STUDY OF COUMARINS WITH IMPROVED SOLUBILITY TO INHIBIT FXIIa, AN EMERGING TARGET IN THROMBOSIS RESEARCH

Research output: Contribution to conferencePoster

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Abstract

Thrombotic diseases, in which a deregulated haemostatic activity occurs, remain a major concern in medicine. Anticoagulants are part of the strategies to address these disorders. However current available drugs are still associated with risk of severe bleeding complications and thus, novel antithrombotics are required1.

In this perspective, coagulation factor XIIa (FXIIa), a serine protease implicated in the coagulation cascade, recently emerged as a promising target in the development of such agents2. Indeed, it was demonstrated that FXII deficiency or inhibition protects against thrombosis without causing spontaneous bleeding in mice3.

Based on these considerations, the aim 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 (figure 1) are to date the only nonpetidic and selective inhibitors of FXIIa described in literature4. However, their low solubility and poor pharmacokinetics resulted in a lack of activity in in vivo models of thrombosis. As consequence, we need to improve these characteristics while keeping the selectivity and potency towards FXIIa.

In this work, we first synthesized new coumarins with improved solubility. Their inhibition potency was then measured on FXIIa and finally, their stability was evaluated.
Original languageEnglish
PagesBook of Abstracts, MedChem 2012, Château de Colonster, Liège - November 30, 2012, P01
Number of pages1
Publication statusPublished - 30 Nov 2012
EventAnnual One-Day Symposium on Medicinal Chemistry of SRC & KVCV (Medchem 2012) - Liège, Belgium
Duration: 30 Nov 2012 → …

Symposium

SymposiumAnnual One-Day Symposium on Medicinal Chemistry of SRC & KVCV (Medchem 2012)
CountryBelgium
CityLiège
Period30/11/12 → …

Fingerprint

Factor XIIa
Coumarins
Solubility
Thrombosis
Research
Hemorrhage
Serine Proteases
Hemostatics
Pharmaceutical Preparations
Anticoagulants
Pharmacokinetics
Medicine
Enzymes
factor XIIa inhibitor

Cite this

Bouckaert, C., Vancraeynest, C., Dolušić, E., Frédérick, R., & Pochet, L. (2012). STUDY OF COUMARINS WITH IMPROVED SOLUBILITY TO INHIBIT FXIIa, AN EMERGING TARGET IN THROMBOSIS RESEARCH. Book of Abstracts, MedChem 2012, Château de Colonster, Liège - November 30, 2012, P01. Poster session presented at Annual One-Day Symposium on Medicinal Chemistry of SRC & KVCV (Medchem 2012), Liège, Belgium.
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title = "STUDY OF COUMARINS WITH IMPROVED SOLUBILITY TO INHIBIT FXIIa, AN EMERGING TARGET IN THROMBOSIS RESEARCH",
abstract = "Thrombotic diseases, in which a deregulated haemostatic activity occurs, remain a major concern in medicine. Anticoagulants are part of the strategies to address these disorders. However current available drugs are still associated with risk of severe bleeding complications and thus, novel antithrombotics are required1.In this perspective, coagulation factor XIIa (FXIIa), a serine protease implicated in the coagulation cascade, recently emerged as a promising target in the development of such agents2. Indeed, it was demonstrated that FXII deficiency or inhibition protects against thrombosis without causing spontaneous bleeding in mice3.Based on these considerations, the aim 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 (figure 1) are to date the only nonpetidic and selective inhibitors of FXIIa described in literature4. However, their low solubility and poor pharmacokinetics resulted in a lack of activity in in vivo models of thrombosis. As consequence, we need to improve these characteristics while keeping the selectivity and potency towards FXIIa.In this work, we first synthesized new coumarins with improved solubility. Their inhibition potency was then measured on FXIIa and finally, their stability was evaluated.",
author = "Charlotte Bouckaert and Christelle Vancraeynest and Eduard Dolušić and Rapha{\"e}l Fr{\'e}d{\'e}rick and Lionel Pochet",
year = "2012",
month = "11",
day = "30",
language = "English",
pages = "Book of Abstracts, MedChem 2012, Ch{\^a}teau de Colonster, Li{\`e}ge -- November 30, 2012, P01",
note = "Annual One-Day Symposium on Medicinal Chemistry of SRC & KVCV (Medchem 2012) ; Conference date: 30-11-2012",

}

Bouckaert, C, Vancraeynest, C, Dolušić, E, Frédérick, R & Pochet, L 2012, 'STUDY OF COUMARINS WITH IMPROVED SOLUBILITY TO INHIBIT FXIIa, AN EMERGING TARGET IN THROMBOSIS RESEARCH', Annual One-Day Symposium on Medicinal Chemistry of SRC & KVCV (Medchem 2012), Liège, Belgium, 30/11/12 pp. Book of Abstracts, MedChem 2012, Château de Colonster, Liège - November 30, 2012, P01.

STUDY OF COUMARINS WITH IMPROVED SOLUBILITY TO INHIBIT FXIIa, AN EMERGING TARGET IN THROMBOSIS RESEARCH. / Bouckaert, Charlotte; Vancraeynest, Christelle; Dolušić, Eduard; Frédérick, Raphaël; Pochet, Lionel.

2012. Book of Abstracts, MedChem 2012, Château de Colonster, Liège - November 30, 2012, P01 Poster session presented at Annual One-Day Symposium on Medicinal Chemistry of SRC & KVCV (Medchem 2012), Liège, Belgium.

Research output: Contribution to conferencePoster

TY - CONF

T1 - STUDY OF COUMARINS WITH IMPROVED SOLUBILITY TO INHIBIT FXIIa, AN EMERGING TARGET IN THROMBOSIS RESEARCH

AU - Bouckaert, Charlotte

AU - Vancraeynest, Christelle

AU - Dolušić, Eduard

AU - Frédérick, Raphaël

AU - Pochet, Lionel

PY - 2012/11/30

Y1 - 2012/11/30

N2 - Thrombotic diseases, in which a deregulated haemostatic activity occurs, remain a major concern in medicine. Anticoagulants are part of the strategies to address these disorders. However current available drugs are still associated with risk of severe bleeding complications and thus, novel antithrombotics are required1.In this perspective, coagulation factor XIIa (FXIIa), a serine protease implicated in the coagulation cascade, recently emerged as a promising target in the development of such agents2. Indeed, it was demonstrated that FXII deficiency or inhibition protects against thrombosis without causing spontaneous bleeding in mice3.Based on these considerations, the aim 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 (figure 1) are to date the only nonpetidic and selective inhibitors of FXIIa described in literature4. However, their low solubility and poor pharmacokinetics resulted in a lack of activity in in vivo models of thrombosis. As consequence, we need to improve these characteristics while keeping the selectivity and potency towards FXIIa.In this work, we first synthesized new coumarins with improved solubility. Their inhibition potency was then measured on FXIIa and finally, their stability was evaluated.

AB - Thrombotic diseases, in which a deregulated haemostatic activity occurs, remain a major concern in medicine. Anticoagulants are part of the strategies to address these disorders. However current available drugs are still associated with risk of severe bleeding complications and thus, novel antithrombotics are required1.In this perspective, coagulation factor XIIa (FXIIa), a serine protease implicated in the coagulation cascade, recently emerged as a promising target in the development of such agents2. Indeed, it was demonstrated that FXII deficiency or inhibition protects against thrombosis without causing spontaneous bleeding in mice3.Based on these considerations, the aim 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 (figure 1) are to date the only nonpetidic and selective inhibitors of FXIIa described in literature4. However, their low solubility and poor pharmacokinetics resulted in a lack of activity in in vivo models of thrombosis. As consequence, we need to improve these characteristics while keeping the selectivity and potency towards FXIIa.In this work, we first synthesized new coumarins with improved solubility. Their inhibition potency was then measured on FXIIa and finally, their stability was evaluated.

M3 - Poster

SP - Book of Abstracts, MedChem 2012, Château de Colonster, Liège - November 30, 2012, P01

ER -

Bouckaert C, Vancraeynest C, Dolušić E, Frédérick R, Pochet L. STUDY OF COUMARINS WITH IMPROVED SOLUBILITY TO INHIBIT FXIIa, AN EMERGING TARGET IN THROMBOSIS RESEARCH. 2012. Poster session presented at Annual One-Day Symposium on Medicinal Chemistry of SRC & KVCV (Medchem 2012), Liège, Belgium.