Abstract
To enhance the potency of 1,2-dibenzamidobenzene-derived inhibitors of factor Xa (fXa), an amidine substituent was incorporated on one of the benzoyl side chains to interact with Asp189 in the S1 specificity pocket. Lead molecule 1 was docked into the active site of fXa to facilitate inhibitor design. Subsequently, iterative SAR studies and molecular modeling led to a 1000-fold increase in fXa affinity and a refined model of the new inhibitors in the fXa active site. Strong support for the computational model was achieved through the acquisition of an X-ray crystal structure using thrombin as a surrogate protein. The amidines in this series show high levels of selectivity for the inhibition of fXa relative to other trypsin-like serine proteases. Furthermore, the fXa affinity of compounds in this series (K(ass) = 50-500 x 10(6) L/mol) translates effectively into both anticoagulant activity in vitro and antithrombotic activity in vivo.
MeSH terms
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Amidines / chemical synthesis*
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Amidines / chemistry
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Amidines / metabolism
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Amidines / pharmacology
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Animals
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Anticoagulants / chemical synthesis*
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Anticoagulants / chemistry
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Anticoagulants / metabolism
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Anticoagulants / pharmacology
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Binding Sites
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Crystallography, X-Ray
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Dogs
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Drug Design
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / metabolism
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Enzyme Inhibitors / pharmacology
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Factor Xa / chemistry
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Factor Xa / metabolism
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Factor Xa Inhibitors*
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Fibrinolytic Agents / chemical synthesis*
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Fibrinolytic Agents / chemistry
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Fibrinolytic Agents / metabolism
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Fibrinolytic Agents / pharmacology
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Humans
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In Vitro Techniques
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Male
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Models, Molecular
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Prothrombin Time
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Rabbits
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Rats
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Rats, Sprague-Dawley
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Structure-Activity Relationship
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Thrombin / chemistry
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Thrombin / metabolism
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Thrombosis / drug therapy
Substances
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Amidines
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Anticoagulants
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Enzyme Inhibitors
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Factor Xa Inhibitors
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Fibrinolytic Agents
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Thrombin
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Factor Xa