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Identification
NameFingolimod
Accession NumberDB08868
TypeSmall Molecule
GroupsApproved, Investigational
Description

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

Structure
Thumb
Synonyms
Fingolimodum
External Identifiers
  • FTY-720A
  • FTY720
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Gilenyacapsule.5 mg/1oralNovartis Pharmaceuticals Corporation2010-09-21Not applicableUs
Gilenyacapsule0.5 mgoralNovartis Pharmaceuticals Canada Inc2011-03-28Not applicableCanada
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
GileniaNot Available
Brand mixturesNot Available
Salts
Name/CASStructureProperties
Fingolimod Hydrochloride
162359-56-0
Thumb
  • InChI Key: SWZTYAVBMYWFGS-UHFFFAOYSA-N
  • Monoisotopic Mass: 343.227807044
  • Average Mass: 343.932
DBSALT000580
Categories
UNII3QN8BYN5QF
CAS number162359-55-9
WeightAverage: 307.4708
Monoisotopic: 307.251129305
Chemical FormulaC19H33NO2
InChI KeyKKGQTZUTZRNORY-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
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as phenylpropylamines. These are compounds containing a phenylpropylamine moiety, which consists of a phenyl group substituted at the third carbon by an propan-1-amine.
KingdomOrganic compounds
Super ClassBenzenoids
ClassBenzene and substituted derivatives
Sub ClassPhenylpropylamines
Direct ParentPhenylpropylamines
Alternative Parents
Substituents
  • Phenylpropylamine
  • Aralkylamine
  • 1,2-aminoalcohol
  • Hydrocarbon derivative
  • Primary amine
  • Primary alcohol
  • Organooxygen compound
  • Organonitrogen compound
  • Primary aliphatic amine
  • Amine
  • Alcohol
  • Aromatic homomonocyclic compound
Molecular FrameworkAromatic homomonocyclic compounds
External Descriptors
Pharmacology
IndicationFingolimod 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.
PharmacodynamicsFingolimod 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 actionFingolimod 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.
Related Articles
AbsorptionThe 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 eliminationNot Available
Half life6-9 days
Clearance

Fingolimod blood clearance is 6.3±2.3 L/h.

ToxicityBradyarrhythmia 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
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
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 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
Capsuleoral.5 mg/1
Capsuleoral0.5 mg
PricesNot Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US5604229 No1999-02-182019-02-18Us
US6004565 No1997-09-232017-09-23Us
US8324283 No2006-03-292026-03-29Us
US9187405 No2007-06-252027-06-25Us
Properties
StateSolid
Experimental Properties
PropertyValueSource
boiling point479.498 °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-4.7ALOGPS
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 RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot 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
ATC CodesL04AA27
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelDownload (423 KB)
MSDSDownload (351 KB)
Interactions
Drug Interactions
Drug
AcebutololAcebutolol may increase the bradycardic activities of Fingolimod.
AmiodaroneFingolimod may increase the arrhythmogenic activities of Amiodarone.
AtenololAtenolol may increase the bradycardic activities of Fingolimod.
BasilBasil may increase the immunosuppressive activities of Fingolimod.
BetaxololBetaxolol may increase the bradycardic activities of Fingolimod.
BisoprololBisoprolol may increase the bradycardic activities of Fingolimod.
BretyliumBretylium may increase the bradycardic activities of Fingolimod.
CarbamazepineThe serum concentration of Fingolimod can be decreased when it is combined with Carbamazepine.
CarteololCarteolol may increase the bradycardic activities of Fingolimod.
CarvedilolCarvedilol may increase the bradycardic activities of Fingolimod.
CeritinibFingolimod may increase the bradycardic activities of Ceritinib.
CitalopramFingolimod may increase the QTc-prolonging activities of Citalopram.
DenosumabThe risk or severity of adverse effects can be increased when Denosumab is combined with Fingolimod.
DiltiazemDiltiazem may increase the bradycardic activities of Fingolimod.
DisopyramideFingolimod may increase the arrhythmogenic activities of Disopyramide.
DofetilideFingolimod may increase the arrhythmogenic activities of Dofetilide.
DronedaroneFingolimod may increase the arrhythmogenic activities of Dronedarone.
EsmololEsmolol may increase the bradycardic activities of Fingolimod.
GoserelinFingolimod may increase the QTc-prolonging activities of Goserelin.
IbutilideFingolimod may increase the arrhythmogenic activities of Ibutilide.
IvabradineFingolimod may increase the bradycardic activities of Ivabradine.
KetoconazoleThe serum concentration of the active metabolites of Fingolimod can be increased when Fingolimod is used in combination with Ketoconazole.
LabetalolLabetalol may increase the bradycardic activities of Fingolimod.
LacosamideFingolimod may increase the atrioventricular blocking (AV block) activities of Lacosamide.
LeflunomideThe risk or severity of adverse effects can be increased when Fingolimod is combined with Leflunomide.
LeuprolideFingolimod may increase the QTc-prolonging activities of Leuprolide.
LevobunololLevobunolol may increase the bradycardic activities of Fingolimod.
MetipranololMetipranolol may increase the bradycardic activities of Fingolimod.
MetoprololMetoprolol may increase the bradycardic activities of Fingolimod.
MifepristoneMifepristone may increase the QTc-prolonging activities of Fingolimod.
NadololNadolol may increase the bradycardic activities of Fingolimod.
NatalizumabThe risk or severity of adverse effects can be increased when Fingolimod is combined with Natalizumab.
NebivololNebivolol may increase the bradycardic activities of Fingolimod.
OctreotideOctreotide may increase the bradycardic activities of Fingolimod.
OsimertinibOsimertinib may increase the immunosuppressive activities of Fingolimod.
PenbutololPenbutolol may increase the bradycardic activities of Fingolimod.
PimecrolimusThe risk or severity of adverse effects can be increased when Pimecrolimus is combined with Fingolimod.
PindololPindolol may increase the bradycardic activities of Fingolimod.
ProcainamideFingolimod may increase the arrhythmogenic activities of Procainamide.
PropranololPropranolol may increase the bradycardic activities of Fingolimod.
QuinidineFingolimod may increase the arrhythmogenic activities of Quinidine.
Rabies vaccineThe therapeutic efficacy of Rabies vaccine can be decreased when used in combination with Fingolimod.
Repository corticotropinRepository corticotropin may increase the immunosuppressive activities of Fingolimod.
RoflumilastRoflumilast may increase the immunosuppressive activities of Fingolimod.
RuxolitinibRuxolitinib may increase the bradycardic activities of Fingolimod.
Sipuleucel-TThe therapeutic efficacy of Sipuleucel-T can be decreased when used in combination with Fingolimod.
SotalolFingolimod may increase the arrhythmogenic activities of Sotalol.
TacrolimusThe risk or severity of adverse effects can be increased when Tacrolimus is combined with Fingolimod.
TimololTimolol may increase the bradycardic activities of Fingolimod.
TofacitinibFingolimod may increase the immunosuppressive activities of Tofacitinib.
TrastuzumabTrastuzumab may increase the neutropenic activities of Fingolimod.
VerapamilVerapamil may increase the bradycardic activities of Fingolimod.
Food InteractionsNot Available

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 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 activ...
Gene Name:
S1PR5
Uniprot ID:
Q9H228
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 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Not Available
Specific Function:
Not Available
Gene Name:
CYP4F2
Uniprot ID:
P78329
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 extent sphinganine, but not other lipids, such as D,L-threo-dihydrosphingosine, N,N-dimethylsphingosine, diacylglycerol, ceramide, or phosphatidylinositol.
Gene Name:
SPHK1
Uniprot ID:
Q9NYA1
Molecular Weight:
42517.245 Da
References
  1. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=cc9e1c8c-0e2b-44e2-878b-27057f786be9#nlm34090-1
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Steroid hydroxylase activity
Specific Function:
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants.
Gene Name:
CYP2D6
Uniprot ID:
P10635
Molecular Weight:
55768.94 Da
References
  1. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=cc9e1c8c-0e2b-44e2-878b-27057f786be9#nlm34090-1
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 or carcinogenic forms.
Gene Name:
CYP2E1
Uniprot ID:
P05181
Molecular Weight:
56848.42 Da
References
  1. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=cc9e1c8c-0e2b-44e2-878b-27057f786be9#nlm34090-1
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Vitamin d3 25-hydroxylase activity
Specific Function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiot...
Gene Name:
CYP3A4
Uniprot ID:
P08684
Molecular Weight:
57342.67 Da
References
  1. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=cc9e1c8c-0e2b-44e2-878b-27057f786be9#nlm34090-1
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
Molecular Weight:
60269.165 Da
References
  1. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=cc9e1c8c-0e2b-44e2-878b-27057f786be9#nlm34090-1
Comments
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Drug created on April 28, 2013 14:17 / Updated on May 23, 2016 02:35