PMID:
     20530221
Authors:
     Hu Y, Yang S, Shilliday FB, Heyde BR, Mandrell KM, Robins RH,
     Xie J, Reding MT, Lai Y, Thompson DC.
Title:
     Novel metabolic bioactivation mechanism for a series of anti-inflammatory agents 
     (2,5-diaminothiophene derivatives) mediated by cytochrome p450 enzymes.
Journal:
     Drug Metab Dispos. 2010 Sep;38(9):1522-31. doi: 10.1124/dmd.110.032581. Epub 2010 
Abstract:
     The thiophene moiety is considered a structural alert in molecular design in drug 
     discovery, largely because several thiophene-containing drugs, including tienilic 
     acid and suprofen, have been withdrawn from the market because of toxicities. 
     Reactive thiophene intermediates, activated via sulfur oxidation or ring 
     epoxidation, are possible culprits for these adverse side effects. In this work, 
     the metabolic activation of an anti-inflammatory agent, 
     1-(3-carbamoyl-5-(2,3,5-trichlorobenzamido)thiophen-2-yl)urea), containing a 
     2,5-diaminothiophene structure, was studied in liver microsomes in the presence 
     of glutathione or N-acetylcysteine as trapping agents. In addition, the 
     glutathione conjugate was detected in bile from a bile duct-cannulated rat study. 
     The structure of the glutathione conjugate was identified by mass spectrometry 
     and (1)H NMR. The glutathione molecule was attached to the thiophene ring, 
     replacing the existing proton. Metabolic phenotyping experiments, using chemical 
     inhibitors or recombinant cytochromes P450 (P450), demonstrated that CYP3A4 was 
     the major P450 enzyme responsible for the metabolic activation, followed by 
     CYP1A2, 2Cs, and 2D6. A novel metabolic activation mechanism is proposed whereby 
     the 2,5-diaminothiophene moiety undergoes oxidation to a 2,5-diimine thiophene 
     reactive intermediate. This mechanism was used to support efforts to eliminate 
     reactive metabolite generation via structural modification of ring substituents 
     using structure-activity relationships. The disruption of formation of the 
     2,5-diimine reactive intermediate resulted in the elimination of glutathione 
     conjugate formation both in vitro and in vivo and provided a rational approach to 
     mitigating potential safety risks associated with this class of thiophenes in 
     drug research and development.

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