Dimethyl fumarate

Identification

Name
Dimethyl fumarate
Accession Number
DB08908
Type
Small Molecule
Groups
Approved, 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
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
International/Other Brands
Tecfidera
Categories
UNII
FO2303MNI2
CAS number
624-49-7
Weight
Average: 144.1253
Monoisotopic: 144.042258744
Chemical Formula
C6H8O4
InChI Key
LDCRTTXIJACKKU-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.

TargetActionsOrganism
AKelch-like ECH-associated protein 1
binder
Human
UTranscription factor p65Not AvailableHuman
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
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteractionDrug group
BCG vaccineThe risk or severity of adverse effects can be increased when Dimethyl fumarate is combined with BCG vaccine.Investigational
Clostridium tetani toxoid antigen (formaldehyde inactivated)The risk or severity of adverse effects can be increased when Dimethyl fumarate is combined with Clostridium tetani toxoid antigen (formaldehyde inactivated).Approved
Corynebacterium diphtheriae toxoid antigen (formaldehyde inactivated)The risk or severity of adverse effects can be increased when Dimethyl fumarate is combined with Corynebacterium diphtheriae toxoid antigen (formaldehyde inactivated).Approved
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 virus inactivated antigen, A.Approved
Rabies virus inactivated antigen, AThe therapeutic efficacy of Rabies virus inactivated antigen, A 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 Rindopepimut.Investigational
RoflumilastRoflumilast may increase the immunosuppressive activities of Dimethyl fumarate.Approved
Rotavirus VaccineThe risk or severity of adverse effects can be increased when Dimethyl fumarate is combined with Rotavirus Vaccine.Approved
Rubella virus vaccineThe risk or severity of adverse effects can be increased when Dimethyl fumarate is combined with Rubella virus vaccine.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
TecemotideThe risk or severity of adverse effects can be increased when Dimethyl fumarate is combined with Tecemotide.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
Yellow fever vaccineThe risk or severity of adverse effects can be increased when Dimethyl fumarate is combined with Yellow fever vaccine.Approved
Zoster vaccineThe risk or severity of adverse effects can be increased when Dimethyl fumarate is combined with Zoster vaccine.Approved
Food Interactions
  • Food does not affect the pharmacokinetics of dimethyl fumarate, but it may reduce dimethyl fumarate induced GI upset and flushing.

References

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
PubChem Compound
637568
PubChem Substance
347827812
ChemSpider
553171
ChEBI
76004
ChEMBL
CHEMBL2107333
PharmGKB
PA166152838
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Dimethyl_fumarate
ATC Codes
N07XX09 — Dimethyl fumarate
AHFS Codes
  • 28:92.00 — Miscellaneous Central Nervous System Agents
FDA label
Download (388 KB)
MSDS
Download (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 Sclerosis1
4Active Not RecruitingTreatmentDisseminated Sclerosis / Relapsing Remitting Multiple Sclerosis (RRMS)1
4CompletedTreatmentDisseminated Sclerosis1
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
4RecruitingTreatmentRelapsing Remitting Multiple Sclerosis (RRMS)1
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

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
CapsuleOral120 mg/1
CapsuleOral240 mg/1
Capsule, delayed releaseOral120 mg
Capsule, delayed releaseOral120.0 mg
Capsule, delayed releaseOral240 mg
Kit
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US7320999No2000-05-182020-05-18Us
US7619001No1998-04-012018-04-01Us
US7803840No1998-04-012018-04-01Us
US8399514No2008-02-072028-02-07Us
US8524773No1998-04-012018-04-01Us
US6509376No1999-10-292019-10-29Us
US8759393No1999-10-292019-10-29Us

Properties

State
Solid
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 features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
GC-MS Spectrum - EI-BGC-MSsplash10-03di-9600000000-85c5795d39a711edce4a
GC-MS Spectrum - EI-BGC-MSsplash10-03di-9500000000-ef1a2c817c752048ca3d
GC-MS Spectrum - EI-BGC-MSsplash10-014i-6900000000-b4104322040a20afbf87
GC-MS Spectrum - EI-BGC-MSsplash10-03di-9500000000-38079515fe54a7a128d6
GC-MS Spectrum - EI-BGC-MSsplash10-03di-9500000000-8e3b99fc3ddb06539d43
GC-MS Spectrum - EI-BGC-MSsplash10-03di-9800000000-d3ec2acefa5532f1d130
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 fatty acid esters. These are carboxylic ester derivatives of a fatty acid.
Kingdom
Organic compounds
Super Class
Lipids and lipid-like molecules
Class
Fatty Acyls
Sub Class
Fatty acid esters
Direct Parent
Fatty acid esters
Alternative Parents
Dicarboxylic acids and derivatives / Methyl esters / Enoate esters / Organic oxides / Hydrocarbon derivatives / Carbonyl compounds
Substituents
Fatty 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 Framework
Aliphatic acyclic compounds
External Descriptors
diester, 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 s...
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...
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 November 22, 2017 12:37