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 Dogné; 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 Dogné, Raphaël Frédérick, Lionel Pochet

Research output: Contribution to journal › Article › peer-review

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

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10.1016/j.ejmech.2016.01.023

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

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Eur J Med Chem 2016
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49 Citations
13 Conference contribution
7 Literature review
5 Poster
5 Article

Pharmacophore And Qsar Models On Coumarins As FXIIa Inhibitors
Bouckaert, C., Meinguet, C., Serra, S. & Pochet, L., 2014.
Research output: Contribution to conference › Poster › peer-review
UTILITY OF A CHROMATOGRAPHIC TECHNIQUE TO OVERCOME LIMITATIONS OF A SPECTROPHOTOMETRIC-UV METHOD IN BIOASSAYS ON COAGULATION FACTOR XIIa
Bouckaert, C., Serra, S., Vancraeynest, C. & Pochet, L., 2014, p. 174.
Research output: Contribution to conference › Poster › peer-review
coauthor on lecture: NOVEL DEVELOPMENT IN COUMARINS AS FXIIa INHIBITORS: IMPROVEMENT OF SOLUBILITY
Bouckaert, C., Vancraeynest, C., Dolušić, E., Frédérick, R. & Pochet, L., 2013, Book of Abstracts, 27èmes Journées franco-belges de Pharmacochimie / 21èmes Conférences européennes du GP2A. Vol. OC05.
Research output: Contribution in Book/Catalog/Report/Conference proceeding › Conference contribution

Open Access
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1 Active
2 Finished

THROMBO: Enzymologic, mechanistic and pharmacological study of specific inhibitors of serine proteases implicated in hemostasis disorders
Pochet, L. (PI), Dogné, J.-M. (CoI), Masereel, B. (CoI) & ROBERT, S. (Researcher)
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. (PI)
1/10/12 → 30/09/14
Project: Research
COUMARINE: Conception and synthesis of inhibitors of serine proteases
Masereel, B. (PI), Pochet, L. (PI), FREDERICK, R. (Researcher) & ROBERT, S. (Researcher)
1/01/01 → 1/02/06
Project: PHD

High Performance Computing Technology Platform
Champagne, B. (Manager)
Technological Platform High Performance Computing
Facility/equipment: Technological Platform
Mass Spectrometry Service
Renard, P. (Manager)
Technological Platform Mass Spectrometry Service
Facility/equipment: Technological Platform
Physical Chemistry and characterization(PC2)
Wouters, J. (Manager), Aprile, C. (Manager) & Fusaro, L. (Manager)
Technological Platform Physical Chemistry and characterization
Facility/equipment: Technological Platform

Conception, synthèse et évaluation biologique de coumarines en tant qu'inhibiteurs de protéases à sérine
Pochet, L. (Author), Masereel, B. (Supervisor), 2000
Student thesis: Doc types › Doctor of Sciences
Design, synthesis and evaluation of coagulation FXIIa inhibitors as potential antithrombotic agents
Bouckaert, C. (Author), Pochet, L. (Supervisor), Dogne, J.-M. (Co-Supervisor), Lanners, S. (President), De Tullio, P. (Jury), Chatelain, C. (Jury) & TEN CATE, H. (Jury), 16 May 2017
Student thesis: Doc types › Doctor of Biomedical and Pharmaceutical Sciences
Development & validation of pharmacological tools for the preclinical testing of anticoagulants
Robert, S. (Author), Pochet, L. (Supervisor), Dogne, J.-M. (Co-Supervisor), Masereel, B. (President), Caron, N. (Jury), Chatelain, C. (Jury) & TEN CATE, H. (Jury), 7 Apr 2011
Student thesis: Doc types › Doctor of Biomedical and Pharmaceutical Sciences

Cite this

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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.",

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doi = "10.1016/j.ejmech.2016.01.023",

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AU - Bouckaert, Charlotte

AU - Serra, Silvia

AU - Rondelet, Grégoire

AU - Dolusic, Eduard

AU - Wouters, Johan

AU - Dogné, 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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JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

M1 - 110

ER -

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

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