Projects per year
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.
|Publication status||Published - 2013|
|Event||XXIV Congress of the International Society of Thrombosis and Haemostasis - Amsterdam, Netherlands|
Duration: 29 Jun 2013 → 4 Jul 2013
|Conference||XXIV Congress of the International Society of Thrombosis and Haemostasis|
|Period||29/06/13 → 4/07/13|
1/01/01 → 1/02/06
Conception, synthèse et évaluation biologique de coumarines en tant qu'inhibiteurs de protéases à sérineAuthor: Pochet, L., 2000
Supervisor: Masereel, B. (Supervisor)
Student thesis: Doc types › Doctor of Sciences
Evaluation biologique de coumarines en tant qu'inhibiteurs de protéases à sérine de la cascade de la coagulationAuthor: Robert, S. H., 2004
Student thesis: Master types › Master in BiologyFile