Abstract
Publisher Summary This chapter presents the automated and bio-analytical procedures used; the design criteria selected as being most important for high-throughput assays using enzymes from either single or multiple species; data that demonstrate the capacity, success rate, and reproducibility achieved; and metabolic stability data typified by a diverse set of 1000 compounds, and more focused results that exemplify a species-dependent structure-activity relationship. It describes early work using a new application of time-of-flight (TOF) mass spectrometry to address the instance when all compounds within a series are metabolically labile. Identifying the labile sites of a molecule helps chemists to design compounds that achieve adequate metabolic stability. In this application, LC-TOF/MS provides accurate mass data that are used to propose molecular formula of metabolites generated during the in vitro incubations. The chapter describes three stages of development leading to a fully automated high-throughput assay of metabolic stability that has assayed over 10,000 compounds. The assay takes advantage of robotics and high-throughput high-performance liquid chromatography (HPLC)-tandem mass spectrometry to overcome the two key bottlenecks to successful and timely assay of a large number of diverse compounds.
Published Version
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