STUDY OF COUMARINS WITH IMPROVED SOLUBILITY TO INHIBIT FXIIa, AN EMERGING TARGET IN THROMBOSIS RESEARCH

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Abstract

Thrombotic diseases, in which a deregulated haemostatic activity occurs, remain a major concern in medicine. Anticoagulants are part of the strategies to address these disorders. However current available drugs are still associated with risk of severe bleeding complications and thus, novel antithrombotics are required1.

In this perspective, coagulation factor XIIa (FXIIa), a serine protease implicated in the coagulation cascade, recently emerged as a promising target in the development of such agents2. Indeed, it was demonstrated that FXII deficiency or inhibition protects against thrombosis without causing spontaneous bleeding in mice3.

Based on these considerations, the aim 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 (figure 1) are to date the only nonpetidic and selective inhibitors of FXIIa described in literature4. However, their low solubility and poor pharmacokinetics resulted in a lack of activity in in vivo models of thrombosis. As consequence, we need to improve these characteristics while keeping the selectivity and potency towards FXIIa.

In this work, we first synthesized new coumarins with improved solubility. Their inhibition potency was then measured on FXIIa and finally, their stability was evaluated.
Original languageEnglish
PagesBook of Abstracts, MedChem 2012, Château de Colonster, Liège - November 30, 2012, P01
Number of pages1
Publication statusPublished - 30 Nov 2012
EventAnnual One-Day Symposium on Medicinal Chemistry of SRC & KVCV (Medchem 2012) - Liège, Belgium
Duration: 30 Nov 2012 → …

Symposium

SymposiumAnnual One-Day Symposium on Medicinal Chemistry of SRC & KVCV (Medchem 2012)
CountryBelgium
CityLiège
Period30/11/12 → …

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    • 1 Participation in conference

    Annual One-Day Symposium on Medicinal Chemistry of SRC & KVCV (Medchem 2012)

    Eduard Dolusic (Contributor)

    30 Nov 2012

    Activity: Participating in or organising an event typesParticipation in conference

    Student Theses

    Conception, synthèse et évaluation biologique de coumarines en tant qu'inhibiteurs de protéases à sérine

    Author: Pochet, L., 2000

    Supervisor: Masereel, B. (Supervisor)

    Student thesis: Doc typesDoctor of Sciences

    Etude du mode de liaison de composés coumariniques, inhibiteurs de thrombine

    Author: De Ruyck, J., 2004

    Supervisor: Durant, F. (Supervisor)

    Student thesis: Master typesMaster in Chemistry

    Evaluation biologique de coumarines en tant qu'inhibiteurs de protéases à sérine de la cascade de la coagulation

    Author: Robert, S. H., 2004

    Supervisor: Masereel, B. (Supervisor) & Pochet, L. (Co-Supervisor)

    Student thesis: Master typesMaster in Biology

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    Bouckaert, C., Vancraeynest, C., Dolušić, E., Frédérick, R., & Pochet, L. (2012). STUDY OF COUMARINS WITH IMPROVED SOLUBILITY TO INHIBIT FXIIa, AN EMERGING TARGET IN THROMBOSIS RESEARCH. Book of Abstracts, MedChem 2012, Château de Colonster, Liège - November 30, 2012, P01. Poster session presented at Annual One-Day Symposium on Medicinal Chemistry of SRC & KVCV (Medchem 2012), Liège, Belgium.