Tetrahydroquinoline Derivatives as Potent and Selective Factor XIa Inhibitors

Antithrombotic agents that are inhibitors of factor XIa (FXIa) have the potential to demonstrate robust efficacy with a low bleeding risk profile. Herein, we describe a series of tetrahydroquinoline (THQ) derivatives as FXIa inhibitors. Compound <b>1</b> was identified as a potent and selective tool compound for proof of concept studies. It exhibited excellent antithrombotic efficacy in rabbit thrombosis models and did not prolong bleeding times. This demonstrates proof of concept for the FXIa mechanism in animal models with a reversible, small molecule inhibitor

Phenylimidazoles as Potent and Selective Inhibitors of Coagulation Factor XIa with in Vivo Antithrombotic Activity

Novel inhibitors of FXIa containing an (<i>S</i>)-2-phenyl-1-(4-phenyl-1<i>H</i>-imidazol-2-yl)­ethanamine core have been optimized to provide compound <b>16b</b>, a potent, reversible inhibitor of FXIa (<i>K</i>_i = 0.3 nM) having in vivo antithrombotic efficacy in the rabbit AV-shunt thrombosis model (ID₅₀ = 0.6 mg/kg + 1 mg kg^–1 h^–1). Initial analog selection was informed by molecular modeling using compounds <b>11a</b> and <b>11h</b> overlaid onto the X-ray crystal structure of tetrahydroquinoline <b>3</b> complexed to FXIa. Further optimization was achieved by specific modifications derived from careful analysis of the X-ray crystal structure of the FXIa/<b>11h</b> complex. Compound <b>16b</b> was well tolerated and enabled extensive pharmacologic evaluation of the FXIa mechanism up to the ID₉₀ for thrombus inhibition