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

Charlotte Bouckaert; Silvia Serra; Grégoire Rondelet; Eduard Dolusic; Johan Wouters; Jean-Michel Dogne; Raphaël Frédérick; Lionel Pochet

doi:10.1016/j.ejmech.2016.01.023

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

Charlotte Bouckaert, Silvia Serra, Grégoire Rondelet, Eduard Dolusic, Johan Wouters, Jean-Michel Dogne, Raphaël Frédérick, Lionel Pochet

Research output: Contribution to journal › Article

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 language	English
Article number	110
Pages (from-to)	181-194
Number of pages	14
Journal	European Journal of Medicinal Chemistry
DOIs	https://doi.org/10.1016/j.ejmech.2016.01.023
Publication status	Published - 3 Mar 2016

Keywords

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

Access to Document

10.1016/j.ejmech.2016.01.023

http://www.sciencedirect.com/science/article/pii/S0223523416300241

Embargoed Document

Eur J Med Chem 2016
3.23 MB

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Projects

1 Active
2 Finished

THROMBO: Enzymologic, mechanistic and pharmacological study of specific inhibitors of serine proteases implicated in hemostasis disorders

POCHET, L., DOGNE, J., MASEREEL, B. & ROBERT, S.

1/09/04 → …

Project: PHD

Prévention de la thrombose sans risque d'hémorragie: mythe ou réalité? Développement d'inhibiteurs sélectifs du FXIIa, une nouvelle cible émergente

POCHET, L.

1/10/12 → 30/09/14

Project: Research

COUMARINE: Conception and synthesis of inhibitors of serine proteases

MASEREEL, B., POCHET, L., FREDERICK, R. & ROBERT, S.

1/01/01 → 1/02/06

Project: PHD

Equipment

High Performance Computing Technology Platform

Benoît Champagne (Manager)

Technological Platform High Performance Computing

Facility/equipment: Technological Platform

Mass Spectrometry Service

Patricia Renard (Manager)

Technological Platform Mass Spectrometry Service

Facility/equipment: Technological Platform

Physical Chemistry and characterization(PC2)

Johan Wouters (Manager) & Carmela Aprile (Manager)

Technological Platform Physical Chemistry and characterization

Facility/equipment: Technological Platform

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 types › Doctor 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 types › Doctor 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 types › Doctor of Biomedical and Pharmaceutical Sciences

Cite this

Bouckaert, C., Serra, S., Rondelet, G., Dolusic, E., Wouters, J., Dogne, J-M., Frédérick, R., & Pochet, L. (2016). Synthesis, evaluation and structure-activity relationship of new 3-carboxamide coumarins as FXIIa inhibitors. European Journal of Medicinal Chemistry, 181-194. [110]. https://doi.org/10.1016/j.ejmech.2016.01.023

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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.",

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Synthesis, evaluation and structure-activity relationship of new 3-carboxamide coumarins as FXIIa inhibitors. / Bouckaert, Charlotte; Serra, Silvia; Rondelet, Grégoire ; Dolusic, Eduard ; Wouters, Johan ; Dogne, Jean-Michel; Frédérick, Raphaël; Pochet, Lionel.

In: European Journal of Medicinal Chemistry, 03.03.2016, p. 181-194.

Research output: Contribution to journal › Article

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

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