Novel coumarins with improved solubility as FXIIa inhibitors

Résultats de recherche: Contribution à un événement scientifique (non publié)Poster

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Résumé

Background: Thrombotic diseases remain a major cause of death in industrialised countries. Anticoagulants have proven their efficacy to address these disorders. However severe bleeding complications are still reported even with the use of recently marketed drugs. Novel and safe antithrombotics are thus required.

In this perspective, coagulation factor XIIa (FXIIa), a serine protease implicated in the contact phase of coagulation cascade, recently emerged as a promising target in the development of such agents. Indeed, it was demonstrated that FXII deficiency or inhibition protects against thrombosis without causing spontaneous bleeding in mice.

Aim: Based on these considerations, the goal of our project is to develop novel selective FXIIa inhibitors to detail the exact role of this enzyme in thrombotic diseases. These compounds could also be a good starting point for the development of new antithrombotic drugs.

The 3-carboxamide coumarins are to date the only nonpetidic and selective inhibitors of FXIIa described in literature. However, their low solubility and poor pharmacokinetics resulted in a lack of activity in in vivo models of thrombosis. As a consequence, we aim to improve these characteristics while keeping the selectivity and potency towards FXIIa.

Methods: Twenty-five compounds were synthesized. Their solubility was investigated in pH 7.9 TRIS-imidazole. Inhibition potency on FXIIa was screened at several concentrations according to the maximum of solubility.

Results: A new series of coumarins with an amino group at position 3 or 6 of the carboxamide coumarin scaffold was first synthesized. While solubility was largely increased the inhibition potency on FXIIa remained relatively low. On the contrary, insertion of an oxygen-based group on strategic positions did not improved solubility but lead to more active compounds.

Conclusion: A new series of 3-carboxamide derivatives was synthesized to selectively inhibit FXIIa and with the aim of improving their solubility. Pharmacomodulations will be fully discussed.
langue originaleAnglais
étatPublié - 2013
EvénementXXIV Congress of the International Society of Thrombosis and Haemostasis - Amsterdam, Pays-Bas
Durée: 29 juin 20134 juil. 2013

Une conférence

Une conférenceXXIV Congress of the International Society of Thrombosis and Haemostasis
PaysPays-Bas
La villeAmsterdam
période29/06/134/07/13

Empreinte digitale

Coumarins
Factor XIIa
Solubility
Thrombosis
Hemorrhage
Serine Proteases
Developed Countries
Pharmaceutical Preparations
Anticoagulants
factor XIIa inhibitor
Cause of Death
Pharmacokinetics
Oxygen
Enzymes

Citer ceci

Bouckaert, C., Vancraeynest, C., Dolušić, E., Frédérick, R., & Pochet, L. (2013). Novel coumarins with improved solubility as FXIIa inhibitors. Poster présenté � XXIV Congress of the International Society of Thrombosis and Haemostasis, Amsterdam, Pays-Bas.
Bouckaert, Charlotte ; Vancraeynest, Christelle ; Dolušić, Eduard ; Frédérick, Raphaël ; Pochet, Lionel. / Novel coumarins with improved solubility as FXIIa inhibitors. Poster présenté � XXIV Congress of the International Society of Thrombosis and Haemostasis, Amsterdam, Pays-Bas.
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title = "Novel coumarins with improved solubility as FXIIa inhibitors",
abstract = "Background: Thrombotic diseases remain a major cause of death in industrialised countries. Anticoagulants have proven their efficacy to address these disorders. However severe bleeding complications are still reported even with the use of recently marketed drugs. Novel and safe antithrombotics are thus required.In this perspective, coagulation factor XIIa (FXIIa), a serine protease implicated in the contact phase of coagulation cascade, recently emerged as a promising target in the development of such agents. Indeed, it was demonstrated that FXII deficiency or inhibition protects against thrombosis without causing spontaneous bleeding in mice.Aim: Based on these considerations, the goal of our project is to develop novel selective FXIIa inhibitors to detail the exact role of this enzyme in thrombotic diseases. These compounds could also be a good starting point for the development of new antithrombotic drugs. The 3-carboxamide coumarins are to date the only nonpetidic and selective inhibitors of FXIIa described in literature. However, their low solubility and poor pharmacokinetics resulted in a lack of activity in in vivo models of thrombosis. As a consequence, we aim to improve these characteristics while keeping the selectivity and potency towards FXIIa.Methods: Twenty-five compounds were synthesized. Their solubility was investigated in pH 7.9 TRIS-imidazole. Inhibition potency on FXIIa was screened at several concentrations according to the maximum of solubility.Results: A new series of coumarins with an amino group at position 3 or 6 of the carboxamide coumarin scaffold was first synthesized. While solubility was largely increased the inhibition potency on FXIIa remained relatively low. On the contrary, insertion of an oxygen-based group on strategic positions did not improved solubility but lead to more active compounds.Conclusion: A new series of 3-carboxamide derivatives was synthesized to selectively inhibit FXIIa and with the aim of improving their solubility. Pharmacomodulations will be fully discussed.",
author = "Charlotte Bouckaert and Christelle Vancraeynest and Eduard Dolušić and Rapha{\"e}l Fr{\'e}d{\'e}rick and Lionel Pochet",
year = "2013",
language = "English",
note = "null ; Conference date: 29-06-2013 Through 04-07-2013",

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Bouckaert, C, Vancraeynest, C, Dolušić, E, Frédérick, R & Pochet, L 2013, 'Novel coumarins with improved solubility as FXIIa inhibitors', XXIV Congress of the International Society of Thrombosis and Haemostasis, Amsterdam, Pays-Bas, 29/06/13 - 4/07/13.

Novel coumarins with improved solubility as FXIIa inhibitors. / Bouckaert, Charlotte; Vancraeynest, Christelle; Dolušić, Eduard; Frédérick, Raphaël; Pochet, Lionel.

2013. Poster présenté � XXIV Congress of the International Society of Thrombosis and Haemostasis, Amsterdam, Pays-Bas.

Résultats de recherche: Contribution à un événement scientifique (non publié)Poster

TY - CONF

T1 - Novel coumarins with improved solubility as FXIIa inhibitors

AU - Bouckaert, Charlotte

AU - Vancraeynest, Christelle

AU - Dolušić, Eduard

AU - Frédérick, Raphaël

AU - Pochet, Lionel

PY - 2013

Y1 - 2013

N2 - Background: Thrombotic diseases remain a major cause of death in industrialised countries. Anticoagulants have proven their efficacy to address these disorders. However severe bleeding complications are still reported even with the use of recently marketed drugs. Novel and safe antithrombotics are thus required.In this perspective, coagulation factor XIIa (FXIIa), a serine protease implicated in the contact phase of coagulation cascade, recently emerged as a promising target in the development of such agents. Indeed, it was demonstrated that FXII deficiency or inhibition protects against thrombosis without causing spontaneous bleeding in mice.Aim: Based on these considerations, the goal of our project is to develop novel selective FXIIa inhibitors to detail the exact role of this enzyme in thrombotic diseases. These compounds could also be a good starting point for the development of new antithrombotic drugs. The 3-carboxamide coumarins are to date the only nonpetidic and selective inhibitors of FXIIa described in literature. However, their low solubility and poor pharmacokinetics resulted in a lack of activity in in vivo models of thrombosis. As a consequence, we aim to improve these characteristics while keeping the selectivity and potency towards FXIIa.Methods: Twenty-five compounds were synthesized. Their solubility was investigated in pH 7.9 TRIS-imidazole. Inhibition potency on FXIIa was screened at several concentrations according to the maximum of solubility.Results: A new series of coumarins with an amino group at position 3 or 6 of the carboxamide coumarin scaffold was first synthesized. While solubility was largely increased the inhibition potency on FXIIa remained relatively low. On the contrary, insertion of an oxygen-based group on strategic positions did not improved solubility but lead to more active compounds.Conclusion: A new series of 3-carboxamide derivatives was synthesized to selectively inhibit FXIIa and with the aim of improving their solubility. Pharmacomodulations will be fully discussed.

AB - Background: Thrombotic diseases remain a major cause of death in industrialised countries. Anticoagulants have proven their efficacy to address these disorders. However severe bleeding complications are still reported even with the use of recently marketed drugs. Novel and safe antithrombotics are thus required.In this perspective, coagulation factor XIIa (FXIIa), a serine protease implicated in the contact phase of coagulation cascade, recently emerged as a promising target in the development of such agents. Indeed, it was demonstrated that FXII deficiency or inhibition protects against thrombosis without causing spontaneous bleeding in mice.Aim: Based on these considerations, the goal of our project is to develop novel selective FXIIa inhibitors to detail the exact role of this enzyme in thrombotic diseases. These compounds could also be a good starting point for the development of new antithrombotic drugs. The 3-carboxamide coumarins are to date the only nonpetidic and selective inhibitors of FXIIa described in literature. However, their low solubility and poor pharmacokinetics resulted in a lack of activity in in vivo models of thrombosis. As a consequence, we aim to improve these characteristics while keeping the selectivity and potency towards FXIIa.Methods: Twenty-five compounds were synthesized. Their solubility was investigated in pH 7.9 TRIS-imidazole. Inhibition potency on FXIIa was screened at several concentrations according to the maximum of solubility.Results: A new series of coumarins with an amino group at position 3 or 6 of the carboxamide coumarin scaffold was first synthesized. While solubility was largely increased the inhibition potency on FXIIa remained relatively low. On the contrary, insertion of an oxygen-based group on strategic positions did not improved solubility but lead to more active compounds.Conclusion: A new series of 3-carboxamide derivatives was synthesized to selectively inhibit FXIIa and with the aim of improving their solubility. Pharmacomodulations will be fully discussed.

M3 - Poster

ER -

Bouckaert C, Vancraeynest C, Dolušić E, Frédérick R, Pochet L. Novel coumarins with improved solubility as FXIIa inhibitors. 2013. Poster présenté � XXIV Congress of the International Society of Thrombosis and Haemostasis, Amsterdam, Pays-Bas.