Fumaric acid

Details

Stereochemistry	ACHIRAL
Molecular Formula	C4H4O4
Molecular Weight	116.0722
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	1
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

OC(=O)\C=C\C(O)=O

InChI

InChIKey=VZCYOOQTPOCHFL-OWOJBTEDSA-N

InChI=1S/C4H4O4/c5-3(6)1-2-4(7)8/h1-2H,(H,5,6)(H,7,8)/b2-1+

HIDE SMILES / InChI

Description
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.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
NADP-dependent malic enzyme, mitochondrial 12 Target ID: CHEMBL6182 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19595601	Inhibitor 8297
Egl nine homolog 2 13 Target ID: Q96KS0 Gene ID: 112398.0 Gene Symbol: EGLN2 Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/17182618	Inhibitor 8297	120.0 µM [IC50]
Egl nine homolog 3 19 Target ID: Q9H6Z9 Gene ID: 112399.0 Gene Symbol: EGLN3 Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/17182618	Inhibitor 8297	60.0 µM [IC50]
Egl nine homolog 1 21 Target ID: Q9GZT9 Gene ID: 54583.0 Gene Symbol: EGLN1 Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/17182618	Inhibitor 8297	80.0 µM [IC50]
NRF2 pathway 13 Target ID: WP2884 Sources: https://www.ncbi.nlm.nih.gov/pubmed/27614618	Activator 1430
pyroptosis 12 Target ID: GO:0070269 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26096886	Inhibitor 8297
Hydroxycarboxylic acid receptor 2 32 Target ID: CHEMBL4420 Sources: https://www.ncbi.nlm.nih.gov/pubmed/20664170 \| http://en.pharmacodia.com/web/drug/1_5666.html	Activator 1430
Nuclear factor erythroid 2-related factor 2 20 Target ID: Q16236 Gene ID: 4780.0 Gene Symbol: NFE2L2 Target Organism: Homo sapiens (Human) Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/204063s014lbl.pdf	Activator 1430
Glutathione S-transferase 12 Target ID: Glutathione S-transferase Sources: https://www.ncbi.nlm.nih.gov/pubmed/1287182	Substrate 661

Conditions

Condition	Modality	Highest Phase	Product
Periapical diseases 12 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19840650	Primary	Not Provided 504	Unknown Approved Use Unknown
Cancer 592 Sources: https://www.ncbi.nlm.nih.gov/pubmed/15987702	Diagnostic	Natural Metabolite	Unknown Approved Use Unknown
Unknown 2578
Relapsing forms of multiple sclerosis 12 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/204063s014lbl.pdf	Secondary	Approved 8429	TECFIDERA Approved Use Indicated for the treatment of patients with relapsing forms of multiple sclerosis Launch Date 2013
Arthritis 89 Sources: https://www.ncbi.nlm.nih.gov/pubmed/28832396	Palliative	Preclinical	Unknown Approved Use Unknown
Multiple sclerosis 104 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204063Orig1s010.pdf	Primary	Approved 8429	TECFIDERA Approved Use TECFIDERA, 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 Date 2013
Ischemic stroke 41 Sources: https://www.ncbi.nlm.nih.gov/pubmed/27614618	Preventing	Preclinical	Unknown Approved Use Unknown
Unknown 2578

C_max

Value	Dose	Co-administered	Analyte	Population
1.87 mg/L DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/204063lbl.pdf	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 DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/204063lbl.pdf	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

T_1/2

Value	Dose	Co-administered	Analyte	Population
1 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/204063lbl.pdf	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

F_unbound

Value	Dose	Co-administered	Analyte	Population
64% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/204063lbl.pdf	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: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/210296s000lbl.pdf Page: 6.1	unhealthy, adult n = 769 Health Status: unhealthy Condition: multiple sclerosis Age Group: adult Sex: unknown Population Size: 769 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/210296s000lbl.pdf Page: 6.1	Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/210296s000lbl.pdf 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: https://pubmed.ncbi.nlm.nih.gov/32629403/	unhealthy, mean 37 years n = 105 Health Status: unhealthy Condition: multiple sclerosis Age Group: mean 37 years Sex: M+F Population Size: 105 Sources: https://pubmed.ncbi.nlm.nih.gov/32629403/	Other AEs: Gastrointestinal disturbance... Other AEs: Gastrointestinal disturbance (53%) Sources: https://pubmed.ncbi.nlm.nih.gov/32629403/

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: https://pubmed.ncbi.nlm.nih.gov/32629403/	unhealthy, mean 37 years n = 105 Health Status: unhealthy Condition: multiple sclerosis Age Group: mean 37 years Sex: M+F Population Size: 105 Sources: https://pubmed.ncbi.nlm.nih.gov/32629403/

Overview

CYP3A4	CYP2C9	CYP2D6	hERG

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP 111 P-gp 1461	CYP450 65	P-gp 257 CYP 76

Drug as perpetrator

Target	Modality	Activity
CYP 147	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/210296s000lbl.pdf#page=10 Page: 10.0	no
CYP 147	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/210296s000lbl.pdf#page=10 Page: 10.0	no
P-gp 1650	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/210296s000lbl.pdf#page=10 Page: 10.0	no
P-gp 1650	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/210296s000lbl.pdf#page=10 Page: 10.0	no

Drug as victim

Target	Modality	Activity	Metabolite	Clinical evidence
CYP450 65	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/210296Orig1s000ClinPharmR.pdf#page=8 Page: 8.0	no

Sourcing

Vendor/Aggregator	ID	URL
3B Scientific (Wuhan) Corp	3B4-0303	http://www.3bsc.com/index/pro_info.php?id=18151
3B Scientific (Wuhan) Corp	3B4-2852	http://www.3bsc.com/index/pro_info.php?id=77486
AK Scientific, Inc. (AKSCI)	O997	http://www.aksci.com/item_detail.php?cat=O997
Aaron Chemicals	AR002URG	http://www.aaronchem.com/2756-87-8
Achemtek	0104-021727	http://www.achemtek.com/2756-87-8
Alfa Chemistry	AP2756878	https://reagents.alfa-chemistry.com/product/mono-methyl-fumarate-cas-2756-87-8-9093.html
Alichem	490019201	http://www.alichem.com/en/products/2756-87-8.html
Ambeed	A983659	https://www.ambeed.com/products/2756-87-8.html
Ambinter	Amb10071357	http://www.ambinter.com/reference/10071357
ApexBio Technology	B7674	http://www.apexbt.com/mmf.html
Aurora Fine Chemicals LLC	A01.295.615	http://online.aurorafinechemicals.com/info?ID=A01.295.615
Aurum Pharmatech LLC	M-3444	http://www.Aurumpharmatech.com/Product/ProductDetails/M_3444
Avantor Inc	TCM2413-5G	https://us.vwr.com/store/product/16813484/fumaric-acid-monomethyl-ester-98-0-by-gc
BLD Pharm	BD00941719	http://www.bldpharm.com/products/2756-87-8.html
BLD Pharm	BD140326	http://www.bldpharm.com/products/2756-87-8.html
BioChemPartner	BCP18454	http://www.biochempartner.com/2756-87-8-BCP18454
BioSynth	J-017996	https://www.biosynth.com/en/products/all-products/products/J-017996.html
BioSynth	J-522708	https://www.biosynth.com/en/products/all-products/products/J-522708.html
CSNpharm	CSN22981	https://www.csnpharm.com/products/mmf.html
Chem Scene	CS-0026484	http://www.chemscene.com/2756-87-8.html
ChemMol	99067199	http://www.chemmol.com/chemmol/99067199.html
Chemspace	CSSB00011216927	https://chem-space.com/CSSB00011216927
DC Chemicals	DC33842	http://www.dcchemicals.com//product_show-Monomethyl_Fumarate.html
Hairui	MOJB01402	http://www.hairuichem.com/en/product/2756-87-8.html
LGC Standards	MM0352.03-0025	https://www.lgcstandards.com/US/en/p/MM0352.03-0025
Lab Network	LN01310370	https://labnetwork.com/frontend-app/p/#!/moleculedetails/LN01310370
MedChem Express	HY-103252	https://www.medchemexpress.com/monomethyl-fumarate.html
MuseChem	R058046	https://www.musechem.com/product/R058046.html
OChem	4292	http://www.ocheminc.com/index.php?act=psearch&pid=56M878
Oakwood	102026	http://www.oakwoodchemical.com/ProductsList.aspx?CategoryID=-2&txtSearch=170495&ExtHyperLink=1
Oakwood	94823	http://www.oakwoodchemical.com/ProductsList.aspx?CategoryID=-2&txtSearch=79997&ExtHyperLink=1
Selleck Chemicals	S6889	http://www.selleckchem.com/products/monomethyl-fumarate.html
Sigma-Aldrich	651419_ALDRICH	https://www.sigmaaldrich.com/catalog/product/aldrich/651419?utm_source=pubchem&utm_campaign=pubchem_2017&utm_medium=referral
Sigma-Aldrich	92571_SIAL	https://www.sigmaaldrich.com/catalog/product/sial/92571?utm_source=pubchem&utm_campaign=pubchem_2017&utm_medium=referral
Smolecule	S536016	http://www.smolecule.com/products/s536016
Smolecule	S759551	https://www.smolecule.com/products/s759551
TCI (Tokyo Chemical Industry)	M2413	http://www.tcichemicals.com/eshop/en/us/commodity/M2413/index.html
THE BioTek	bt-275065	https://www.thebiotek.com/product/inhibitors/bt-275065
Tocris	4511	https://www.tocris.com/products/mmf_4511
VladaChem	VL278632-1G	https://www.vladachem.com/product.php?products=2756-87-8
abcr GmbH	AB503712	http://www.abcr.com/shop/en/AB503712
abcr GmbH	AB558870	http://www.abcr.com/shop/en/AB558870
eNovation Chemicals	D382932	http://www.enovationchem.com/productDetails.asp?productID=D382932
eNovation Chemicals	D533508	https://www.enovationchem.com/ProductDetails.asp?ProductID=D533508
eNovation Chemicals	D695687	https://www.enovationchem.com/ProductDetails.asp?ProductID=D695687
iChemical	EBD2637923	http://www.ichemical.com/products/2756-87-8.html?utm_source=PubChem&utm_medium=website&utm_campaign=product%20catalogs

PubMed

Title	Date	PubMed
Antifungal properties of 2-bromo-3-fluorosuccinic acid esters and related compounds.	1977 Apr	321785
The influence of long-term treatment with timolol on human tear lysozyme albumin content.	1982	7075967
Urinary loss of glucose, phosphate, and protein by diffusion into proximal straight tubules injured by D-serine and maleic acid.	1985 Jun	3925238
Menstrual migraine and intermittent ergonovine therapy.	1989 Jun	2759844
Automated screening of urine samples for carbohydrates, organic and amino acids after treatment with urease.	1991 Jan 2	2026685
Ocular surface alteration after long-term treatment with an antiglaucomatous drug.	1992 Jul	1495787
Physiology and pathophysiology of organic acids in cerebrospinal fluid.	1993	8412012
Disposition of [14C]velnacrine maleate in rats, dogs, and humans.	1993 Nov-Dec	7905382
[Studies on the mechanisms of renal damages induced by nephrotoxic compounds].	1995 Dec	8583688
Abnormal substrate levels that depend upon mitochondrial function in cerebrospinal fluid from Alzheimer patients.	1998	9693263
Morphological effect of the type, concentration and etching time of acid solutions on enamel and dentin surfaces.	1998	9835798
Hepatic infarction following percutaneous ethanol injection therapy for hepatocellular carcinoma.	1998 Nov	9872612
In vitro shear bond strength of adhesive to normal and fluoridated enamel under various contaminated conditions.	1999 Aug	10635272
Determination of trimebutine and desmethyl-trimebutine in human plasma by HPLC.	2000 Jul	10965422
Molecular mechanism for the regulation of human mitochondrial NAD(P)+-dependent malic enzyme by ATP and fumarate.	2002 Jul	12121650
An in vitro study on restoring bond strength of a GIC to saliva contaminated enamel under unrinse condition.	2002 Jul-Aug	12450709
The comparison of plasma deproteinization methods for the detection of low-molecular-weight metabolites by (1)H nuclear magnetic resonance spectroscopy.	2002 May 15	12009699
Neocortical neurons cultured from mice with expanded CAG repeats in the huntingtin gene: unaltered vulnerability to excitotoxins and other insults.	2003	12895502
Aqueous humour flow after a single oral dose of isosorbide-5-mononitrate in healthy volunteers.	2003 Aug	12859262
Molecular machinery for non-vesicular trafficking of ceramide.	2003 Dec 18	14685229
Effect of inducers of DT-diaphorase on the haemolytic activity and nephrotoxicity of 2-amino-1,4-naphthoquinone in rats.	2005 Aug 15	16045903
Enhanced cytotoxicity of bioreductive antitumor agents with dimethyl fumarate in human glioblastoma cells.	2005 Feb	15655414
Tumor-necrosis-factor-related apoptosis-inducing-ligand (TRAIL)-mediated death of neurons in living human brain tissue is inhibited by flupirtine-maleate.	2005 Oct	16043230
Effects of antiglaucoma drugs on collagen gel contraction mediated by human corneal fibroblasts.	2006 Jun	16778650
Molecular mechanisms of Nrf2-mediated antioxidant response.	2009 Feb	18618599
DMF inhibits PDGF-BB induced airway smooth muscle cell proliferation through induction of heme-oxygenase-1.	2010 Oct 20	20961405
Small molecule activators of the Nrf2-HO-1 antioxidant axis modulate heme metabolism and inflammation in BV2 microglia cells.	2013 Oct	23942037
Role of Nuclear Factor (Erythroid-Derived 2)-Like 2 Signaling for Effects of Fumaric Acid Esters on Dendritic Cells.	2017	29312359
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	29263788
Monomethyl fumarate inhibits pain behaviors and amygdala activity in a rat arthritis model.	2017 Dec	28832396
Bioanalysis of monomethyl fumarate in human plasma by a sensitive and rapid LC-MS/MS method and its pharmacokinetic application.	2017 Nov 30	28873360
Dual action by fumaric acid esters synergistically reduces adhesion to human endothelium.	2018 Dec	28984166
Dimethyl fumarate treatment alters NK cell function in multiple sclerosis.	2018 Feb	29108094
Multiple mechanisms of dimethyl fumarate in amyloid β-induced neurotoxicity in human neuronal cells.	2018 Feb	28990726
Dimethyl fumarate influences innate and adaptive immunity in multiple sclerosis.	2018 Jan	28958667
Monomethyl fumarate treatment impairs maturation of human myeloid dendritic cells and their ability to activate T cells.	2019 Jan	29106333

Patents

Sample Use Guides

In Vivo Use Guide

462 mg twice daily

Route of Administration: Oral

In Vitro Use Guide

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.

Name

Type

Language

Fumaric acid

Official Name

English

TRANS-BUTENEDIOIC ACID

Systematic Name

English

2(TRANS)-BUTENEDIOIC ACID

Systematic Name

English

BOLETIC-ACID

Common Name

English

INS NO.297

Code

English

SODIUM AUROTHIOMALATE IMPURITY B [EP IMPURITY]

Common Name

English

FEMA NO. 2488

Code

English

MALIC ACID IMPURITY A [EP IMPURITY]

Common Name

English

FUMARIC ACID [MI]

Common Name

English

E-297

Code

English

2-BUTENEDIOIC ACID, (E)-

Common Name

English

Fumaric acid [WHO-DD]

Common Name

English

FUMARIC ACID [USP IMPURITY]

Common Name

English

ETHYLENEDICARBOXYLIC ACID

Systematic Name

English

ALLOMALEIC-ACID

Common Name

English

(E)-BUTENEDIOIC ACID

Systematic Name

English

FUMARIC ACID [INCI]

Common Name

English

FUMARIC ACID [HSDB]

Common Name

English

FUMARICUM ACIDUM [HPUS]

Common Name

English

FUMARIC ACID [MART.]

Common Name

English

NSC-2752

Code

English

TRANS-1,2-ETHYLENEDICARBOXYLIC ACID

Common Name

English

FUMARICUM ACIDUM

Common Name

English

FUMARIC ACID [VANDF]

Common Name

English

FUMARIC ACID [USP-RS]

Common Name

English

FUMARIC ACID [FHFI]

Common Name

English

FUMARIC ACID [II]

Common Name

English

INS-297

Code

English

FUMARIC ACID [FCC]

Common Name

English

Classification Tree Code System Code

LOINC

13743-0