Reactive metabolite trapping screens and potential pitfalls: bioactivation of a homomorpholine and formation of an unstable thiazolidine adduct.
CHEMICAL RESEARCH IN TOXICOLOGY(2014)
摘要
Successful early attrition of potential problematic compounds is of great importance in the pharmaceutical industry. The lead compound in a recent project targeting neuropathic pain was susceptible to metabolic bioactivation, which produced reactive metabolites and showed covalent binding to protein. Therefore, as a part of the backup series for this compound several structural modifications were explored to mediate the reactive metabolite and covalent binding risk. A homomorpholine containing series of compounds was identified without compromising potency. However, when these compounds were incubated with human liver microsomes in the presence of GSH, Cys-Gly adducts were identified, instead of intact GSH conjugates. This article examines the formation of the Cys-Gly adduct with AZX ([M+H](+) 486) as a representative compound for this series. The AZX-Cys-Gly-adduct ([M+H](+) 662) showed evidence of ring contraction by formation of a thiazolidine-glycine and was additionally shown to be unstable. During its isolation for structural characterization by H-1 NMR spectroscopy, it was found to have decomposed to a product with [M+H](+) 446. The characterization and identification of this labile GSH-derived adduct using LC-MS/MS and H-1 NMR are described, along with observations around stability. In addition, various structurally related trapping reagents were employed in an attempt to further investigate the reaction mechanism along with a methoxylamine trapping experiment to confirm the structure of the postulated reactive intermediate.
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