title: Synthesis, evaluation and structure-activity relationship of new 3-carboxamide coumarins as FXIIa inhibitors.
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.
authors.affiliation: Department of Pharmacy, Namur Medicine & Drug Innovation Center (NAMEDIC), Namur Research Institute for Life Sciences (NARILIS), University of Namur, 61, Rue de Bruxelles, 5000 Namur, Belgium.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Bouckaert
authors.affiliation: Department of Pharmacy, Namur Medicine & Drug Innovation Center (NAMEDIC), Namur Research Institute for Life Sciences (NARILIS), University of Namur, 61, Rue de Bruxelles, 5000 Namur, Belgium.
authors.forename: Silvia
authors.initials: S
authors.lastname: Serra
authors.affiliation: Department of Chemistry, Namur Medicine & Drug Innovation Center (NAMEDIC), Namur Research Institute for Life Sciences (NARILIS), University of Namur, Rue de Bruxelles, 61, 5000 Namur, Belgium.
authors.forename: Grégoire
authors.initials: G
authors.lastname: Rondelet
authors.affiliation: Department of Organic Chemistry, Namur Medicine & Drug Innovation Center (NAMEDIC), Namur Research Institute for Life Sciences (NARILIS), University of Namur, 61, Rue de Bruxelles, 5000 Namur, Belgium.
authors.forename: Eduard
authors.initials: E
authors.lastname: Dolušić
authors.affiliation: Department of Chemistry, Namur Medicine & Drug Innovation Center (NAMEDIC), Namur Research Institute for Life Sciences (NARILIS), University of Namur, Rue de Bruxelles, 61, 5000 Namur, Belgium.
authors.forename: Johan
authors.initials: J
authors.lastname: Wouters
authors.affiliation: Department of Pharmacy, Namur Medicine & Drug Innovation Center (NAMEDIC), Namur Research Institute for Life Sciences (NARILIS), University of Namur, 61, Rue de Bruxelles, 5000 Namur, Belgium.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Dogné
authors.affiliation: Medicinal Chemistry Research Group (CMFA), Louvain Drug Research Institute (LDRI), Université Catholique de Louvain, 73, Avenue E. Mounier, 1200 Brussels, Belgium.
authors.forename: Raphaël
authors.initials: R
authors.lastname: Frédérick
authors.affiliation: Department of Pharmacy, Namur Medicine & Drug Innovation Center (NAMEDIC), Namur Research Institute for Life Sciences (NARILIS), University of Namur, 61, Rue de Bruxelles, 5000 Namur, Belgium. Electronic address: lionel.pochet@unamur.be.
authors.forename: Lionel
authors.initials: L
authors.lastname: Pochet
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D003374:Coumarins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015956:Factor XIIa / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D062105:Molecular Docking Simulation; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D003374:Coumarins; D005343:Fibrinolytic Agents; D015956:Factor XIIa
keywords: Antithrombotic agents; Benzopyrans; Coumarins; FXII; Factor XII; Factor XIIa