Fixing clearance as early as lead optimization using high throughput in vitro incubations in combination with exact mass detection and automatic structure elucidation of metabolites

New enabling MS technologies have made it possible to elucidate metabolic pathways present in ex vivo (blood, bile and/or urine) or in vitro (liver microsomes, hepatocytes and/or S9) samples. When investigating samples from high throughput assays the challenge that the user is facing now is to extract the appropriate information and compile it so that it is understandable to all. Medicinal chemist may then design the next generation of (better) drug candidates combining the needs for potency and metabolic stability and their synthetic creativity. This review focuses on the comparison of these enabling MS technologies and the IT tools developed for their interpretation.

► Fixing metabolic clearance as early as possible to generate better compounds during lead optimization is crucial.
► The information about the soft spots is present in the samples generated to measure intrinsic clearance.
► New instrumentation with the needed mass revolving power, accuracy, speed and sensitivity became available.
► Data acquisition, data mining, structure elucidation of metabolites and reporting can be automated using software packages.
► Structure metabolism relationship building can be handed over to the synthetic chemists to speed up the optimization loop.