DIMETHYL FUMARATE

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+

HIDE SMILES / InChI

Description

Dimethyl fumarate (DMF) is the methyl ester of fumaric acid. DMF was initially recognized as a very effective hypoxic cell radiosensitizer. Later, DMF combined with three other fumaric acid esters (FAE) was licensed in Germany as oral therapy for psoriasis (trade name Fumaderm). Phase III clinical trials found that DMF (BG-12) successfully reduced relapse rate and increased time to progression of disability in multiple sclerosis (trade name Tecfidera). DMF is thought to have immunomodulatory properties without significant immunosuppression. 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.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
NRF2 pathway 7	Activator 1,447
pyroptosis 6	Inhibitor 8,504
Hydroxycarboxylic acid receptor 2 28	Activator 1,447
Nuclear factor erythroid 2-related factor 2 15	Activator 1,447
Glutathione S-transferase 6	Substrate 661

Conditions

Condition	Modality	Highest Phase	Product
Relapsing forms of multiple sclerosis 6	Secondary	Approved 8,583	TECFIDERA
Arthritis 87	Palliative	Preclinical	Unknown
Multiple sclerosis 107	Primary	Approved 8,583	TECFIDERA
Ischemic stroke 35	Preventing	Preclinical	Unknown
Relapsing forms of multiple sclerosis 6	Primary	Approved 8,583	Vumerity
Unknown 2,596

C_max

Value	Dose	Co-administered	Analyte	Population
1.57 μg/mL	462 mg single, oral		MONOMETHYL FUMARATE plasma	Homo sapiens
0.88 μg/mL	462 mg single, oral		MONOMETHYL FUMARATE plasma	Homo sapiens
1.63 μg/mL	462 mg single, oral		MONOMETHYL FUMARATE plasma	Homo sapiens
0.955 μg/mL	462 mg single, oral		MONOMETHYL FUMARATE plasma	Homo sapiens
0.9 μg/mL	462 mg single, oral	ALCOHOL	MONOMETHYL FUMARATE plasma	Homo sapiens
1 μg/mL	462 mg single, oral	ALCOHOL	MONOMETHYL FUMARATE plasma	Homo sapiens
0.6 μg/mL	462 mg single, oral	ALCOHOL	MONOMETHYL FUMARATE plasma	Homo sapiens
2.11 mg/L	462 mg 2 times / day multiple, oral		MONOMETHYL FUMARATE plasma	Homo sapiens
1.87 mg/L	240 mg 2 times / day multiple, oral		MONOMETHYL FUMARATE plasma	Homo sapiens

AUC

Value	Dose	Analyte	Population
3.57 μg × h/mL	462 mg single, oral	MONOMETHYL FUMARATE plasma	Homo sapiens
3.336 μg × h/mL	462 mg single, oral	MONOMETHYL FUMARATE plasma	Homo sapiens
4.879 μg × h/mL	462 mg single, oral	MONOMETHYL FUMARATE plasma	Homo sapiens
4.939 μg × h/mL	462 mg single, oral	MONOMETHYL FUMARATE plasma	Homo sapiens
4.743 μg × h/mL	462 mg single, oral	MONOMETHYL FUMARATE plasma	Homo sapiens
2.83 μg × h/mL	462 mg single, oral	MONOMETHYL FUMARATE plasma	Homo sapiens
3.09 μg × h/mL	462 mg single, oral	MONOMETHYL FUMARATE plasma	Homo sapiens
2.5 μg × h/mL	462 mg single, oral	MONOMETHYL FUMARATE plasma	Homo sapiens
8.32 mg × h/L	462 mg 2 times / day multiple, oral	MONOMETHYL FUMARATE plasma	Homo sapiens
8.21 mg × h/L	240 mg 2 times / day multiple, oral	MONOMETHYL FUMARATE plasma	Homo sapiens

T_1/2

Value	Dose	Co-administered	Analyte	Population
1 h	single, oral		MONOMETHYL FUMARATE plasma	Homo sapiens
1 h	240 mg 2 times / day multiple, oral		MONOMETHYL FUMARATE plasma	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
75%			MONOMETHYL FUMARATE plasma	Homo sapiens
64%	240 mg 2 times / day multiple, oral		MONOMETHYL FUMARATE plasma	Homo sapiens

Doses

Show entries

Dose	Population	Adverse events
190 mg 2 times / day multiple, oral Highest studied dose	unhealthy, adult
190 mg 2 times / day multiple, oral Highest studied dose	unhealthy, mean 37 years	Other AEs: Gastrointestinal disturbance...
462 mg 2 times / day multiple, oral Recommended	unhealthy, ADULT	Disc. AE: Adverse event, Gastrointestinal adverse event...
462 mg 2 times / day multiple, oral Recommended	unhealthy, ADULT	Disc. AE: Adverse event, Gastrointestinal adverse event...
240 mg 2 times / day multiple, oral Studied dose	unhealthy, ADULT	Disc. AE: Gastrointestinal events, Elevated hepatic transaminases...

Showing 1 to 5 of 5 entries

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AEs

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AE	Significance	Dose	Population
Gastrointestinal disturbance	53%	190 mg 2 times / day multiple, oral Highest studied dose	unhealthy, mean 37 years
Adverse event	0.8% Disc. AE	462 mg 2 times / day multiple, oral Recommended	unhealthy, ADULT
Gastrointestinal adverse event	0.8% Disc. AE	462 mg 2 times / day multiple, oral Recommended	unhealthy, ADULT
Gastrointestinal adverse event	0.7% Disc. AE	462 mg 2 times / day multiple, oral Recommended	unhealthy, ADULT
Adverse event	5.6% Disc. AE	462 mg 2 times / day multiple, oral Recommended	unhealthy, ADULT

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 2,252 inducer 1,087	inhibitor 2,438	inhibitor 2,507

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2C19 2,057 P-gp 1,741 BCRP 910 MATE1 415 CYP2C8 1,057 CYP2B6 926 CYP3A5 136 CYP1A2 2,153 MATE2-K 77 OAT1 725 OAT3 747 OCT2 779 CYP 110	CYP 303 BCRP 697 CYP450 59	P-gp 301 CYP2B6 669 CYP1A2 832 CYP 74

Drug as perpetrator

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Target	Modality	Activity	Metabolite
BCRP 985	inhibitor 4,027	no
BCRP 985	inhibitor 4,027	no	2-hydroxyethyl succinimide (HES, RDC-6567) 6
CYP 150	inducer 1,966	no
CYP 150	inhibitor 4,027	no
CYP1A2 2,333	inducer 1,966	no

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Drug as victim

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Target	Modality	Activity	Metabolite
BCRP 697	substrate 4,014	no
CYP 303	substrate 4,014	no	Monomethyl fumarate 6
CYP450 59	substrate 4,014	no

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Sourcing

Sourcing

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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
Aaron Chemicals	AR002URG	http://www.aaronchem.com/2756-87-8
abcr GmbH	AB503712	http://www.abcr.com/shop/en/AB503712
abcr GmbH	AB558870	http://www.abcr.com/shop/en/AB558870

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PubMed

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Title	Date	PubMed
Antifungal properties of 2-bromo-3-fluorosuccinic acid esters and related compounds.	1977 Apr	321785
Effect of inducers of DT-diaphorase on the haemolytic activity and nephrotoxicity of 2-amino-1,4-naphthoquinone in rats.	2005 Aug 15	16045903
Structure-activity comparison of the cytotoxic properties of diethyl maleate and related molecules: identification of diethyl acetylenedicarboxylate as a thiol cross-linking agent.	2011 Jan 14	21105742
Multiple mechanisms of dimethyl fumarate in amyloid β-induced neurotoxicity in human neuronal cells.	2018 Feb	28990726
Monomethyl fumarate treatment impairs maturation of human myeloid dendritic cells and their ability to activate T cells.	2019 Jan	29106333

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Patents

Sample Use Guides

In Vivo Use Guide

Male and female weanling Sprague-Dawley rats were used for activity evaluation. The experiment was a three-factor, two-bytwo- by-two design with two dietary variables; arsenic as Na2HAsO4 7H20, 0 or 0.5 mkg/g, and DEM (Dimethyl maleate), 0 or 0.25%; gender was the third variable. The rats were fed their respective diets for 10 wk, fasted for 16 h, weighed, then decapitated subsequent to ether anesthesia and a cardiac blood draw with a heparin-coated syringe and needle.

Route of Administration: Oral

In Vitro Use Guide

Hepatic microsomal fractions were isolated from Male, Sprague-Dawley rats. Reaction mixtures contained 50 mkM of phosphate buffer (p11 7.4)) 15 mkM of magnesium chloride, 10 mkM of DL-isocitric acid, 1 mkM of NADP+, 1 unit of isocitrate dehydrogenase (Sigma), varying amounts of substrates and diethyl maleate and approximately 3 mg of microsomal protein in a final volume of 3.0 ml. Reaction mixtures were incubated for 15 min at 37°C.

Show entries

Name

Type

Language

DIMETHYL FUMARATE

Official Name

English

FUMARIC ACID DIMETHYL ESTER

Preferred Name

English

FAG-201

Code

English

NSC-167432

Code

English

BG-00012

Code

English

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Classification Tree

Code System

Code

Agent Affecting Integumentary System

NCI_THESAURUS

C29708

Other nervous system drugs

WHO-ATC

N07XX09

Antineoplastic Agent

NCI_THESAURUS

C798

Positive

EU-Orphan Drug

EU/3/18/1990

Designated

FDA ORPHAN DRUG

406713

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Code System

Code

Type

Description

NCI_THESAURUS

C63670

PRIMARY

IUPHAR

7045

PRIMARY

NSC

25942

PRIMARY

RXCUI

1373478

PRIMARY

RxNorm

MESH

C056020

PRIMARY

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ACTIVE MOIETY


					45IUB1PX8R

Monomethyl Fumarate

METABOLITE INACTIVE (PARENT)


					9OXV3T5998

2-(((2R)-2-AMINO-2-CARBOXYETHYL)THIO)BUTANEDIOIC ACID 1-METHYL ESTER

METABOLITE INACTIVE (PARENT)


					88XHZ13131

Fumaric acid

SMILES

InChI

CNS Activity

Originator

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Funbound

Doses

AEs

Overview

OverviewOther

Drug as perpetrator​

Drug as victim

Sourcing

PubMed

Patents

Sample Use Guides

C_max

T_1/2

F_unbound

Drug as perpetrator