Identification
NameDimethyl fumarate
Accession NumberDB08908
TypeSmall Molecule
GroupsApproved, Investigational
Description

Dimethyl fumarate is an anti-inflammatory. It is indicated for multiple sclerosis patients with relapsing forms and is also being investigated for the treatment of psoriasis. The mechanism of action of dimethyl fumarate in multiple sclerosis is not well understood. It is thought to involve dimethyl fumarate degradation to its active metabolite monomethyl fumarate (MMF) then MMF up-regulates the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway that is activated in response to oxidative stress. Dimethyl fumarate is marketed under the brand name Tecfidera.

Structure
Thumb
Synonyms
(e)-But-2-enedioic acid dimethyl ester
1,2-Bis(methoxycarbonyl)-trans-ethylene
dimethyl (E) butenedioate
Dimethyl trans-ethylenedicarboxylate
Fumaric acid, dimethyl ester
trans-1,2-Ethylenedicarboxylic acid dimethyl ester
trans-Butenedioic acid dimethyl ester
External IDs AZL O 211089 / AZL-O-211089 / BG 00012 / BG 12 / BG-00012 / BG-12 / BG00012 / FAG-201 / FP-187 / FP187
Product Ingredients Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
TecfideraCapsule, delayed release120.0 mgOralBiogen2013-04-12Not applicableCanada
TecfideraCapsule, delayed release240 mgOralBiogen Idec Limited2014-01-30Not applicableEu
TecfideraCapsule240 mg/1OralBiogen2013-03-27Not applicableUs
TecfideraCapsule, delayed release240 mgOralBiogen2014-02-04Not applicableCanada
TecfideraKitBiogen2013-03-27Not applicableUs
TecfideraCapsule, delayed release120 mgOralBiogen Idec Limited2014-01-30Not applicableEu
TecfideraCapsule120 mg/1OralBiogen2013-03-27Not applicableUs
Tecfidera Pvc Alu)Capsule, delayed release240 mgOralBiogen Idec Limited2014-01-30Not applicableEu
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
TecfideraNot Available
Brand mixturesNot Available
Categories
UNIIFO2303MNI2
CAS number624-49-7
WeightAverage: 144.1253
Monoisotopic: 144.042258744
Chemical FormulaC6H8O4
InChI KeyLDCRTTXIJACKKU-ONEGZZNKSA-N
InChI
InChI=1S/C6H8O4/c1-9-5(7)3-4-6(8)10-2/h3-4H,1-2H3/b4-3+
IUPAC Name
1,4-dimethyl (2E)-but-2-enedioate
SMILES
[H]\C(=C(\[H])C(=O)OC)C(=O)OC
Pharmacology
Indication

Used in multiple sclerosis patients with relapsing forms.

Structured Indications
Pharmacodynamics

The physiological effects dimethyl fumarate has on the body is not well understood. It is known that dimethyl fumarate has anti-inflammatory and cytoprotective effects, which both are likely involved in its actions in multiple sclerosis patients.

Mechanism of action

The mechanism of action of dimethyl fumarate in multiple sclerosis is not well understood. It is thought to involve dimethyl fumarate degradation to its active metabolite monomethyl fumarate (MMF). MMF up-regulates the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway that is activated in response to oxidative stress. As well MMF is an agonist at the nicotinic acid receptor, but the relevance of this is not known.

TargetKindPharmacological actionActionsOrganismUniProt ID
Kelch-like ECH-associated protein 1Proteinyes
binder
HumanQ14145 details
Transcription factor p65ProteinunknownNot AvailableHumanQ04206 details
Related Articles
Absorption

Once ingested, dimethyl fumarate is rapidly hydroylyzed by esterases to MMF. Thus there is negligible amount of dimethyl fumarate in the body, and all pharmacokinetic information is quantified with MMF. In multiple sclerosis patients, the time to maximum concentration of MMF is 2 to 2.5 hours and the maximum concentration is 1.87 mg/L.

Volume of distribution

In healthy people, MMF has a variable volume of distribution of 53 to 73 litres.

Protein binding

MMF has a plasma protein binding range of 27 to 45%, and the binding is concentration independent.

Metabolism

Dimethly fumarate is hydrozlied to its metabolite MMF in the GIT, tissues, and blood by esterases. MMF then undergoes subsequent metabolism in the tricarboxylic acid (TCA) cycle. Altogether the main metabolites formed are MMF, glucose, citric acid, and fumaric.

Route of elimination

The main route of elimination is by CO2 exhalation that accounts for 60% of the dose. The other minor routes are through the kidney (16% metabolites and trace amounts of unchanged MMF) and the feces (1%).

Half life

MMF has a short half life of about 1 hour, and MMF does not accumulate after repeated doses of dimethyl fumarate.

Clearance

MMF clearance was not quantified.

Toxicity

The most common side effects observed were nausea, diarrhea, abdominal pain, and flushing.

Affected organisms
  • Humans and other mammals
PathwaysNot Available
Pharmacogenomic Effects/ADRs Not Available
Interactions
Drug Interactions
DrugInteractionDrug group
BCG vaccineThe therapeutic efficacy of Bcg can be decreased when used in combination with Dimethyl fumarate.Investigational
DenosumabThe risk or severity of adverse effects can be increased when Denosumab is combined with Dimethyl fumarate.Approved
FingolimodDimethyl fumarate may increase the immunosuppressive activities of Fingolimod.Approved, Investigational
G17DTThe risk or severity of adverse effects can be increased when Dimethyl fumarate is combined with G17DT.Investigational
GI-5005The risk or severity of adverse effects can be increased when Dimethyl fumarate is combined with GI-5005.Investigational
INGN 201The risk or severity of adverse effects can be increased when Dimethyl fumarate is combined with INGN 201.Investigational
INGN 225The risk or severity of adverse effects can be increased when Dimethyl fumarate is combined with INGN 225.Investigational
LeflunomideThe risk or severity of adverse effects can be increased when Dimethyl fumarate is combined with Leflunomide.Approved, Investigational
NatalizumabThe risk or severity of adverse effects can be increased when Dimethyl fumarate is combined with Natalizumab.Approved, Investigational
PimecrolimusThe risk or severity of adverse effects can be increased when Pimecrolimus is combined with Dimethyl fumarate.Approved, Investigational
Rabies virus inactivated antigen, AThe risk or severity of adverse effects can be increased when Dimethyl fumarate is combined with Rabies vaccine.Approved
Rabies virus inactivated antigen, AThe therapeutic efficacy of Rabies vaccine can be decreased when used in combination with Dimethyl fumarate.Approved
RindopepimutThe risk or severity of adverse effects can be increased when Dimethyl fumarate is combined with CDX-110.Investigational
RoflumilastRoflumilast may increase the immunosuppressive activities of Dimethyl fumarate.Approved
Sipuleucel-TThe therapeutic efficacy of Sipuleucel-T can be decreased when used in combination with Dimethyl fumarate.Approved
SRP 299The risk or severity of adverse effects can be increased when Dimethyl fumarate is combined with SRP 299.Investigational
TacrolimusThe risk or severity of adverse effects can be increased when Tacrolimus is combined with Dimethyl fumarate.Approved, Investigational
TG4010The risk or severity of adverse effects can be increased when Dimethyl fumarate is combined with TG4010.Investigational
TofacitinibDimethyl fumarate may increase the immunosuppressive activities of Tofacitinib.Approved, Investigational
TrastuzumabTrastuzumab may increase the neutropenic activities of Dimethyl fumarate.Approved, Investigational
Food Interactions
  • Food does not affect the pharmacokinetics of dimethyl fumarate, but it may reduce dimethyl fumarate induced GI upset and flushing.
References
Synthesis ReferenceNot Available
General References
  1. Papadopoulou A, D'Souza M, Kappos L, Yaldizli O: Dimethyl fumarate for multiple sclerosis. Expert Opin Investig Drugs. 2010 Dec;19(12):1603-12. doi: 10.1517/13543784.2010.534778. Epub 2010 Nov 11. [PubMed:21067468 ]
External Links
ATC CodesN07XX09 — Dimethyl fumarate
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelDownload (388 KB)
MSDSDownload (355 KB)
Clinical Trials
Clinical Trials
PhaseStatusPurposeConditionsCount
1Active Not RecruitingTreatmentAdult Brain Glioblastoma / Adult Giant Cell Glioblastoma / Adult Gliosarcoma1
1CompletedNot AvailableHealthy Volunteers1
1CompletedBasic ScienceHealthy Volunteers1
1CompletedBasic ScienceRelapsing Remitting Multiple Sclerosis (RRMS)1
1CompletedTreatmentHealthy Volunteers3
1RecruitingTreatmentChronic Lymphocytic Leukaemia (CLL) / Small Lymphocytic Lymphoma (SLL)1
1RecruitingTreatmentPulmonary Hypertension (PH) / Sclerosis, Progressive Systemic1
2Active Not RecruitingTreatmentRelapsing Remitting Multiple Sclerosis (RRMS)1
2CompletedTreatmentDisseminated Sclerosis1
2CompletedTreatmentDisseminated Sclerosis / Relapsing Remitting Multiple Sclerosis (RRMS)1
2CompletedTreatmentPlaque Psoriasis1
2CompletedTreatmentRelapsing Forms of Multiple Sclerosis1
2CompletedTreatmentRelapsing Remitting Multiple Sclerosis (RRMS)1
2CompletedTreatmentRheumatoid Arthritis1
2RecruitingTreatmentMultiple Sclerosis, Primary Progressive1
2WithdrawnTreatmentPsoriatic Arthritis1
2, 3RecruitingTreatmentDisseminated Sclerosis / Relapsing Remitting Multiple Sclerosis (RRMS)1
3Active Not RecruitingTreatmentDisseminated Sclerosis / Relapsing Remitting Multiple Sclerosis (RRMS)2
3Active Not RecruitingTreatmentRelapsing Remitting Multiple Sclerosis (RRMS)2
3CompletedSupportive CareHealthy Volunteers1
3CompletedTreatmentRelapsing Remitting Multiple Sclerosis (RRMS)3
3RecruitingTreatmentRelapsing Remitting Multiple Sclerosis (RRMS)3
3TerminatedTreatmentDisseminated Sclerosis1
3TerminatedTreatmentSecondary Progressive Multiple Sclerosis (SPMS)1
3WithdrawnTreatmentPlaque Psoriasis1
3WithdrawnTreatmentRelapsing Forms of Multiple Sclerosis / Relapsing Remitting Multiple Sclerosis (RRMS)1
4Active Not RecruitingBasic ScienceRelapsing Remitting Multiple Sclerosis (RRMS)1
4Active Not RecruitingTreatmentDisseminated Sclerosis2
4Active Not RecruitingTreatmentDisseminated Sclerosis / Relapsing Remitting Multiple Sclerosis (RRMS)1
4CompletedTreatmentRelapsing Forms of Multiple Sclerosis1
4CompletedTreatmentRelapsing Remitting Multiple Sclerosis (RRMS)2
4Not Yet RecruitingTreatmentRelapsing Remitting Multiple Sclerosis (RRMS)1
4RecruitingOtherRelapsing Remitting Multiple Sclerosis (RRMS)1
4RecruitingTreatmentDisseminated Sclerosis1
4TerminatedHealth Services ResearchDisseminated Sclerosis1
4WithdrawnBasic ScienceDisseminated Sclerosis / Relapsing Remitting Multiple Sclerosis (RRMS)1
4WithdrawnTreatmentDisseminated Sclerosis / Relapsing Remitting Multiple Sclerosis (RRMS)1
4WithdrawnTreatmentRelapsing Remitting Multiple Sclerosis (RRMS)1
Not AvailableActive Not RecruitingNot AvailableRelapsing Remitting Multiple Sclerosis (RRMS)1
Not AvailableCompletedNot AvailableDisseminated Sclerosis2
Not AvailableCompletedNot AvailableMultiple Sclerosis, Dimethyl Fumarate, Diffusion Tensor Imaging Magnetic Resonance Imaging1
Not AvailableCompletedNot AvailableRelapsing Forms of Multiple Sclerosis1
Not AvailableCompletedNot AvailableRelapsing Remitting Multiple Sclerosis (RRMS)1
Not AvailableCompletedTreatmentObstructive Sleep Apnea (OSA) / OSA / Sleep Apnea Syndrome1
Not AvailableRecruitingNot AvailableDisseminated Sclerosis3
Not AvailableRecruitingNot AvailableDisseminated Sclerosis / Exposure During Pregnancy1
Not AvailableRecruitingNot AvailableRelapsing Remitting Multiple Sclerosis (RRMS)1
Not AvailableTerminatedNot AvailableDisseminated Sclerosis1
Not AvailableTerminatedNot AvailableRelapsing Remitting Multiple Sclerosis (RRMS)1
Not AvailableWithdrawnNot AvailableDisseminated Sclerosis1
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
CapsuleOral120 mg/1
CapsuleOral240 mg/1
Capsule, delayed releaseOral120 mg
Capsule, delayed releaseOral120.0 mg
Capsule, delayed releaseOral240 mg
Kit
PricesNot Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US7320999 No2000-05-182020-05-18Us
US7619001 No1998-04-012018-04-01Us
US7803840 No1998-04-012018-04-01Us
US8399514 No2008-02-072028-02-07Us
US8524773 No1998-04-012018-04-01Us
US6509376 No1999-10-292019-10-29Us
US8759393 No1999-10-292019-10-29Us
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point (°C)103 to 104From MSDS.
boiling point (°C)192 to 193From MSDS.
water solubilityHighly soluble in water.From FDA label.
Predicted Properties
PropertyValueSource
Water Solubility12.9 mg/mLALOGPS
logP0.45ALOGPS
logP0.72ChemAxon
logS-1ALOGPS
pKa (Strongest Basic)-6.5ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area52.6 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity34.15 m3·mol-1ChemAxon
Polarizability13.76 Å3ChemAxon
Number of Rings0ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET featuresNot Available
Spectra
Mass Spec (NIST)Not Available
Spectra
Spectrum TypeDescriptionSplash Key
Predicted GC-MSPredicted GC-MS Spectrum - GC-MSNot Available
GC-MSGC-MS Spectrum - EI-Bsplash10-03di-9600000000-85c5795d39a711edce4aView in MoNA
GC-MSGC-MS Spectrum - EI-Bsplash10-03di-9500000000-ef1a2c817c752048ca3dView in MoNA
GC-MSGC-MS Spectrum - EI-Bsplash10-014i-6900000000-b4104322040a20afbf87View in MoNA
GC-MSGC-MS Spectrum - EI-Bsplash10-03di-9500000000-38079515fe54a7a128d6View in MoNA
GC-MSGC-MS Spectrum - EI-Bsplash10-03di-9500000000-8e3b99fc3ddb06539d43View in MoNA
GC-MSGC-MS Spectrum - EI-Bsplash10-03di-9800000000-d3ec2acefa5532f1d130View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, NegativeNot Available
Taxonomy
DescriptionThis compound belongs to the class of chemical entities known as fatty acid esters. These are carboxylic ester derivatives of a fatty acid.
KingdomChemical entities
Super ClassOrganic compounds
ClassLipids and lipid-like molecules
Sub ClassFatty Acyls
Direct ParentFatty acid esters
Alternative ParentsDicarboxylic acids and derivatives / Methyl esters / Enoate esters / Organic oxides / Hydrocarbon derivatives / Carbonyl compounds
SubstituentsFatty acid ester / Dicarboxylic acid or derivatives / Alpha,beta-unsaturated carboxylic ester / Enoate ester / Methyl ester / Carboxylic acid ester / Carboxylic acid derivative / Organic oxygen compound / Organic oxide / Hydrocarbon derivative
Molecular FrameworkAliphatic acyclic compounds
External Descriptorsdiester, methyl ester, enoate ester (CHEBI:76004 )

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
binder
General Function:
Transcription factor binding
Specific Function:
Acts as a substrate adapter protein for the E3 ubiquitin ligase complex formed by CUL3 and RBX1 and targets NFE2L2/NRF2 for ubiquitination and degradation by the proteasome, thus resulting in the suppression of its transcriptional activity and the repression of antioxidant response element-mediated detoxifying enzyme gene expression. Retains NFE2L2/NRF2 and may also retain BPTF in the cytosol. ...
Gene Name:
KEAP1
Uniprot ID:
Q14145
Uniprot Name:
Kelch-like ECH-associated protein 1
Molecular Weight:
69665.765 Da
References
  1. Oh CJ, Kim JY, Choi YK, Kim HJ, Jeong JY, Bae KH, Park KG, Lee IK: Dimethylfumarate attenuates renal fibrosis via NF-E2-related factor 2-mediated inhibition of transforming growth factor-beta/Smad signaling. PLoS One. 2012;7(10):e45870. doi: 10.1371/journal.pone.0045870. Epub 2012 Oct 8. [PubMed:23056222 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
General Function:
Ubiquitin protein ligase binding
Specific Function:
NF-kappa-B is a pleiotropic transcription factor present in almost all cell types and is the endpoint of a series of signal transduction events that are initiated by a vast array of stimuli related to many biological processes such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis. NF-kappa-B is a homo- or heterodimeric complex formed by the Rel-like domain-co...
Gene Name:
RELA
Uniprot ID:
Q04206
Uniprot Name:
Transcription factor p65
Molecular Weight:
60218.53 Da
References
  1. Kastrati I, Siklos MI, Calderon-Gierszal EL, El-Shennawy L, Georgieva G, Thayer EN, Thatcher GR, Frasor J: Dimethyl Fumarate Inhibits the Nuclear Factor kappaB Pathway in Breast Cancer Cells by Covalent Modification of p65 Protein. J Biol Chem. 2016 Feb 12;291(7):3639-47. doi: 10.1074/jbc.M115.679704. Epub 2015 Dec 18. [PubMed:26683377 ]
Drug created on June 19, 2013 19:12 / Updated on September 01, 2017 12:00