Pyridine and pyridinone-based factor XIa inhibitors.

The structure–activity relationships (SAR) of six-membered ring replacements for the imidazole ring scaffold is described. This work led to the discovery of the potent and selective pyridine (S)-23 and pyridinone (±)-24 factor XIa inhibitors. SAR and X-ray crystal structure data highlight the key differences between imidazole and six-membered ring analogs. 2014 Elsevier Ltd. All rights reserved. Factor XIa (FXIa), a trypsin-like serine protease, functions early in the intrinsic pathway of the blood coagulation cascade. It has been demonstrated to play a key role in the amplification of thrombin production which leads to the growth and maturation of thrombi. 1 Based on the preclinical and genetic evidence, FXIa is a potential target for anticoagulant therapy. FXI deficient mice are protected in venous and arterial thrombosis models. Moreover, they do not show an increase in bleeding relative to wild-type mice.