Coumadin (warfarin) is a commonly used anticoagulation drug for the treatment and/or prevention of thromboembolic events. Maintaining an optimal drug dose is challenging due to high inter-individual variability in patient response and a narrow therapeutic range. We are collaborating to use warfarin metabolite profiles from patients to improve understanding of the link between warfarin metabolism and response to treatment. Phase 1 of warfarin metabolism produces a variety of hydroxywarfarins which are converted to their glucuronide derivatives in Phase 2. Our project requires the enantioselective synthesis of authentic standards for metabolic profiling. We are exploring a variety of syntheses of the dihydroxycoumarin precursors. These are then converted to the corresponding hydroxywarfarins via an enantioselective, catalytic coupling using diphenylethylenediamine (dpen) enantiomers.  For example, we demonstrated for the first time the enantioselective synthesis of R- and S-6-hydroxywarfarin (97%ee and 93%ee, respectively) as determined by chiral HPLC. A variety of glucuronidation procedures are also under investigation to prepare enantiomers of the Phase 2 metabolites.

Approaches to the synthesis of glucuronide derivatives of enantiomerically-enriched warfarin (Coumadin<sup>®</sup>) metabolites

245th National Meeting (2013)

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Approaches to the synthesis of glucuronide derivatives of enantiomerically-enriched warfarin (Coumadin®) metabolites

Approaches to the synthesis of glucuronide derivatives of enantiomerically-enriched warfarin (Coumadin^®) metabolites