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Chem Res Toxicol. 2010 Mar 15;23(3):653-63. doi: 10.1021/tx900414g.

Cytochrome P450-mediated epoxidation of 2-aminothiazole-based AKT inhibitors: identification of novel GSH adducts and reduction of metabolic activation through structural changes guided by in silico and in vitro screening.

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Pharmacokinetics and Drug Metabolism and Chemistry Research and Discovery, Amgen Inc, One Amgen Center Drive, M/S 30E-2-B, Thousand Oaks, California 91320, USA.


A 2-aminothiazole derivative 1 was developed as a potential inhibitor of the oncology target AKT, a serine/threonine kinase. When incubated in rat and human liver microsomes in the presence of NADPH, 1 underwent significant metabolic activation on its 2-aminothiazole ring, leading to substantial covalent protein binding. Upon addition of glutathione, covalent binding was reduced significantly, and multiple glutathione adducts were detected. Novel metabolites from the in vitro incubates were characterized by LC-MS and NMR to discern the mechanism of bioactivation. An in silico model was developed based on the proposed mechanism and was employed to predict bioactivation in 23 structural analogues. The predictions were confirmed empirically for the bioactivation liability, in vitro, by LC-MS methods screening for glutathione incorporation. New compounds were identified with a low propensity for bioactivation.

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