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The SARfaris: GPCR, Kinase, ADME

Thursday, 19 September 2013

New Drug Approvals 2013 - Pt. XIV - Tecfidera™

ATC Code: N07XX09 (2014)
Wikipedia: Dimethyl Fumerate

On March 27th the FDA approved Dimethyl Fumarate (DMF, trade name TECFIDERA™) for the treatment of adults with relapsing forms of multiple sclerosis (MS). DMF and the metabolite, monomethyl fumerate (MMF), activate the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway via inhibition of Kelch-like ECH-associated protein 1 (KEAP1, cytosolic inhibitor of Nrf2). 

The KEAP1 (CHEMBL2069156) is a naturally occuring cytosolic inhibitor of Nrf2 and DMF/MMF acts through chemical modification of KEAP1.

The NrF2 pathway is the primary cellular defence against the cytotoxic effects of oxidative stress. After translocation to the nucleus, Nrf2 heterodimerizes with MafF, MafG, and MafK. The combined heterodimer binds to antioxidant/electrophile response element (ARE/EpRE) and subsequently initiates transcription of these genes.

KEAP1 acts as the cytosolic anchor of Nrf2, sequestering Nrf2 in the cytoplasm during basal conditions. In addition KEAP1 contains a nuclear export signal and it is hypothesised to be the primary redox sensor. Thus DMF mediated inhibition of KEAP, leads to an increase of NrF2 translocation and increase in transcription of ARE/EpRE. This is hypothesized to be the working mechanism of DMF/MMF in MS. In addition, MMF has been shown to be an agonist of the nicotinic acid receptor (CHEMBL3785).
Dimethyl Fumarate (CHEMBL2107333 ; Chemspider : 553171;  Pubchem : 99431554 ) is a small molecule drug with a molecular weight of 144.1 Da, an AlogP of 0.49 , 4 rotatable bonds and does not violate the rule of 5.

Canonical SMILES : COC(=O)\C=C\C(=O)OC
InChi: InChI=1S/C6H8O4/c1-9-5(7)3-4-6(8)10-2/h3-4H,1-2H3/b4-3+

The recommended starting dose of TECFIDERA is 120 mg twice daily, for 7 days. Subsequently the dosage should be increased to a 240 mg twice daily maintenance dose. Tecfidera can be taken with or without food.

In humans, dimethyl fumarate is extensively metabolized by esterases, which are ubiquitous in the gastrointestinal tract, blood, and tissues, before it reaches the systemic circulation. Further metabolism of MMF occurs through the tricarboxylic acid (TCA) cycle, with no involvement of the cytochrome P450 (CYP) system. MMF, fumaric and citric acid, and glucose are the major metabolites in plasma.

Exhalation of CO2 is the primary route of elimination, accounting for approximately 60% of the TECFIDERA dose. Renal and fecal elimination are minor routes of elimination, accounting for 16% and 1% of the dose respectively. Trace amounts of unchanged MMF were present in urine.

The terminal half-life of MMF is approximately 1 hour and no circulating MMF is present at 24 hours in the majority of individuals. Accumulation of MMF does not occur with repeated dosing.

The license holder is Biogen Idec. the full prescribing information can be found here.


Filip Stefaniak said...

There is a small mistake:

> Canagliflozin (CHEMBL2107333 ; Chemspider : 553171; Pubchem : 99431554 ) is a small molecule drug with a molecular weight of 144.1 Da

Canagliflozin is an inhibitor of subtype 2 sodium-glucose transport protein (SGLT2)

Gerard JP van Westen said...

Indeed this is the case, that should have read Dimethyl Fumarate, and it is fixed.

Thanks :)