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Mechanism-based thrombin inhibitors: design, synthesis, and molecular docking of a new selective 2-oxo-2H-1-benzopyran derivative.

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Frédérick, Raphaël [UCL] Robert, S. [FUNDP] Charlier, Caroline [FUNDP] Wouters, Johan [FUNDP] Masereel, Bernard [FUNDP] Pochet, Lionel [FUNDP]

New 2-oxo-2H-1-benzopyran derivatives were prepared to optimize 2a,b, initially developed as mechanism-based alpha-chymotrypsin (alpha-CT) inhibitors, into potent and selective thrombin (THR) inhibitors. From this study, 22, characterized by a 2-(N-ethyl-2'-oxoacetamide)-5'-chlorophenyl ester side chain, was shown to be a good THR inhibitor (ki/KI = 3455 M(-1) x s(-1)), displaying an excellent selectivity profile against other serine proteases such as factor Xa, trypsin, and alpha-CT. Docking analysis of this compound into the different protein structures revealed the molecular basis responsible for its potency and selectivity.

Document type Article de périodique (Journal article) – Journal Article, Research Support, Non-U.S. Gov't
Access type Accès restreint
Publication date 2007
Journal information "Journal of medicinal chemistry" - Vol. 50, no. 15, p. 3645-3650 (2007)
Peer reviewed yes
Publisher American Chemical Society ((United States) Washington, DC)
issn 0022-2623
e-issn 1520-4804
Publication status Publié
Affiliations FUNDP
UCL - MD/FARM - Ecole de pharmacie
MESH Subject Benzopyrans - chemical synthesis - chemistry ; Coumarins - chemical synthesis - chemistry ; Drug Design ; Models, Molecular ; Structure-Activity Relationship ; Thrombin - antagonists & inhibitors - chemistry
Links
Bibliographic reference Frédérick, Raphaël ; Robert, S. ; Charlier, Caroline ; Wouters, Johan ; Masereel, Bernard ; et. al. Mechanism-based thrombin inhibitors: design, synthesis, and molecular docking of a new selective 2-oxo-2H-1-benzopyran derivative.. In: Journal of medicinal chemistry, Vol. 50, no. 15, p. 3645-3650 (2007)
Permanent URL http://hdl.handle.net/2078.2/8137