Abstract

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.
Original languageEnglish
Article number110
Pages (from-to)181-194
Number of pages14
JournalEuropean Journal of Medicinal Chemistry
DOIs
Publication statusPublished - 3 Mar 2016

Keywords

  • Coumarins; Factor XIIa; Factor XII; FXII; antithrombotic agents; benzopyrans

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  • 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

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

    Author: Bouckaert, C., 16 May 2017

    Supervisor: Pochet, L. (Supervisor), Dogne, J. (Co-Supervisor), Lanners, S. (President), De Tullio, P. (External person) (Jury), Chatelain, C. (External person) (Jury) & TEN CATE, H. (External person) (Jury)

    Student thesis: Doc typesDoctor of Biomedical and Pharmaceutical Sciences

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

    Author: Robert, S., 7 Apr 2011

    Supervisor: Pochet, L. (Supervisor), Dogne, J. (Co-Supervisor), Masereel, B. (President), Caron, N. (Jury), Chatelain, C. (External person) (Jury) & TEN CATE, H. (External person) (Jury)

    Student thesis: Doc typesDoctor of Biomedical and Pharmaceutical Sciences

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