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2,7-Disubstituted-pyrrolotriazine kinase inhibitors with an unusually high degree of reactive metabolite formation.

Wells-Knecht, Kevin J; Ott, Gregory R; Cheng, Mangeng; Wells, Gregory J; Breslin, Henry J; Gingrich, Diane E; Weinberg, Linda; Mesaros, Eugen F; Huang, Zeqi; Yazdanian, Mehran; Ator, Mark A; Aimone, Lisa D; Zeigler, Kelli; Dorsey, Bruce D.
Chem Res Toxicol; 24(11): 1994-2003, 2011 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-22023349
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.
Selo DaSilva