Document Detail


3,6-disubstituted coumarins as mechanism-based inhibitors of thrombin and factor Xa.
MedLine Citation:
PMID:  16302799     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
In this work, coumarins were screened on thrombin (THR) and factor Xa (FXa), two of the most promising targets for the development of anticoagulant drugs. This allowed us to highlight compound 30, characterized by a 2,5-dichlorophenyl ester in the 3-position and a chloromethyl moiety in the 6-position, as a very potent THR inhibitor (ki/KI= 37,000 M(-1) s(-1)). Moreover, this compound exhibits good selectivity over FXa (168-fold) and trypsin (54-fold). The mechanism of inactivation was investigated in this series and significantly differs from that previously observed with alpha-chymotrypsin. Indeed, the addition of hydrazine on the THR-inhibitor complex promotes a partial induced THR reactivation. This reactivation, confirmed by LC/MS, showed the resurgence of the native THR and a new dihydrazide complex. Docking experiments were then efficiently used to explain the trends observed in the enzymatic assays as well as to corroborate the postulated inhibition mechanism. Finally, the cell permeability of our derivatives was estimated using a computational approach.
Authors:
Raphaël Frédérick; Séverine Robert; Caroline Charlier; Jérôme de Ruyck; Johan Wouters; Bernard Pirotte; Bernard Masereel; Lionel Pochet
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  48     ISSN:  0022-2623     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2005 Dec 
Date Detail:
Created Date:  2005-11-23     Completed Date:  2006-02-09     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  7592-603     Citation Subset:  IM    
Affiliation:
Department of Pharmacy and CBS Laboratory, University of Namur, FUNDP, 61, Rue de Bruxelles, B-5000 Namur, Belgium.
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MeSH Terms
Descriptor/Qualifier:
Animals
Caco-2 Cells
Cattle
Cell Membrane Permeability
Chromatography, Liquid
Computer Simulation
Coumarins / chemical synthesis*,  chemistry
Enzyme Activation
Factor Xa / antagonists & inhibitors*,  chemistry
Humans
Kinetics
Mass Spectrometry
Models, Molecular
Structure-Activity Relationship
Thrombin / antagonists & inhibitors*,  chemistry
Chemical
Reg. No./Substance:
0/6-chloromethyl-3-(2,5-dichlorophenoxycarbonyl)-2-benzopyrone; 0/Coumarins; EC 3.4.21.5/Thrombin; EC 3.4.21.6/Factor Xa

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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