Abstract
Recent efforts in the field of thrombin inhibitor research have focused on the identification of compounds with good oral bioavailability and pharmacokinetics. In this manuscript we describe a metabolism-based approach to the optimization of the 3-(2-phenethylamino)-6-methylpyrazinone acetamide template (e.g., 1) which resulted in the modification of each of the three principal components (i.e., P1, P2, P3) comprising this series. As a result of these studies, several potent thrombin inhibitors (e.g., 20, 24, 25) were identified which exhibit high levels of oral bioavailability and long plasma half-lives.
MeSH terms
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Acetamides / chemical synthesis
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Acetamides / pharmacokinetics*
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Acetamides / pharmacology
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Administration, Oral
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Animals
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Anticoagulants / chemical synthesis
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Anticoagulants / pharmacokinetics*
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Anticoagulants / pharmacology
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Biological Availability
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Crystallography, X-Ray
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Dogs
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Macaca mulatta
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Models, Molecular
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Protease Inhibitors / chemical synthesis*
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Protease Inhibitors / chemistry
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Protease Inhibitors / pharmacology
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Pyrazines / chemical synthesis
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Pyrazines / pharmacokinetics*
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Pyrazines / pharmacology
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Pyridines / chemical synthesis
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Pyridines / pharmacokinetics*
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Pyridines / pharmacology
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Rats
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Structure-Activity Relationship
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Thrombin / antagonists & inhibitors*
Substances
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Acetamides
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Anticoagulants
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Protease Inhibitors
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Pyrazines
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Pyridines
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Thrombin