Abstract
We describe a series of highly potent and efficacious thrombin inhibitors based on a 3-amino-4-sulfonylpyridinone acetamide template. The functionally dense sulfonyl group stabilizes the aminopyridinone, conformationally constrains the 4-substituent, and forms a hydrogen bond to the insertion loop tyrosine OH. We also describe a related series of fused bicyclic dihydrothiadiazinedioxide derivatives, of which one had improved pharmacokinetics in dogs after oral dosing.
MeSH terms
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Acetamides / chemistry*
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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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Disease Models, Animal
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Dogs
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Ferric Compounds / toxicity
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Humans
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Models, Molecular
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Pyridones / chemistry*
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Pyridones / pharmacokinetics
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Pyridones / pharmacology*
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Rats
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Structure-Activity Relationship
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Sulfones / chemistry
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Sulfones / pharmacokinetics
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Sulfones / pharmacology
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Thiadiazines / chemistry*
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Thiadiazines / pharmacokinetics
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Thiadiazines / pharmacology*
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Thrombin / antagonists & inhibitors*
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Thrombosis / chemically induced
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Trypsin Inhibitors / chemistry
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Trypsin Inhibitors / pharmacokinetics
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Trypsin Inhibitors / pharmacology
Substances
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Acetamides
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Ferric Compounds
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Pyridones
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Sulfones
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Thiadiazines
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Trypsin Inhibitors
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Thrombin