Factor XIa (FXIa) is a key factor in the intrinsic pathway of the coagulation cascade that is involved in the amplification of the procoagulation signal. Mounting evidence suggests that direct inhibition of FXIa can block pathologic thrombus formation while preserving normal hemostasis and thus has emerged as a major target for anticoagulant therapy. Animal studies using direct inhibitors of FXIa from Bristol-Myers Squibb have demonstrated good antithrombotic efficacy and with low bleeding. Based on the potential efficacy and safety of inhibiting FXIa, we targeted the discovery of an intravenous agent for the treatment of cerebrovascular ischemic events in the hospital setting. This presentation will focus on a structure based drug design effort that culminated in the discovery of a clinical candidate BMS-962212,  suitable for intravenous administration. Key insights, structure activity relationships (SAR), and pharmaceutic properties will be presented. BMS-962212 is a potential first in class, reversible, direct, and highly selective intravenous small molecule inhibitor of FXIa (FXIa Ki= 0.7 nM)

Discovery of BMS-962212 a highly potent, selective inhibitor of coagulation FXIa

253rd National Meeting (2017)

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