2,7-Disubstituted-Pyrrolotriazine Kinase Inhibitors with an Unusually High Degree of Reactive Metabolite Formation

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• 作者：Kevin J. Wells-Knecht ; Gregory R. Ott ; Mangeng Cheng ; Gregory J. Wells ; Henry J. Breslin ; Diane E. Gingrich ; Linda Weinberg ; Eugen F. Mesaros ; Zeqi Huang ; Mehran Yazdanian ; Mark A. Ator ; Lisa D. Aimone ; Kelli Zeigler ; Bruce D. Dorsey
• 刊名：Chemical Research in Toxicology
• 出版年：2011
• 出版时间：November 21, 2011
• 年：2011
• 卷：24
• 期：11
• 页码：1994-2003
• 全文大小：1018K
• 年卷期：v.24,no.11(November 21, 2011)
• ISSN：1520-5010

文摘

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鈥?0 times higher than previously reported for high reactive metabolite-forming compounds such as clozapine and troglitazone.