Reactivity of dimethyl fumarate and methylhydrogen fumarate towards glutathione and N-acetyl-l-cysteine—Preparation of S-substituted thiosuccinic acid esters

摘要: Abstract Dimethyl fumarate (DMF) is used successfully to treat psoriasis. In spite of its proven clinical efficacy, the mode metabolism and pharmacodynamics DMF are still not completely understood. Some previous studies have indicated that orally applied for a considerable part quickly hydrolysed methylhydrogen (MHF) at basic pH conditions as present in upper intestine, especially presence biological fluids containing esterases. On other hand it was shown due high lipophilicity rapidly penetrates into cells may thus least be absorbed after po application without being hydrolysed. hand, no detectable amounts were hitherto found plasma samples administration. order shed light on possible further routes presystemic DMF, reactivity towards glutathione (GSH) carried out. GSH millimolar concentrations almost all cells. nature an α,β-unsaturated carboxylic acid ester can react spontaneously with thiols via Michael-type addition. It could reacts rates under near-physiological conditions. Studies reaction kinetics 7.4 show addition proceeds yield 1:1 mixture both diastereomeric 2-(S-glutathionyl)-succinic dimethyl esters. MHF identical well leading four products (2 pairs). However, reacted much lower rate. The structures thiol conjugates confirmed unambiguously by extensive NMR measurements. corresponding mercapturic acids grounds spontaneous observed expected major metabolites unhydrolysed which makes way enterocytes. MHF, slow GSH, higher chances than more essential groups macromolecules.