Abstract
Structural determination of metabolites of new chemical entities (NCEs) plays a pivotal role in drug discovery and development. In early drug discovery, characterization of metabolites is essential for selecting compounds with favorable pharmacokinetic properties, aiding medicinal chemists in identifying metabolic “soft spots” and rationalizing the drug safety profile. In development, elucidation of biotransformation pathways of a drug candidate by identifying its circulatory and excretory metabolites is equally important to understand its physiological effects. Mass spectrometry (MS) has played an invaluable role in the structural characterization of drug metabolites. The use of accurate mass measurements in metabolite identification has added a critical and much-needed feature to distinguishing isobaric molecular ions and assigning empirical formulae to product ions for structural elucidation. Often, however, MS alone is insufficient to provide unequivocal structural elucidation of metabolites. In these cases, multiple analytical and wet chemistry techniques, such as liquid chromatography–nuclear magnetic resonance (LC-NMR) spectroscopy, chemical derivatization, and hydrogen–deuterium exchange (HDX) combined with MS, are used to characterize the novel and isomeric metabolites of drug candidates. This article describes the application of various analytical strategies (LC-NMR, HDX, and chemical derivatization) in conjunction with liquid chromatography–tandem mass spectrometry (LC-MS/MS) for the identification of drug metabolites. Examples from the literature and our own work are given to illustrate the power of using one or more of these techniques combined with LC-MS/MS in the structural determination of novel/unusual metabolites. Keywords: novel and unusual metabolites; LC-NMR; derivatization; hydrogen–deuterium exchange
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