Résumé

Inhibitors of the coagulation factor XIIa (FXIIa) are attractive to detail the roles of this protease in hemostasis and thrombosis, to suppress artifact due to contact pathway activation in blood coagulation assays, and they are promising as antithrombotic therapy. The 3-carboxamide coumarins have been previously described as small-molecular-weight FXIIa inhibitors. In this study, we report a structure-activity relationship (SAR) study around this scaffold with the aim to discover new selective FXIIa inhibitors with an improved physico-chemical profile. To better understand these SAR, docking experiments were undertaken. For this purpose, we built an original hybrid model of FXIIa. This model has the advantage to gather the best features from the recently published crystal structure of FXIIa in its zymogen form and a more classical homology model. Results with the hybrid model are encouraging as they help understanding the activity and selectivity of our best compounds.
langue originaleAnglais
Numéro d'article110
Pages (de - à)181-194
Nombre de pages14
journalEuropean Journal of Medicinal Chemistry
Les DOIs
Etat de la publicationPublié - 3 mars 2016

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

    Author: Pochet, L., 2000

    Superviseur: Masereel, B. (Promoteur)

    Thèse de l'étudiant: Doc typesDocteur en Sciences

    Design, synthesis and evaluation of coagulation FXIIa inhibitors as potential antithrombotic agents

    Author: Bouckaert, C., 16 mai 2017

    Superviseur: Pochet, L. (Promoteur), Dogne, J. (Copromoteur), Lanners, S. (Président), De Tullio, P. (Personne externe) (Jury), Chatelain, C. (Personne externe) (Jury) & TEN CATE, H. (Personne externe) (Jury)

    Thèse de l'étudiant: Doc typesDocteur en Sciences Biomédicales et Pharmaceutiques

    Development & validation of pharmacological tools for the preclinical testing of anticoagulants

    Author: Robert, S., 7 avr. 2011

    Superviseur: Pochet, L. (Promoteur), Dogne, J. (Copromoteur), Masereel, B. (Président), Caron, N. (Jury), Chatelain, C. (Personne externe) (Jury) & TEN CATE, H. (Personne externe) (Jury)

    Thèse de l'étudiant: Doc typesDocteur en Sciences Biomédicales et Pharmaceutiques

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