00 — Immunosuppressive Agents
FDA label
Download (423 KB)
MSDS
Download (351 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0CompletedOtherAnaplastic Astrocytoma (AA) / Glioblastomas1
1CompletedNot AvailableImpaired Renal Function1
1CompletedNot AvailableRelapsing Remitting Multiple Sclerosis (RRMS)1
1CompletedTreatmentAutoimmune Diseases / Disseminated or Multiple Sclerosis Nos / Disseminated Sclerosis / Multiple Sclerosis, Acute Relapsing / Multiple Sclerosis, Chronic Progressive / Multiple Sclerosis, Primary Progressive1
1CompletedTreatmentHealthy Volunteers1
1, 2CompletedTreatmentRett's Syndrome1
2Active Not RecruitingTreatmentSchizophrenic Disorders1
2CompletedTreatmentAmyotrophic Lateral Sclerosis (ALS)1
2CompletedTreatmentAsthma Bronchial1
2CompletedTreatmentCerebral Stroke / Ischemic Cerebrovascular Accident / Stroke, Acute / Strokes / Vascular Accident1
2CompletedTreatmentDisseminated Sclerosis3
2CompletedTreatmentTransplantation, Renal2
2Not Yet RecruitingTreatmentInflammatory Reaction / Strokes1
2TerminatedTreatmentAcute Demylelinating Optic Neuritis1
2WithdrawnTreatmentAcute Noninfectious Posterior, Intermediate, or Pan Uveitis1
2, 3CompletedTreatmentDisseminated Sclerosis1
2, 3RecruitingTreatmentDisseminated Sclerosis / Relapsing Remitting Multiple Sclerosis (RRMS)1
2, 3TerminatedTreatmentDisseminated Sclerosis1
3Active Not RecruitingTreatmentDisseminated Sclerosis1
3CompletedTreatmentDisseminated Sclerosis4
3CompletedTreatmentMultiple Sclerosis, Primary Progressive2
3CompletedTreatmentPolyradiculoneuropathy, Chronic Inflammatory Demyelinating1
3CompletedTreatmentRelapsing Forms of Multiple Sclerosis1
3CompletedTreatmentRelapsing Multiple Sclerosis (RMS)2
3CompletedTreatmentRelapsing Remitting Multiple Sclerosis (RRMS)1
3CompletedTreatmentTransplantation, Kidney3
3CompletedTreatmentTransplantation, Renal4
3TerminatedTreatmentRelapsing Remitting Multiple Sclerosis (RRMS)1
3WithdrawnTreatmentRelapsing Remitting Multiple Sclerosis (RRMS)1
4CompletedBasic ScienceAutonomic Nervous System Dysfunction / Disseminated Sclerosis1
4CompletedBasic ScienceRelapsing Remitting Multiple Sclerosis (RRMS)1
4CompletedSupportive CareDisseminated Sclerosis / Relapsing-Remitting1
4CompletedTreatmentDisseminated Sclerosis2
4CompletedTreatmentRelapsing Forms of Multiple Sclerosis1
4CompletedTreatmentRelapsing Remitting Multiple Sclerosis (RRMS)7
4Not Yet RecruitingTreatmentRelapsing Remitting Multiple Sclerosis (RRMS)1
4RecruitingBasic ScienceRelapsing Multiple Sclerosis (RMS)1
4RecruitingOtherDisseminated Sclerosis1
4RecruitingTreatmentRelapsing Remitting Multiple Sclerosis (RRMS)1
4TerminatedTreatmentDepression / Relapsing Remitting Multiple Sclerosis (RRMS)1
4TerminatedTreatmentRelapsing Remitting Multiple Sclerosis (RRMS)2
4Unknown StatusTreatmentRelapsing Remitting Multiple Sclerosis (RRMS)1
4WithdrawnTreatmentDisseminated Sclerosis1
Not AvailableCompletedNot AvailableDisseminated Sclerosis2
Not AvailableCompletedNot AvailableRelapsing Remitting Multiple Sclerosis (RRMS)1
Not AvailableRecruitingNot AvailableDisseminated Sclerosis3
Not AvailableRecruitingNot AvailableRelapsing Remitting Multiple Sclerosis (RRMS)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
CapsuleOral0.25 mg/1
CapsuleOral0.5 mg
CapsuleOral0.5 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US9187405Yes2015-11-172027-12-25Us
US6004565No1999-12-212017-09-23Us
US5604229Yes1997-02-182019-08-18Us
US8324283Yes2012-12-042026-09-29Us
US9592208Yes2017-03-142032-09-30Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
boiling point (°C)479.498 °C at 760 mmHgACD/PhysChem
water solubilitySolublehttp://www.medsafe.govt.nz/profs/datasheet/g/gilenyacap.pdf
logP4.178ACD/PhysChem
Predicted Properties
PropertyValueSource
Water Solubility0.0069 mg/mLALOGPS
logP4ALOGPS
logP4.06ChemAxon
logS-4.6ALOGPS
pKa (Strongest Acidic)14.41ChemAxon
pKa (Strongest Basic)9.38ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area66.48 Å2ChemAxon
Rotatable Bond Count12ChemAxon
Refractivity93.28 m3·mol-1ChemAxon
Polarizability38.81 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9884
Blood Brain Barrier+0.5779
Caco-2 permeable-0.5055
P-glycoprotein substrateSubstrate0.6975
P-glycoprotein inhibitor INon-inhibitor0.9505
P-glycoprotein inhibitor IINon-inhibitor0.9391
Renal organic cation transporterNon-inhibitor0.823
CYP450 2C9 substrateNon-substrate0.8251
CYP450 2D6 substrateNon-substrate0.6702
CYP450 3A4 substrateNon-substrate0.7685
CYP450 1A2 substrateInhibitor0.5519
CYP450 2C9 inhibitorNon-inhibitor0.8526
CYP450 2D6 inhibitorInhibitor0.6567
CYP450 2C19 inhibitorNon-inhibitor0.8152
CYP450 3A4 inhibitorNon-inhibitor0.7348
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8945
Ames testNon AMES toxic0.8647
CarcinogenicityNon-carcinogens0.8562
BiodegradationNot ready biodegradable0.9062
Rat acute toxicity1.9996 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.933
hERG inhibition (predictor II)Non-inhibitor0.7302
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

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
Aralkylamine / Benzenoid / Monocyclic benzene moiety / 1,2-aminoalcohol / Organic oxygen compound / Organopnictogen compound / Hydrocarbon derivative / Primary amine / Primary alcohol / Organooxygen compound
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
primary amino compound, aminodiol (CHEBI:63115)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Modulator
General Function
Sphingosine-1-phosphate receptor activity
Specific 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...
Gene Name
S1PR5
Uniprot ID
Q9H228
Uniprot Name
Sphingosine 1-phosphate receptor 5
Molecular Weight
41774.515 Da
References
  1. 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. [PubMed:23579459]
  2. 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. [PubMed:23579456]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Transcription regulatory region sequence-specific dna binding
Specific Function
Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an impo...
Gene Name
HDAC1
Uniprot ID
Q13547
Uniprot Name
Histone deacetylase 1
Molecular Weight
55102.615 Da
References
  1. 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. [PubMed:24859201]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Not Available
Specific Function
Not Available
Gene Name
CYP4F2
Uniprot ID
P78329
Uniprot Name
Phylloquinone omega-hydroxylase CYP4F2
Molecular Weight
59852.825 Da
References
  1. Link [Link]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Sphingosine-1-phosphate receptor activity
Specific 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...
Gene Name
SPHK1
Uniprot ID
Q9NYA1
Uniprot Name
Sphingosine kinase 1
Molecular Weight
42517.245 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Metabolizes several precarcinogens, drugs, and solvents to reactive metabolites. Inactivates a number of drugs and xenobiotics and also bioactivates many xenobiotic substrates to their hepatotoxic ...
Gene Name
CYP2E1
Uniprot ID
P05181
Uniprot Name
Cytochrome P450 2E1
Molecular Weight
56848.42 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Leukotriene-b4 20-monooxygenase activity
Specific Function
Catalyzes leukotriene B4 omega-hydroxylation and arachidonic acid omega-hydroxylation but with an activity much lower than that of CYP4F2. Catalyzes the hydroxylation of the antihistamine ebastine.
Gene Name
CYP4F12
Uniprot ID
Q9HCS2
Uniprot Name
Cytochrome P450 4F12
Molecular Weight
60269.165 Da

Drug created on April 28, 2013 14:17 / Updated on December 10, 2018 13:39