Discovery and assessment of water soluble coumarins as inhibitors of the coagulation contact pathway

Charlotte Bouckaert, Shu Zhu, José W.P. Govers-Riemslag, Maxime Depoorter, Scott L. Diamond, Lionel Pochet

Résultats de recherche: Contribution à un journal/une revueArticle

Résumé

Over the last decade, the coagulation factor XIIa (FXIIa) has seen renewed interest as a therapeutic target. Indeed, its inhibition could offer a protection against thrombosis without increasing the risk of bleeding. Moreover, it could answer the need for a safe prevention of blood-contacting medical devices-related thrombosis. Among the FXII and FXIIa inhibitors already described in literature, organic small-molecular-weight inhibitors are rather left behind. In this study, we were focused on the discovery and assessment of water soluble small molecules. First, a search within our library of compounds flagged two promising hits. Indeed, enzymes and plasma assays suggested they have a greater activity on the contact factors (FXIa, plasma kallikrein and FXIIa) than on the TF pathway. Then, simple pharmacomodulations were undertaken with the aim to design more selective FXIIa inhibitors. This afforded compounds having different degrees of selectivity. All compounds were finally screened in whole blood using an 8-channel microfluidic model and thromboelastometry measurements. Interestingly, all molecules interfered with the thrombus formation and one of them could be considered as a small organic contact inhibitor.

langueAnglais
Pages126-133
Nombre de pages8
journalThrombosis Research
Volume157
Les DOIs
étatPublié - 1 sept. 2017

Empreinte digitale

Coumarins
Thrombosis
Water
Factor XIIa
factor XIIa inhibitor
Plasma Kallikrein
Thrombelastography
Microfluidics
Enzyme Assays
Molecular Weight
Hemorrhage
Equipment and Supplies
Therapeutics

mots-clés

    Citer ceci

    Bouckaert, Charlotte ; Zhu, Shu ; Govers-Riemslag, José W.P. ; Depoorter, Maxime ; Diamond, Scott L. ; Pochet, Lionel. / Discovery and assessment of water soluble coumarins as inhibitors of the coagulation contact pathway. Dans: Thrombosis Research. 2017 ; Vol 157. p. 126-133
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    Discovery and assessment of water soluble coumarins as inhibitors of the coagulation contact pathway. / Bouckaert, Charlotte; Zhu, Shu; Govers-Riemslag, José W.P.; Depoorter, Maxime; Diamond, Scott L.; Pochet, Lionel.

    Dans: Thrombosis Research, Vol 157, 01.09.2017, p. 126-133.

    Résultats de recherche: Contribution à un journal/une revueArticle

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