Factor XIIa (FXIIa) is a plasma serine protease belonging to the intrinsic coagulation pathway. Several animal models have revealed an important contribution for FXIIa to thromboembolic diseases. Not only that but FXIIa was also found to contribute to inflammation by activating bradykinin-producing kallikrein-kinin system. Interestingly, patients and animals with FXII deficiency appear to have normal hemostasis. Therefore, FXIIa inhibition may serve as a promising therapeutic intervention strategy to achieve effective and safe anticoagulation as well as anti-inflammation. Despite this promise, very few small molecule inhibitors of human FXIIa have been reported. We chemically synthesized and biochemically studied a focused library of triazol-3-yl benzamide derivatives for FXIIa inhibition under physiologic conditions. We identified a specific triazol-3-yl benzamide derivative as the most potent inhibitor in this series with an IC50 value of about 0.11 µM and a fluorescence-based binding affinity of about 0.98 µM. The molecule dose-dependently inhibited FXIIa-mediated activation of FXI, a physiologic substrate of FXIIa, with an IC50 value of about 2 µM. It also exhibited a significant margin of selectivity of at least 150-fold against a series of related serine proteases including thrombin, FXa, FIXa, FXIa, FVIIa/TF, plasmin, plasma kallikrein, trypsin, and chymotrypsin. This derivative also selectively doubled clotting time in activated partial thromboplastin time assay of the intrinsic coagulation pathway without significant effect on prothrombin time of the extrinsic pathway in normal human plasma. Overall, this work puts forward small molecule triazol-3-yl benzamides as potent and selective inhibitors of human FXIIa for further development as safe and effective anticoagulants with potential anti-inflammatory activity.

Triazol-3-yl benzamides as potent and selective inhibitors of human factor XIIa

255th National Meeting (2018)

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