Novel coumarins with improved solubility as FXIIa inhibitors

Background: Thrombotic diseases remain a major cause of death in industrialised countries. Anticoagulants have proven their efficacy to address these disorders. However severe bleeding complications are still reported even with the use of recently marketed drugs. Novel and safe antithrombotics are thus required.

In this perspective, 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 demonstrated that FXII deficiency or inhibition protects against thrombosis without causing spontaneous bleeding in mice.

Aim: Based on these considerations, the goal 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 are to date the only nonpetidic and selective inhibitors of FXIIa described in literature. However, their low solubility and poor pharmacokinetics resulted in a lack of activity in in vivo models of thrombosis. As a consequence, we aim to improve these characteristics while keeping the selectivity and potency towards FXIIa.

Methods: Twenty-five compounds were synthesized. Their solubility was investigated in pH 7.9 TRIS-imidazole. Inhibition potency on FXIIa was screened at several concentrations according to the maximum of solubility.

Results: A new series of coumarins with an amino group at position 3 or 6 of the carboxamide coumarin scaffold was first synthesized. While solubility was largely increased the inhibition potency on FXIIa remained relatively low. On the contrary, insertion of an oxygen-based group on strategic positions did not improved solubility but lead to more active compounds.

Conclusion: A new series of 3-carboxamide derivatives was synthesized to selectively inhibit FXIIa and with the aim of improving their solubility. Pharmacomodulations will be fully discussed.