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Thrombosis is the leading cause of death in developed countries. There is a significant need for novel antithrombotics with an improved safety profile to replace Warfarin which has been in use for ~60 years and has significant bleeding issues. Factor Xa is at the junction of the intrinsic and extrinsic pathways of the coagulation cascade. Preclinical data has demonstrated that blocking FXa is an effective approach for anticoagulation with improved safety profile. Utilizing structure-based drug design tools, focused screening, and ADME-T innovations, we at Bristol-Myers Squibb had discovered a novel class of potent, selective and orally bioavailable Factor Xa inhibitors culminating in Eliquis®/Apixaban. Eliquis® was recently approved by FDA and named the “Best New Medicine of 2012” by Med Ad News. Eliquis® is currently a “block-buster” drug with annual sales of ~$5B. In 2015, the Eliquis discovery team received the American Chemical Society Heroes of Chemistry Award for a successful commercial product that benefits human well-being.
During the optimization process, we have also discovered the powerful Chan-Lam Coupling reaction of copper promoted C-X bond cross-coupling via boronic acids, a complementary reaction to the Nobel prize Suzuki-Miyaura C-C bond Coupling reaction. In addition, at the molecular recognition frontier, we have pioneered the first rational use of halogen bonding in structure-based drug design.
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