Inhibition of Factor XI (FXI) has emerged as a promising approach to anti-coagulant therapy with a potentially improved therapeutic index.  Studies of patients with FXI deficiency together with, clinical research on FXI antisense oligonucleotides for the prevention of venous thrombosis, and preclinical studies supporting the mechanism provide a high degree of confidence that FXI inhibition would be a promising strategy for safer anticoagulation.  Given the high degree of validation, a comprehensive screening approach to the inhibition of this protease was undertaken, resulting in the discovery of a novel mechanism of inhibition.  Small molecules were identified that prevented the cleavage of the FXI zymogen to the active form of the protease (FXIa).  The unique mechanism of action was selective for FXI in the context of other coagulation and fibrinolytic enzymes.  This talk will describe the advancement of early leads to activation inhibitors with improved physicochemical properties and anti-thrombotic activity as measured by activated partial thromboplastin time (aPTT).  These improvements resulted in chemical matter that enabled the identification of a novel small molecule binding site on FXI and an in vivo tool compound to provide preclinical validation of the mechanism of action.  As the series faced challenges in ADME optimization, an alternative optimization approach was developed that focused on the development of a minimum pharmacophore, followed by rapid improvement in lipophilic ligand efficiency (LLE) enabled by high throughput technologies.  Novel and classic optimization techniques lead to chemical matter with improved physicochemical properties and anti-thrombotic activity, enabling the identification of the binding site and in vivo validation of this novel mechanism of FXI inhibition.<br/>

Factor XI activation inhibitors: Advancing a novel mechanism of FXI inhibition

ACS Fall 2020 Virtual Meeting

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