You are using an unsupported browser. Please upgrade your browser to a newer version to get the best experience on DrugBank.
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
BG-12
dimethyl (E) butenedioate
Dimethyl trans-ethylenedicarboxylate
Fumaric acid, dimethyl ester
Tecfidera
trans-1,2-Ethylenedicarboxylic acid dimethyl ester
trans-Butenedioic acid dimethyl ester
External Identifiers Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Tecfideracapsule120 mg/1oralBiogen Inc.2013-03-27Not applicableUs
Tecfideracapsule (delayed release)240 mgoralBiogen Canada Inc2014-02-04Not applicableCanada
Tecfideracapsule (delayed release)120.0 mgoralBiogen Canada Inc2013-04-12Not applicableCanada
TecfiderakitBiogen Inc.2013-03-27Not applicableUs
Tecfideracapsule240 mg/1oralBiogen Inc.2013-03-27Not applicableUs
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixturesNot Available
SaltsNot Available
Categories
UNIIFO2303MNI2
CAS number624-49-7
WeightAverage:
Monoisotopic:
Chemical FormulaNot Available
InChI KeyNot Available
InChI
IUPAC Name
1,4-dimethyl (2E)-but-2-enedioate
SMILES
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as fatty acid esters. These are carboxylic ester derivatives of a fatty acid.
KingdomOrganic compounds
Super ClassLipids and lipid-like molecules
ClassFatty Acyls
Sub ClassFatty acid esters
Direct ParentFatty acid esters
Alternative Parents
Substituents
  • Fatty acid ester
  • Dicarboxylic acid or derivatives
  • Alpha,beta-unsaturated carboxylic ester
  • Enoate ester
  • Methyl ester
  • Carboxylic acid ester
  • Carboxylic acid derivative
  • Hydrocarbon derivative
  • Organooxygen compound
  • Carbonyl group
  • Aliphatic acyclic compound
Molecular FrameworkAliphatic acyclic compounds
External Descriptors
Pharmacology
IndicationUsed in multiple sclerosis patients with relapsing forms.
PharmacodynamicsThe 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 actionThe 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.
Related Articles
AbsorptionOnce 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 bindingMMF 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 eliminationThe 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 lifeMMF 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.

ToxicityThe most common side effects observed were nausea, diarrhea, abdominal pain, and flushing.
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 AbsorptionNot AvailableNot Available
Blood Brain BarrierNot AvailableNot Available
Caco-2 permeableNot AvailableNot Available
P-glycoprotein substrateNot AvailableNot Available
P-glycoprotein inhibitor INot AvailableNot Available
P-glycoprotein inhibitor IINot AvailableNot Available
Renal organic cation transporterNot AvailableNot Available
CYP450 2C9 substrateNot AvailableNot Available
CYP450 2D6 substrateNot AvailableNot Available
CYP450 3A4 substrateNot AvailableNot Available
CYP450 1A2 substrateNot AvailableNot Available
CYP450 2C9 inhibitorNot AvailableNot Available
CYP450 2D6 inhibitorNot AvailableNot Available
CYP450 2C19 inhibitorNot AvailableNot Available
CYP450 3A4 inhibitorNot AvailableNot Available
CYP450 inhibitory promiscuityNot AvailableNot Available
Ames testNot AvailableNot Available
CarcinogenicityNot AvailableNot Available
BiodegradationNot AvailableNot Available
Rat acute toxicityNot AvailableNot applicable
hERG inhibition (predictor I)Not AvailableNot Available
hERG inhibition (predictor II)Not AvailableNot Available
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
Capsuleoral120 mg/1
Capsuleoral240 mg/1
Capsule (delayed release)oral120.0 mg
Capsule (delayed release)oral240 mg
Kit
PricesNot Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US6509376 No1999-10-292019-10-29Us
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
US8759393 No1999-10-292019-10-29Us
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point103 to 104From MSDS.
boiling point192 to 193From MSDS.
water solubilityHighly soluble in water.From FDA label.
Predicted Properties
PropertyValueSource
Water Solubility12.9 mg/mLALOGPS
logP0.45ALOGPS
logP0.72ChemAxon
logS-1.1ALOGPS
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 FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
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
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelDownload (388 KB)
MSDSDownload (355 KB)
Interactions
Drug InteractionsNo interactions found.
Food InteractionsNot Available

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
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 ]
Comments
comments powered by Disqus
Drug created on June 19, 2013 19:12 / Updated on August 24, 2016 01:53