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
étatPublié - 3 mars 2016

Empreinte digitale

Factor XIIa
Coumarins
Structure-Activity Relationship
Enzyme Precursors
Blood Coagulation
Hemostasis
Artifacts
Thrombosis
Peptide Hydrolases
Molecular Weight
Coagulation
Scaffolds
Assays
Blood
Crystal structure
Chemical activation
Molecular weight
factor XIIa inhibitor
Experiments
Therapeutics

Citer ceci

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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.",
keywords = "Coumarins; Factor XIIa; Factor XII; FXII; antithrombotic agents; benzopyrans",
author = "Charlotte Bouckaert and Silvia Serra and Gr{\'e}goire Rondelet and Eduard Dolusic and Johan Wouters and Jean-Michel Dogne and Rapha{\"e}l Fr{\'e}d{\'e}rick and Lionel Pochet",
year = "2016",
month = "3",
day = "3",
doi = "10.1016/j.ejmech.2016.01.023",
language = "English",
pages = "181--194",
journal = "European journal of medicinal chemistry / Chimica therapeutica",
issn = "0223-5234",
publisher = "Elsevier Masson SAS",

}

TY - JOUR

T1 - Synthesis, evaluation and structure-activity relationship of new 3-carboxamide coumarins as FXIIa inhibitors

AU - Bouckaert, Charlotte

AU - Serra, Silvia

AU - Rondelet, Grégoire

AU - Dolusic, Eduard

AU - Wouters, Johan

AU - Dogne, Jean-Michel

AU - Frédérick, Raphaël

AU - Pochet, Lionel

PY - 2016/3/3

Y1 - 2016/3/3

N2 - 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.

AB - 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.

KW - Coumarins; Factor XIIa; Factor XII; FXII; antithrombotic agents; benzopyrans

U2 - 10.1016/j.ejmech.2016.01.023

DO - 10.1016/j.ejmech.2016.01.023

M3 - Article

SP - 181

EP - 194

JO - European journal of medicinal chemistry / Chimica therapeutica

JF - European journal of medicinal chemistry / Chimica therapeutica

SN - 0223-5234

M1 - 110

ER -