Dimethyl fumarate

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Dimethyl fumarate
IUPAC name

Dimethyl (E)-butenedioate

Other names

trans-1,2-Ethylenedicarboxylic acid dimethyl ester
(E)-2-Butenedioic acid dimethyl ester

Identifiers
CAS number 624-49-7 YesY
ChemSpider 553171 YesY
UNII FO2303MNI2 YesY
EC number 210-849-0
ChEBI CHEBI:76004 N
ATC code N07XX09
Jmol-3D images Image 1
Properties
Molecular formula C6H8O4
Molar mass 144.127 g/mol
Appearance White crystalline solid
Density 1.37 g/cm³, solid
Melting point 102–105 °C[1]
Boiling point 192–193 °C[1]
Hazards
EU classification Harmful (Xn)
R-phrases R21 R38 R41 R43
S-phrases S26 S36 S37 S39
Related compounds
Related diesters Diethyl fumarate, dimethyl maleate, dimethyl malonate, dimethyl adipate
Related compounds Fumaric acid
Methyl acrylate
 N (verify) (what is: YesY/N?)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
Infobox references

Dimethyl fumarate (DMF) is the methyl ester of fumaric acid. DMF was initially recognized as a very effective hypoxic cell radiosensitizer.[2] Later, DMF combined with three other fumaric acid esters (FAE) was licensed in Germany as oral therapy for psoriasis (trade name Fumaderm).[3] Other diseases, such as necrobiosis lipoidica, granuloma annulare, and sarcoidosis were also found to respond to treatment with DMF in case reports or small patient series.[4] 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).[5][6] DMF is thought to have immunomodulatory properties without significant immunosuppression.[7]

In a non-medical use, DMF was applied as a biocide in furniture or shoes to prevent growths of mold during storage or transport in a humid climate. However, due to incidences of allergic reactions after skin contact the European Union banned DMF in consumer products since 1998, and since January 2009 the import of products containing DMF was also banned.[8]

Reactions

Dimethyl fumarate is an ester and an α,β-unsaturated electrophilic compound which can quickly undergo Michael additions with nucleophiles. DMF is also an effective diene acceptor in the ordinary Diels-Alder reaction, where the reactivity of its vinylidenic bond is enhanced by the two electron-withdrawing ester groups. Due to the geometry of the starting ester, the Diels-Alder product will have a trans configuration. With this reaction, compounds with bicyclo skeletons can be synthesized, e.g. a diester with a norbornene (bicyclo[2.2.1]heptene) skeleton from dimethyl fumarate and cyclopentadiene.

Mechanism of action

Dimethyl fumarate is a lipophilic, highly mobile molecule in human tissue. As a α,β-unsaturated electrophilic compound, dimethyl fumarate is rapidly attacked by the detoxifying agent glutathione (GSH) in a Michael addition reaction.[9][10][11] Dimethyl fumarate is highly reactive: when administered orally, it does not survive long enough to be absorbed into blood without being attacked by GSH. However, part of it is hydrolyzed by esterases to produce monomethylfumarate, which is more resistant.[12] GSH depletion and subsequent induction of the anti-inflammatory stress protein HO-1 is thought to be one of the mechanisms responsible for the immunomodulatory actions of DMF.[13]

Other postulated mechanisms of action include direct cytoprotective effects through upregulation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and subsequent induction of an antioxidant response.[14]

Medical use

The medical use of fumaric acid esters (FAE) was first described in 1959 by the German chemist W. Schweckendiek who reported on successful internal and external treatment of his own psoriasis.[15] Later, various controlled clinical trials confirmed the effectiveness of FAEs in psoriasis [16][17][18] and in 1994 a defined mixture of DMF and the Ca, Mg and Zn salts of the corresponding monoethylester, ethylhydrogen fumarate, was registered in Germany (Fumaderm, Fumapharm AG; now owned by Biogen Idec, Inc.).[3] Long-term studies have established the safety of FAE without an increased risk of infections, malignancies, or significant long-term toxic effects,[7][19][20][21] which are often seen with alternative systemic psoriasis therapies such as methotrexate[22] or cyclosporine.[23] A recent reports suggest a positive effect of continuous systemic anti-psoriatic therapy with FAE on the risk for cardiovascular disease.[24] The most common side effects seen with the medical use of FAE are gastro-intestinal symptoms and flushing, which can be the cause of treatment discontinuation in some patients. However, often these tolerability issues are self-limiting or can be mitigated by dose adaptation and appropriate patient counseling.[3] Upon stopping of drug administration the symptoms will disappear within a few days. A possible link to DMF treatment and the rare but serious brain disease, progressive multifocal leukoencephalopathy (PML), has been noted.[25]

Today, FAE are the most frequently prescribed medication for systemic treatment of psoriasis in Germany.[26] Apparently no attempts were made to receive marketing authorizations outside of Germany, however, FAE are also frequently used in other European countries on an off-label basis,[27][28][29] and European[30] and US guidelines[31] include FAE in their recommendations of first-line therapies for moderate to severe psoriasis.

FAE were also found to be effective in other conditions, including necrobiosis lipoidica, granuloma annulare, sarcoidosis, alopecia areata, cheilitis granulomatosa, recurrent oral aphthae, pityriasis rubra pilaris, annular elastolytic giant-cell granuloma or non-infectious chronic uveitis.[4]

Other in vitro and animal studies suggest that FAE can be used for the treatment of asthma bronchiale [32] or even melanoma.[33][34]

Pre-clinical studies and clinical trials have indicated that DMF is the most active FAE and that the additional FAE salts in the combination product Fumaderm are not required.[35]

An FAE drug product containing only DMF is now in late stage clinical development: The Danish company Forward Pharma A/S develops a small tablet containing DMF (FP187) for the treatment of moderate to severe psoriasis.[36][37] The American company Biogen Idec developed DMF as a capsule containing microtablets for the treatment of multiple sclerosis, under the code name BG-12; it was approved for sale as Tecfidera on March 27, 2013.[38][39] Tecfidera was shown to have a significant effect on relapse rate and time to progression in phase III clinical trials.[5][6]

DMF was recommended for approval in the European Union as a peroral treatment for MS by EMA March 21, 2013 under the name Tecfidera.[40] On March 27, 2013 FDA approved Tecfidera capsules to treat adults with relapsing forms of MS.[38][39]

Non-medical use

Dimethyl fumarate has been found to be an allergic sensitizer at very low concentrations, producing eczema that is difficult to treat. Concentrations as low as 1 ppm may produce allergic reactions.[41] There are only a handful of equally potent sensitizers.[42]

The sensitizing risk was brought to public attention by the "poison chair" incident, where Chinese manufacturer Linkwise produced two-seater sofas with dimethyl fumarate sachets inside to inhibit mould while they were in storage or transport.[43][44] In Finland where the chairs were sold from 2006–2007, sixty users were given serious rashes.[42] The cause was identified as dimethyl fumarate-induced allergic reaction by Tapio Rantanen from Finland, and his original article became the cover story in the July issue of the British Journal of Dermatology.[41] In the United Kingdom, sofas sold by Argos, Land of Leather and Walmsley Furnishing containing the chemical caused over a hundred injuries.[42][44] Argos withdrew the sofas from stores and contacted buyers to collect those that had been sold — with Land of Leather withdrawing the sofas without notifying buyers and Walmsley saying they had removed the sachets from sofas they sold after the danger came to light.[44] Complaints have been made that dates on the sofas were altered and sofas containing the sachets sold.[44] Land of Leather and Walmsley are facing a ₤10 million class action suit over their reaction to the incident, joining the manufacturer in denying the sofas are connected to their customers injuries.[44][45][46] The danger came to public attention when the BBC Watchdog program alerted consumers to the sofas.[44][45][47]

In the European Union the use of dimethyl fumarate for consumer products has been forbidden since 1998, and since January 2009 the import of products containing dimethyl fumarate is also forbidden.[8]

The EU Commission Decision 2009/251 of 17 March 2009 requiring Member States to ensure that products containing the biocide dimethylfumarate are not placed or made available on the market has definitely forbidden any marketing of products containing dimethyl fumarate into the European Union.[48] The ban on dimethyl fumarate as laid down in Decision 2009/251 establishes a maximum concentration of dimethyl fumarate in products of 0.1 ppm. Products containing more than 0.1 ppm dimethyl fumarate shall be withdrawn from the market and recalled by consumers as of 1 May 2009.

References

  1. ↑ 1.0 1.1 Acros MSDS
  2. ↑ Held, Kathryn D.; Epp, Edward R.; Clark, Edward P.; Biaglow, John E. (1988). "Effect of Dimethyl Fumarate on the Radiation Sensitivity of Mammalian Cells in Vitro". Radiation Research 115 (3): 495–502. doi:10.2307/3577299. JSTOR 3577299. PMID 3174933. 
  3. ↑ 3.0 3.1 3.2 Mrowietz, Ulrich; Altmeyer, Peter; Bieber, Thomas; Röcken, Martin; Schopf, Rudolf E.; Sterry, Wolfram (2007). "Treatment of psoriasis with fumaric acid esters (Fumaderm®)". JDDG 5 (8): 716–7. doi:10.1111/j.1610-0387.2007.06346.x. PMID 17659047. 
  4. ↑ 4.0 4.1 Meissner, Markus; Valesky, Eva Maria; Kippenberger, Stefan; Kaufmann, Roland (2012). "Dimethyl fumarate - only an anti-psoriatic medication?". JDDG 10 (11): 793–801. doi:10.1111/j.1610-0387.2012.07996.x. PMID 22897153. 
  5. ↑ 5.0 5.1 Gold, Ralf; Kappos, Ludwig; Arnold, Douglas L.; Bar-Or, Amit; Giovannoni, Gavin; Selmaj, Krzysztof; Tornatore, Carlo; Sweetser, Marianne T.; Yang, Minhua; Sheikh, Sarah I.; Dawson, Katherine T.; Define Study, Investigators (2012). "Placebo-Controlled Phase 3 Study of Oral BG-12 for Relapsing Multiple Sclerosis". New England Journal of Medicine 367 (12): 1098–107. doi:10.1056/NEJMoa1114287. PMID 22992073. 
  6. ↑ 6.0 6.1 Fox, Robert J.; Miller, David H.; Phillips, J. Theodore; Hutchinson, Michael; Havrdova, Eva; Kita, Mariko; Yang, Minhua; Raghupathi, Kartik; Novas, Mark; Sweetser, Marianne T.; Viglietta, Vissia; Dawson, Katherine T.; Confirm Study, Investigators (2012). "Placebo-Controlled Phase 3 Study of Oral BG-12 or Glatiramer in Multiple Sclerosis". New England Journal of Medicine 367 (12): 1087–97. doi:10.1056/NEJMoa1206328. PMID 22992072. 
  7. ↑ 7.0 7.1 McEntee, Joanne. "Fumaderm®: what is the evidence for its efficacy and safety". North West Medicines Information Centre. Retrieved 29 November 2012. 
  8. ↑ 8.0 8.1 "Consumers: EU to ban dimethylfumarate (DMF) in consumer products, such as sofas and shoes" (Press release). European Commission. Retrieved 29 November 2012. 
  9. ↑ Boyland, E; Chasseaud, LF (1967). "Enzyme-catalysed conjugations of glutathione with unsaturated compounds". The Biochemical journal 104 (1): 95–102. PMC 1270549. PMID 6035529. 
  10. ↑ Kubal, Gina; Meyer, David J.; Norman, Richard E.; Sadler, Peter J. (1995). "Investigations of Glutathione Conjugation in Vitro by 1H NMR Spectroscopy. Uncatalyzed and Glutathione Transferase-Catalyzed Reactions". Chemical Research in Toxicology 8 (5): 780–91. doi:10.1021/tx00047a019. PMID 7548762. 
  11. ↑ Schmidt, Thomas J.; Ak, Muharrem; Mrowietz, Ulrich (2007). "Reactivity of dimethyl fumarate and methylhydrogen fumarate towards glutathione and N-acetyl-l-cysteine—Preparation of S-substituted thiosuccinic acid esters". Bioorganic & Medicinal Chemistry 15 (1): 333–42. doi:10.1016/j.bmc.2006.09.053. PMID 17049250. 
  12. ↑ Schmidt, Thomas J.; Aka, Muharrem; Mrowietz, Ulrich (2007). "Reactivity of dimethyl fumarate and methylhydrogen fumarate towards glutathione and N-acetyl-l-cysteine—Preparation of S-substituted thiosuccinic acid esters". Bioorganic & Medicinal Chemistry 15 (1): 333–342. doi:10.1016/j.bmc.2006.09.053. PMID 17049250. 
  13. ↑ Lehmann, Joachim C U; Listopad, Joanna J; Rentzsch, Christine U; Igney, Frederik H; Von Bonin, Arne; Hennekes, Hartwig H; Asadullah, Khusru; Docke, Wolf-Dietrich F (2007). "Dimethylfumarate Induces Immunosuppression via Glutathione Depletion and Subsequent Induction of Heme Oxygenase 1". Journal of Investigative Dermatology 127 (4): 835–45. doi:10.1038/sj.jid.5700686. PMID 17235328. 
  14. ↑ Scannevin, R. H.; Chollate, S.; Jung, M.-y.; Shackett, M.; Patel, H.; Bista, P.; Zeng, W.; Ryan, S.; Yamamoto, M.; Lukashev, M.; Rhodes, K. J. (2012). "Fumarates Promote Cytoprotection of Central Nervous System Cells against Oxidative Stress via the Nuclear Factor (Erythroid-Derived 2)-Like 2 Pathway". Journal of Pharmacology and Experimental Therapeutics 341 (1): 274–84. doi:10.1124/jpet.111.190132. PMID 22267202. 
  15. ↑ Schweckendiek, W (1959). "Heilung von Psoriasis vulgaris" [Treatment of psoriasis vulgaris]. Medizinische Monatsschrift (in German) 13 (2): 103–4. PMID 13643669. 
  16. ↑ Nugteren-Huying, WM; Van Der Schroeff, JG; Hermans, J; Suurmond, D (1990). "Fumaric acid therapy in psoriasis; a double-blind, placebo-controlled study". Nederlands tijdschrift voor geneeskunde 134 (49): 2387–91. PMID 2263264. 
  17. ↑ Altmeyer, Peter J.; Matthes, Ulrich; Pawlak, Frank; Hoffmann, Klaus; Frosch, Peter J.; Ruppert, Peter; Wassilew, Sawko W.; Horn, Thomas; Kreysel, Hans W.; Lutz, Gerhard; Barth, Joachim; Rietzschel, Ilona; Joshi, Rajendra K. (1994). "Antipsoriatic effect of fumaric acid derivatives". Journal of the American Academy of Dermatology 30 (6): 977–81. doi:10.1016/S0190-9622(94)70121-0. PMID 8188891. 
  18. ↑ Kolbach, Dinanda N.; Nieboer, Cornells (1992). "Fumaric acid therapy in psoriasis: Results and side effects of 2 years of treatment". Journal of the American Academy of Dermatology 27 (5): 769–71. doi:10.1016/S0190-9622(08)80228-9. PMID 1430403. 
  19. ↑ Reich, Kristian; Thaci, Diamant; Mrowietz, Ulrich; Kamps, Anja; Neureither, Marcus; Luger, Thomas (2009). "Efficacy and safety of fumaric acid esters in the long-term treatment of psoriasis – A retrospective study (FUTURE)". Journal der Deutschen Dermatologischen Gesellschaft 7 (7): 603–11. doi:10.1111/j.1610-0387.2009.07120.x. PMID 19459898. 
  20. ↑ Mrowietz, U; Christophers, E; Altmeyer, P (1998). "Treatment of psoriasis with fumaric acid esters: Results of a prospective multicentre study". British Journal of Dermatology 138 (3): 456–60. doi:10.1046/j.1365-2133.1998.02124.x. PMID 9580799. 
  21. ↑ Hoefnagel, J.J.; Thio, H.B.; Willemze, R.; Bouwes Bavinck, J.N. (2003). "Long-term safety aspects of systemic therapy with fumaric acid esters in severe psoriasis". British Journal of Dermatology 149 (2): 363–9. doi:10.1046/j.1365-2133.2003.05433.x. PMID 12932244. 
  22. ↑ "FDA Label Methotrexate Tablets". DAVA Pharmaceuticals, Inc. Retrieved 29 November 2012. 
  23. ↑ "FDA Label Sandimmune". Novartis Pharmaceuticals Corporation. Retrieved 29 November 2012. 
  24. ↑ Boehncke, Sandra; Fichtlscherer, Stephan; Salgo, Rebekka; Garbaraviciene, Jurate; Beschmann, Heike; Diehl, Sandra; Hardt, Katja; Thaçi, Diamant et al. (2010). "Systemic therapy of plaque-type psoriasis ameliorates endothelial cell function: Results of a prospective longitudinal pilot trial". Archives of Dermatological Research 303 (6): 381–8. doi:10.1007/s00403-010-1108-6. PMID 21170539. 
  25. ↑ Van Oosten, Bob; et al (April 25, 2013). "PML in a Patient Treated with Dimethyl Fumarate from a Compounding Pharmacy". N Engl J Med 368 (368): 1658–1659. doi:10.1056/NEJMc1215357. 
  26. ↑ Psobest - German Psoriasis Registry. "Current Patient Count". IVDP, CVderm. Retrieved 29 November 2012. 
  27. ↑ Meiran, Nachshon; Gotler, Alex (2001). "Modelling cognitive control in task switching and ageing". European Journal of Cognitive Psychology 13: 165. doi:10.1080/09541440042000269. 
  28. ↑ Harries, M.J.; Chalmers, R.J.G.; Griffiths, C.E.M. (2005). "Fumaric acid esters for severe psoriasis: A retrospective review of 58 cases". British Journal of Dermatology 153 (3): 549–51. doi:10.1111/j.1365-2133.2005.06728.x. PMID 16120141. 
  29. ↑ "Fumaric Acid Esters Patient Information Leaflet". British Association of Dermatologists. Retrieved 29 November 2012. 
  30. ↑ Pathirana, D; Ormerod, AD; Saiag, P; Smith, C; Spuls, PI; Nast, A; Barker, J; Bos, JD; Burmester, G-R; Chimenti, S; Dubertret, L; Eberlein, B; Erdmann, R; Ferguson, J; Girolomoni, G; Gisondi, P; Giunta, A; Griffiths, C; Hönigsmann, H; Hussain, M; Jobling, R; Karvonen, S-L; Kemeny, L; Kopp, I; Leonardi, C; MacCarone, M; Menter, A; Mrowietz, U; Naldi, L; Nijsten, T (2009). "European S3-Guidelines on the systemic treatment of psoriasis vulgaris". Journal of the European Academy of Dermatology and Venereology 23: 1. doi:10.1111/j.1468-3083.2009.03389.x. 
  31. ↑ Menter, Alan; Korman, Neil J.; Elmets, Craig A.; Feldman, Steven R.; Gelfand, Joel M.; Gordon, Kenneth B.; Gottlieb, Alice B.; Koo, John Y.M.; Lebwohl, Mark; Lim, Henry W.; Van Voorhees, Abby S.; Beutner, Karl R.; Bhushan, Reva (2009). "Guidelines of care for the management of psoriasis and psoriatic arthritis". Journal of the American Academy of Dermatology 61 (3): 451–85. doi:10.1016/j.jaad.2009.03.027. PMID 19493586. 
  32. ↑ Seidel, P.; Merfort, I.; Hughes, J. M.; Oliver, B. G. G.; Tamm, M.; Roth, M. (2009). "Dimethylfumarate inhibits NF- B function at multiple levels to limit airway smooth muscle cell cytokine secretion". AJP: Lung Cellular and Molecular Physiology 297 (2): L326–39. doi:10.1152/ajplung.90624.2008. PMID 19465513. 
  33. ↑ Loewe, R.; Valero, T.; Kremling, S.; Pratscher, B.; Kunstfeld, R.; Pehamberger, H.; Petzelbauer, P. (2006). "Dimethylfumarate Impairs Melanoma Growth and Metastasis". Cancer Research 66 (24): 11888–96. doi:10.1158/0008-5472.CAN-06-2397. PMID 17178886. 
  34. ↑ Valero, Teresa; Steele, Silvia; Neumüller, Karin; Bracher, Andreas; Niederleithner, Heide; Pehamberger, Hubert; Petzelbauer, Peter; Loewe, Robert (2009). "Combination of Dacarbazine and Dimethylfumarate Efficiently Reduces Melanoma Lymph Node Metastasis". Journal of Investigative Dermatology 130 (4): 1087–94. doi:10.1038/jid.2009.368. PMID 19940857. 
  35. ↑ Yazdi, Martin Rostami; Mrowietz, Ulrich (2008). "Fumaric acid esters". Clinics in Dermatology 26 (5): 522–6. doi:10.1016/j.clindermatol.2008.07.001. PMID 18755371. 
  36. ↑ ClinicalTrials.gov NCT01230138 Pivotal Efficacy and Safety Registration Trial of FP187 in Moderate to Severe Plaque Psoriasis
  37. ↑ http://www.forward-pharma.com/news_room.html[][]
  38. ↑ 38.0 38.1 "Biogen Idec’s TECFIDERA™ (Dimethyl Fumarate) Approved in US as a First-Line Oral Treatment for Multiple Sclerosis". Biogen Idec Press Release. Mar 27, 2013. 
  39. ↑ 39.0 39.1 "FDA approves new multiple sclerosis treatment: Tecfidera". FDA news release. Mar 27, 2013. Retrieved 2013-04-05. 
  40. ↑ http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002601/smops/Positive/human_smop_000498.jsp&mid=WC0b01ac058001d127
  41. ↑ 41.0 41.1 Rantanen, T. (2008). "The cause of the Chinese sofa/chair dermatitis epidemic is likely to be contact allergy to dimethylfumarate, a novel potent contact sensitizer". British Journal of Dermatology 159 (1): 218–21. doi:10.1111/j.1365-2133.2008.08622.x. PMID 18503603. 
  42. ↑ 42.0 42.1 42.2 "Myrkkytuoli-ihottumien syy selvisi". YLE Uutiset (in Finnish) (YLE). 2008-04-24. Retrieved 2008-06-10. 
  43. ↑ http://www.thisisnottingham.co.uk/displayNode.jsp?nodeId=176452&command=displayContent&sourceNode=134483&contentPK=20867636&folderPk=78482&pNodeId=134462
  44. ↑ 44.0 44.1 44.2 44.3 44.4 44.5 Bracchi, Paul (21 June 2008). "This baby was burned red raw by a sofa giving off toxic fumes. As our investigation reveals, there are hundreds of other victims". Daily Mail (London). 
  45. ↑ 45.0 45.1 BBC - Consumer - TV and radio - itchy sofas
  46. ↑ BBC: Judge rejects 'toxic sofa' claims in burns injury cases, 18 March 2010
  47. ↑ "BBC: 3 reports on dimethyl fumarate in furniture". April 2010. 
  48. ↑ "2009/251/EC: Commission Decision of 17 March 2009". 

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