This proposal concerns the utilization of warfarin as a model system for an albumin-based structure-guided approach to improving the therapeutic index and/or drug displacement interactions of existing high potential pharmaceuticals. Warfarin has been on the market for many decades and is widely used in the prevention of thromboembolic disease and stroke. Racemic sodium warfarin (Coumadin), a product of DuPont Pharmaceuticals, currently represents one of the top 200 pharmaceuticals with an estimated annual sales of approximately $600 million. Warfarin is known to possess problematic binding to serum plasma albumin and has a narrow therapeutic index. Furthermore, warfarin is a pharmaceutical for which the mode of action, pharmacokinetic interactions, and toxicity are well understood. These and other factors make warfarin a good choice as a model system for a comprehensive structure-based study and development program. The atomic structures of several warfarin derivative/albumin complexes will be determined with varying, but representative, albumin affinity. This information will be used to assess the potential for creating a second generation warfarin-based therapeutic with improved properties. Progress and validation of applications in this area should provide new and complimentary information which can potentially be used in the guidance of the early stages of any drug development program.
