coauthor on lecture: NOVEL DEVELOPMENT IN COUMARINS AS FXIIa INHIBITORS: IMPROVEMENT OF SOLUBILITY

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. Novel and safe antithrombotics are thus required.

In this context, 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 agents1. Indeed, it was shown that FXII deficiency as well as FXIIa inhibition protects against thrombosis without causing spontaneous bleeding in mice2.

Based on these considerations, the purpose of our project is to develop novel selective FXIIa inhibitors to detail the exact role of this enzyme in thrombotic diseases. These compounds could also be a good starting point for the development of new antithrombotic drugs.

The 3-carboxamide coumarins were previously described as nonpetidic and selective inhibitors of FXIIa3. However, their low solubility and poor pharmacokinetics resulted in a lack of activity in in vivo models of thrombosis4. Therefore, we aim to improve these characteristics while keeping the selectivity and potency towards FXIIa.

A new series of coumarins with an amino group at position 3 or 6 of the carboxamide coumarin scaffold was first synthesized. The introduction of a negative charge at these strategic positions was also investigated. The solubility and the inhibition potency of these newly synthesized compounds will be presented and the SAR will be fully discussed.