coauthor on lecture: NOVEL DEVELOPMENT IN COUMARINS AS FXIIa INHIBITORS: IMPROVEMENT OF SOLUBILITY

Research output: Contribution in Book/Catalog/Report/Conference proceedingConference contribution

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Abstract

Thrombotic diseases, in which a deregulated clot formation occurs, remain a major cause of death in industrialised countries. Anticoagulants are part of the strategies to address these disorders. However current available drugs are still associated with risk of severe bleeding complications. Novel and safe antithrombotics are thus required.

In this context, 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 agents1. Indeed, it was shown that FXII deficiency as well as FXIIa inhibition protects against thrombosis without causing spontaneous bleeding in mice2.

Based on these considerations, the purpose 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 were previously described as nonpetidic and selective inhibitors of FXIIa3. However, their low solubility and poor pharmacokinetics resulted in a lack of activity in in vivo models of thrombosis4. Therefore, we aim to improve these characteristics while keeping the selectivity and potency towards FXIIa.

A new series of coumarins with an amino group at position 3 or 6 of the carboxamide coumarin scaffold was first synthesized. The introduction of a negative charge at these strategic positions was also investigated. The solubility and the inhibition potency of these newly synthesized compounds will be presented and the SAR will be fully discussed.
Original languageEnglish
Title of host publicationBook of Abstracts, 27èmes Journées franco-belges de Pharmacochimie / 21èmes Conférences européennes du GP2A
VolumeOC05
Publication statusPublished - 2013
Event27èmes Journées franco-belges de Pharmacochimie (JFB) - Lille, France
Duration: 5 Jun 20137 Jun 2013

Conference

Conference27èmes Journées franco-belges de Pharmacochimie (JFB)
CountryFrance
CityLille
Period5/06/137/06/13

Fingerprint

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

Cite this

Bouckaert, C., Vancraeynest, C., Dolušić, E., Frédérick, R., & Pochet, L. (2013). coauthor on lecture: NOVEL DEVELOPMENT IN COUMARINS AS FXIIa INHIBITORS: IMPROVEMENT OF SOLUBILITY. In Book of Abstracts, 27èmes Journées franco-belges de Pharmacochimie / 21èmes Conférences européennes du GP2A (Vol. OC05)
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title = "coauthor on lecture: NOVEL DEVELOPMENT IN COUMARINS AS FXIIa INHIBITORS: IMPROVEMENT OF SOLUBILITY",
abstract = "Thrombotic diseases, in which a deregulated clot formation occurs, remain a major cause of death in industrialised countries. Anticoagulants are part of the strategies to address these disorders. However current available drugs are still associated with risk of severe bleeding complications. Novel and safe antithrombotics are thus required. In this context, 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 agents1. Indeed, it was shown that FXII deficiency as well as FXIIa inhibition protects against thrombosis without causing spontaneous bleeding in mice2.Based on these considerations, the purpose 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 were previously described as nonpetidic and selective inhibitors of FXIIa3. However, their low solubility and poor pharmacokinetics resulted in a lack of activity in in vivo models of thrombosis4. Therefore, we aim to improve these characteristics while keeping the selectivity and potency towards FXIIa.A new series of coumarins with an amino group at position 3 or 6 of the carboxamide coumarin scaffold was first synthesized. The introduction of a negative charge at these strategic positions was also investigated. The solubility and the inhibition potency of these newly synthesized compounds will be presented and the SAR 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",
volume = "OC05",
booktitle = "Book of Abstracts, 27{\`e}mes Journ{\'e}es franco-belges de Pharmacochimie / 21{\`e}mes Conf{\'e}rences europ{\'e}ennes du GP2A",

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Bouckaert, C, Vancraeynest, C, Dolušić, E, Frédérick, R & Pochet, L 2013, coauthor on lecture: NOVEL DEVELOPMENT IN COUMARINS AS FXIIa INHIBITORS: IMPROVEMENT OF SOLUBILITY. in Book of Abstracts, 27èmes Journées franco-belges de Pharmacochimie / 21èmes Conférences européennes du GP2A. vol. OC05, 27èmes Journées franco-belges de Pharmacochimie (JFB), Lille, France, 5/06/13.

coauthor on lecture: NOVEL DEVELOPMENT IN COUMARINS AS FXIIa INHIBITORS: IMPROVEMENT OF SOLUBILITY. / Bouckaert, Charlotte; Vancraeynest, Christelle; Dolušić, Eduard; Frédérick, Raphaël; Pochet, Lionel.

Book of Abstracts, 27èmes Journées franco-belges de Pharmacochimie / 21èmes Conférences européennes du GP2A. Vol. OC05 2013.

Research output: Contribution in Book/Catalog/Report/Conference proceedingConference contribution

TY - GEN

T1 - coauthor on lecture: NOVEL DEVELOPMENT IN COUMARINS AS FXIIa INHIBITORS: IMPROVEMENT OF SOLUBILITY

AU - Bouckaert, Charlotte

AU - Vancraeynest, Christelle

AU - Dolušić, Eduard

AU - Frédérick, Raphaël

AU - Pochet, Lionel

PY - 2013

Y1 - 2013

N2 - Thrombotic diseases, in which a deregulated clot formation occurs, remain a major cause of death in industrialised countries. Anticoagulants are part of the strategies to address these disorders. However current available drugs are still associated with risk of severe bleeding complications. Novel and safe antithrombotics are thus required. In this context, 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 agents1. Indeed, it was shown that FXII deficiency as well as FXIIa inhibition protects against thrombosis without causing spontaneous bleeding in mice2.Based on these considerations, the purpose 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 were previously described as nonpetidic and selective inhibitors of FXIIa3. However, their low solubility and poor pharmacokinetics resulted in a lack of activity in in vivo models of thrombosis4. Therefore, we aim to improve these characteristics while keeping the selectivity and potency towards FXIIa.A new series of coumarins with an amino group at position 3 or 6 of the carboxamide coumarin scaffold was first synthesized. The introduction of a negative charge at these strategic positions was also investigated. The solubility and the inhibition potency of these newly synthesized compounds will be presented and the SAR will be fully discussed.

AB - Thrombotic diseases, in which a deregulated clot formation occurs, remain a major cause of death in industrialised countries. Anticoagulants are part of the strategies to address these disorders. However current available drugs are still associated with risk of severe bleeding complications. Novel and safe antithrombotics are thus required. In this context, 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 agents1. Indeed, it was shown that FXII deficiency as well as FXIIa inhibition protects against thrombosis without causing spontaneous bleeding in mice2.Based on these considerations, the purpose 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 were previously described as nonpetidic and selective inhibitors of FXIIa3. However, their low solubility and poor pharmacokinetics resulted in a lack of activity in in vivo models of thrombosis4. Therefore, we aim to improve these characteristics while keeping the selectivity and potency towards FXIIa.A new series of coumarins with an amino group at position 3 or 6 of the carboxamide coumarin scaffold was first synthesized. The introduction of a negative charge at these strategic positions was also investigated. The solubility and the inhibition potency of these newly synthesized compounds will be presented and the SAR will be fully discussed.

M3 - Conference contribution

VL - OC05

BT - Book of Abstracts, 27èmes Journées franco-belges de Pharmacochimie / 21èmes Conférences européennes du GP2A

ER -

Bouckaert C, Vancraeynest C, Dolušić E, Frédérick R, Pochet L. coauthor on lecture: NOVEL DEVELOPMENT IN COUMARINS AS FXIIa INHIBITORS: IMPROVEMENT OF SOLUBILITY. In Book of Abstracts, 27èmes Journées franco-belges de Pharmacochimie / 21èmes Conférences européennes du GP2A. Vol. OC05. 2013