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  • Title: 2,7-Disubstituted-pyrrolotriazine kinase inhibitors with an unusually high degree of reactive metabolite formation.
    Author: Wells-Knecht KJ, Ott GR, Cheng M, Wells GJ, Breslin HJ, Gingrich DE, Weinberg L, Mesaros EF, Huang Z, Yazdanian M, Ator MA, Aimone LD, Zeigler K, Dorsey BD.
    Journal: Chem Res Toxicol; 2011 Nov 21; 24(11):1994-2003. PubMed ID: 22023349.
    Abstract:
    There are numerous published studies establishing a link between reactive metabolite formation and toxicity of various drugs. Although the correlation between idiosyncratic reactions and reactive metabolite formation is not 1:1, the association between the two is such that many pharmaceutical companies now monitor for reactive metabolites as a standard part of drug candidate testing and selection. The most common method involves in vitro human microsomal incubations in the presence of a thiol trapping agent, such as glutathione (GSH), followed by LC/MS analysis. In this study, we describe several 2,7-disubstituted-pyrrolotriazine analogues that are extremely potent reactive metabolite precursors. Utilizing a UPLC/UV/MS method, unprecedented levels of GSH adducts were measured that are 5-10 times higher than previously reported for high reactive metabolite-forming compounds such as clozapine and troglitazone.
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