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Factor XII inhibitors

Coagulation factor XIIa (FXIIa) is an actor in blood coagulation cascade. Inhibitors of this enzyme could lead to the development of new antithrombotics with safer profile.

Description

Thrombotic diseases, in which a deregulated clot formation occurs, remain a major cause of death in industrialised countries. Anticoagulants are part of the strategies to address these disorders. However, current available drugs are still associated with risk of severe bleeding complications. New strategies are thus required to treat and to prevent thrombotic disorders with decreased risks of bleedings.

Coagulation factor XIIa (FXIIa), a serine protease implicated in the contact phase of coagulation cascade, recently emerged as a promising target in the development of such agents. Indeed, it was in mice demonstrated that FXII deficiency or inhibition protects against thrombosis without impairing normal haemostasis.

Based on these considerations, the objective of our project is to develop novel small molecular weight FXIIa inhibitors. These compounds could help to detail the exact role of this protease in thrombotic diseases but could also be a good starting point for the development of new antithrombotic drugs.

The required resources, from synthesis to bioassays, are available within the NAMEDIC.

Funding

This project is funded by the Fonds National de la Recherche Scientifique (FRS-FNRS)

Main publications

  • Robert, S.; Bertolla, C.; Masereel, B.; Dogne, J. M.; Pochet, L., Novel 3-carboxamide-coumarins as potent and selective FXIIa inhibitors. Journal of Medicinal Chemistry, 2008, 51 (11), 3077-80.
  • Decrem, Y.; Rath, G.; Blasioli, V.; Cauchie, P.; Robert, S.; Beaufays, J.; Frere, J. M.; Feron, O.; Dogne, J. M.; Dessy, C.; Vanhamme, L.; Godfroid, E., Ir-CPI, a coagulation contact phase inhibitor from the tick Ixodes ricinus inhibits thrombus formation. The Journal of experimental medicine, 2009, 206 (11), 2381-95
  • Kraft, P.; Schwarz, T.; Pochet, L.; Stoll, G.; Kleinschnitz, C., COU254, a specific 3-carboxamide-coumarin inhibitor of coagulation factor XII, does not protect mice from acute ischemic stroke. Experimental & translational stroke medicine, 2010, 2 (1), 5.