Novel inhibitors of FXIa containingan (S)-2-phenyl-1-(4-phenyl-1H-imidazol-2-yl)ethanaminecore have been optimized to providecompound 16b, a potent, reversible inhibitor of FXIa(Ki= 0.3 nM) having in vivo antithromboticefficacy in the rabbit AV-shunt thrombosis model (ID50=0.6 mg/kg + 1 mg kg–1h–1). Initialanalog selection was informed by molecular modeling usingcompounds 11aand 11hoverlaid onto theX-ray crystal structure of tetrahydroquinoline 3complexedto FXIa. Further optimization was achieved by specific modificationsderived from careful analysis of the X-ray crystal structure of theFXIa/11hcomplex. Compound 16bwas welltolerated and enabled extensive pharmacologic evaluation of the FXIamechanism up to the ID90for thrombus inhibition. [ABSTRACT FROM AUTHOR]