Details
| Stereochemistry | ACHIRAL |
| Molecular Formula | C6H8O4 |
| Molecular Weight | 144.1253 |
| Optical Activity | NONE |
| Defined Stereocenters | 0 / 0 |
| E/Z Centers | 1 |
| Charge | 0 |
SHOW SMILES / InChI
SMILES
COC(=O)\C=C\C(=O)OC
InChI
InChIKey=LDCRTTXIJACKKU-ONEGZZNKSA-N
InChI=1S/C6H8O4/c1-9-5(7)3-4-6(8)10-2/h3-4H,1-2H3/b4-3+
DescriptionSources: https://www.ncbi.nlm.nih.gov/pubmed/12522577 | https://www.ncbi.nlm.nih.gov/pubmed/27614618 | https://www.ncbi.nlm.nih.gov/pubmed/20664170 | https://multiplesclerosisnewstoday.com/alks-8700-multiple-sclerosis/https://www.ncbi.nlm.nih.gov/pubmed/15987702 | https://www.ncbi.nlm.nih.gov/pubmed/17182618https://www.ncbi.nlm.nih.gov/pubmed/28340950http://www.google.ru/patents/US3887480 | https://www.google.com/patents/US4668735http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/204063s014lbl.pdfhttp://onlinelibrary.wiley.com/doi/10.1002/047084289X.rd344/fullCurator's Comment: description was created based on several sources, including
https://www.ncbi.nlm.nih.gov/pubmed/20647102 | https://www.ncbi.nlm.nih.gov/pubmed/19595601
Sources: https://www.ncbi.nlm.nih.gov/pubmed/12522577 | https://www.ncbi.nlm.nih.gov/pubmed/27614618 | https://www.ncbi.nlm.nih.gov/pubmed/20664170 | https://multiplesclerosisnewstoday.com/alks-8700-multiple-sclerosis/https://www.ncbi.nlm.nih.gov/pubmed/15987702 | https://www.ncbi.nlm.nih.gov/pubmed/17182618https://www.ncbi.nlm.nih.gov/pubmed/28340950http://www.google.ru/patents/US3887480 | https://www.google.com/patents/US4668735http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/204063s014lbl.pdfhttp://onlinelibrary.wiley.com/doi/10.1002/047084289X.rd344/full
Curator's Comment: description was created based on several sources, including
https://www.ncbi.nlm.nih.gov/pubmed/20647102 | https://www.ncbi.nlm.nih.gov/pubmed/19595601
Dimethyl maleate is an organic compound, the (Z)-isomer of the dimethyl ester of fumaric acid. Dimethyl maleate can be synthesized from maleic anhydride and methanol, with sulfuric acid acting as acid catalyst, via a nucleophilic acyl substitution for the monomethyl ester, followed by a Fischer esterification reaction for the dimethyl ester. Dimethyl maleate is used in many organic syntheses as a dienophile for diene synthesis. It is used as an additive and intermediate for plastics, pigments, pharmaceuticals, and agricultural products. It is also an intermediate for the production of paints, adhesives, and copolymers.
Originator
Sources: http://adisinsight.springer.com/drugs/800038403http://www.ncbi.nlm.nih.gov/pubmed/15991882http://pubs.rsc.org/en/content/articlehtml/1925/CT/CT9252701868
Curator's Comment: In September 2003, Biogen (now Biogen Idec) licensed exclusive worldwide rights (excluding Germany) from Fumapharm to develop and market BG 12.
Approval Year
Targets
| Primary Target | Pharmacology | Condition | Potency |
|---|---|---|---|
Target ID: CHEMBL6182 |
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Target ID: Q96KS0 Gene ID: 112398.0 Gene Symbol: EGLN2 Target Organism: Homo sapiens (Human) |
120.0 µM [IC50] | ||
Target ID: Q9H6Z9 Gene ID: 112399.0 Gene Symbol: EGLN3 Target Organism: Homo sapiens (Human) |
60.0 µM [IC50] | ||
Target ID: Q9GZT9 Gene ID: 54583.0 Gene Symbol: EGLN1 Target Organism: Homo sapiens (Human) |
80.0 µM [IC50] | ||
Target ID: WP2884 |
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Target ID: GO:0070269 |
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Target ID: Q16236 Gene ID: 4780.0 Gene Symbol: NFE2L2 Target Organism: Homo sapiens (Human) |
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Target ID: Glutathione S-transferase |
Conditions
| Condition | Modality | Targets | Highest Phase | Product |
|---|---|---|---|---|
| Primary | Unknown Approved UseUnknown |
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| Diagnostic | Unknown Approved UseUnknown |
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| Secondary | TECFIDERA Approved UseIndicated for the treatment of patients with relapsing forms of multiple sclerosis Launch Date1.36434234E12 |
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| Palliative | Unknown Approved UseUnknown |
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| Primary | TECFIDERA Approved UseTECFIDERA, dimethyl fumarate undergoes rapid presystemic
hydrolysis by esterases and is converted to its active metabolite, monomethyl fumarate (MMF). TECFIDERA is indicated for the treatment of patients with relapsing forms of multiple sclerosis. Launch Date1.36425597E12 |
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| Preventing | Unknown Approved UseUnknown |
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Cmax
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
1.87 mg/L |
240 mg 2 times / day multiple, oral dose: 240 mg route of administration: Oral experiment type: MULTIPLE co-administered: |
MONOMETHYL FUMARATE plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: FED |
AUC
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
8.21 mg × h/L |
240 mg 2 times / day multiple, oral dose: 240 mg route of administration: Oral experiment type: MULTIPLE co-administered: |
MONOMETHYL FUMARATE plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: FED |
T1/2
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
1 h |
240 mg 2 times / day multiple, oral dose: 240 mg route of administration: Oral experiment type: MULTIPLE co-administered: |
MONOMETHYL FUMARATE plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: FED |
Funbound
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
64% |
240 mg 2 times / day multiple, oral dose: 240 mg route of administration: Oral experiment type: MULTIPLE co-administered: |
MONOMETHYL FUMARATE plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: FED |
Doses
| Dose | Population | Adverse events |
|---|---|---|
190 mg 2 times / day multiple, oral Highest studied dose Dose: 190 mg, 2 times / day Route: oral Route: multiple Dose: 190 mg, 2 times / day Sources: Page: 6.1 |
unhealthy, adult n = 769 Health Status: unhealthy Condition: multiple sclerosis Age Group: adult Sex: unknown Population Size: 769 Sources: Page: 6.1 |
|
190 mg 2 times / day multiple, oral Highest studied dose Dose: 190 mg, 2 times / day Route: oral Route: multiple Dose: 190 mg, 2 times / day Sources: |
unhealthy, mean 37 years n = 105 Health Status: unhealthy Condition: multiple sclerosis Age Group: mean 37 years Sex: M+F Population Size: 105 Sources: |
Other AEs: Gastrointestinal disturbance... |
AEs
| AE | Significance | Dose | Population |
|---|---|---|---|
| Gastrointestinal disturbance | 53% | 190 mg 2 times / day multiple, oral Highest studied dose Dose: 190 mg, 2 times / day Route: oral Route: multiple Dose: 190 mg, 2 times / day Sources: |
unhealthy, mean 37 years n = 105 Health Status: unhealthy Condition: multiple sclerosis Age Group: mean 37 years Sex: M+F Population Size: 105 Sources: |
PubMed
| Title | Date | PubMed |
|---|---|---|
| Antifungal properties of 2-bromo-3-fluorosuccinic acid esters and related compounds. | 1977 Apr |
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| The influence of long-term treatment with timolol on human tear lysozyme albumin content. | 1982 |
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| Urinary loss of glucose, phosphate, and protein by diffusion into proximal straight tubules injured by D-serine and maleic acid. | 1985 Jun |
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| Microperfusion study of proximal tubule bicarbonate transport in maleic acid-induced renal tubular acidosis. | 1986 Mar |
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| Do contrast media aggravate Fanconi's syndrome in rats? A comparison of diatrizoate, iohexol, and ioxilan. | 1988 Sep |
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| Menstrual migraine and intermittent ergonovine therapy. | 1989 Jun |
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| Automated screening of urine samples for carbohydrates, organic and amino acids after treatment with urease. | 1991 Jan 2 |
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| Antifungal activity of fumaric acid in mice infected with Candida albicans. | 1991 Nov |
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| Ocular surface alteration after long-term treatment with an antiglaucomatous drug. | 1992 Jul |
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| Physiology and pathophysiology of organic acids in cerebrospinal fluid. | 1993 |
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| Disposition of [14C]velnacrine maleate in rats, dogs, and humans. | 1993 Nov-Dec |
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| Age-related reference values for urinary organic acids in a healthy Turkish pediatric population. | 1994 Jun |
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| [Studies on the mechanisms of renal damages induced by nephrotoxic compounds]. | 1995 Dec |
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| Efficacy of 101 antimicrobials and other agents on the development of Cryptosporidium parvum in vitro. | 1996 Dec |
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| Glycine attenuates Fanconi syndrome induced by maleate or ifosfamide in rats. | 1996 Mar |
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| Abnormal substrate levels that depend upon mitochondrial function in cerebrospinal fluid from Alzheimer patients. | 1998 |
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| Morphological effect of the type, concentration and etching time of acid solutions on enamel and dentin surfaces. | 1998 |
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| A synthetic polycation, a copolymer of 1-vinyl-3-methylimidazole iodide with maleic acid diethyl ester, increases passive ionic permeability in erythrocyte membranes modified by fatty acids. | 1998 |
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| Hepatic infarction following percutaneous ethanol injection therapy for hepatocellular carcinoma. | 1998 Nov |
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| In vitro shear bond strength of adhesive to normal and fluoridated enamel under various contaminated conditions. | 1999 Aug |
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| Experience with intraarterial infusion of styrene maleic acid neocarzinostatin (SMANCS)-lipiodol in pancreatic cancer. | 1999 Jul-Aug |
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| Determination of trimebutine and desmethyl-trimebutine in human plasma by HPLC. | 2000 Jul |
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| Subcritical mineralization of sodium salt of dodecyl benzene sulfonate using sonication-wet oxidation (SONIWO) technique. | 2001 Jun |
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| Molecular mechanism for the regulation of human mitochondrial NAD(P)+-dependent malic enzyme by ATP and fumarate. | 2002 Jul |
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| An in vitro study on restoring bond strength of a GIC to saliva contaminated enamel under unrinse condition. | 2002 Jul-Aug |
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| The comparison of plasma deproteinization methods for the detection of low-molecular-weight metabolites by (1)H nuclear magnetic resonance spectroscopy. | 2002 May 15 |
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| Neocortical neurons cultured from mice with expanded CAG repeats in the huntingtin gene: unaltered vulnerability to excitotoxins and other insults. | 2003 |
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| Aqueous humour flow after a single oral dose of isosorbide-5-mononitrate in healthy volunteers. | 2003 Aug |
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| Molecular machinery for non-vesicular trafficking of ceramide. | 2003 Dec 18 |
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| Dynamic alterations of fibronectin layers on copolymer substrates with graded physicochemical characteristics. | 2004 Mar 30 |
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| Determination of ergometrine maleate by fluorescence detection. | 2005 May-Jun |
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| Tumor-necrosis-factor-related apoptosis-inducing-ligand (TRAIL)-mediated death of neurons in living human brain tissue is inhibited by flupirtine-maleate. | 2005 Oct |
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| Protein adsorption from flowing solutions on pure and maleic acid copolymer modified glass particles. | 2006 Aug 1 |
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| Effects of antiglaucoma drugs on collagen gel contraction mediated by human corneal fibroblasts. | 2006 Jun |
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| Probing carboxylate Gibbs transfer energies via liquid|liquid transfer at triple phase boundary electrodes: ion-transfer voltammetry versus COSMO-RS predictions. | 2008 Jul 14 |
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| Quantitative morphometry of respiratory tract epithelial cells as a tool for testing chemopreventive agent efficacy. | 2010 Mar |
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| Integration of metabolomics and transcriptomics data to aid biomarker discovery in type 2 diabetes. | 2010 May |
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| Fumaric acid attenuates the eotaxin-1 expression in TNF-α-stimulated fibroblasts by suppressing p38 MAPK-dependent NF-κB signaling. | 2013 Aug |
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| Evaluation of aggregating brain cell cultures for the detection of acute organ-specific toxicity. | 2013 Jun |
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| Small molecule activators of the Nrf2-HO-1 antioxidant axis modulate heme metabolism and inflammation in BV2 microglia cells. | 2013 Oct |
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| Curcumin prevents maleate-induced nephrotoxicity: relation to hemodynamic alterations, oxidative stress, mitochondrial oxygen consumption and activity of respiratory complex I. | 2014 Nov |
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| Role of Nuclear Factor (Erythroid-Derived 2)-Like 2 Signaling for Effects of Fumaric Acid Esters on Dendritic Cells. | 2017 |
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| Recent advances in understanding NRF2 as a druggable target: development of pro-electrophilic and non-covalent NRF2 activators to overcome systemic side effects of electrophilic drugs like dimethyl fumarate. | 2017 |
|
| Monomethyl fumarate inhibits pain behaviors and amygdala activity in a rat arthritis model. | 2017 Dec |
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| Bioanalysis of monomethyl fumarate in human plasma by a sensitive and rapid LC-MS/MS method and its pharmacokinetic application. | 2017 Nov 30 |
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| Dual action by fumaric acid esters synergistically reduces adhesion to human endothelium. | 2018 Dec |
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| Dimethyl fumarate treatment alters NK cell function in multiple sclerosis. | 2018 Feb |
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| Multiple mechanisms of dimethyl fumarate in amyloid β-induced neurotoxicity in human neuronal cells. | 2018 Feb |
|
| Dimethyl fumarate influences innate and adaptive immunity in multiple sclerosis. | 2018 Jan |
|
| Monomethyl fumarate treatment impairs maturation of human myeloid dendritic cells and their ability to activate T cells. | 2019 Jan |
Patents
Sample Use Guides
In Vivo Use Guide
Curator's Comment: In group of dogs experimental Fanconi syndrome (generalized proximal tubular dysfunction) was induced with maleic acid (25 mg/kg iv, pH 7.3). https://www.ncbi.nlm.nih.gov/pubmed/1858895
462 mg twice daily
Route of Administration:
Oral
In Vitro Use Guide
Curator's Comment: Maleic acid-induced inhibition of sugar and amino acid transport in the rat renal tubule was studied.
NK cells from healthy controls were treated with 10 and 100 uM of monomethyl fumarate for 12 hours then washed and co-cultured for 24 hours at 1:5 E:T ratio with or without autologous labeled T cells. Using CD107a expression to measure NK cell degranulation, is was noted an increase in the proportion of degranulated NK cells following treatment with different monomethyl fumarate concentrations. These changes occurred without dramatic effects on NK cell viability.
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| Classification Tree | Code System | Code | ||
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NCI_THESAURUS |
C29708
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WHO-ATC |
N07XX09
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NCI_THESAURUS |
C798
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EU-Orphan Drug |
EU/3/18/1990
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FDA ORPHAN DRUG |
406713
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WHO-ATC |
L04AX07
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FDA ORPHAN DRUG |
607917
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WHO-VATC |
QN07XX09
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EMA ASSESSMENT REPORTS |
TECFIDERA (AUTHORIZED: MULTIPLE SCLEROSIS)
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C63670
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7045
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25942
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1373478
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C056020
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QQ-86
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7725
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637568
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m11738
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76004
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DB08908
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DTXSID4060787
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100000079228
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210-849-0
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SUB13608MIG
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4757
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CHEMBL2107333
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DIMETHYL FUMARATE
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Dimethyl fumarate
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FO2303MNI2
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624-49-7
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FO2303MNI2
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167432
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ACTIVE MOIETY
METABOLITE INACTIVE (PARENT)
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SUBSTANCE RECORD
