1. 3-amino-4-sulfonylpyridinone acetamide and related pyridothiadiazine thrombin inhibitors.
- Author
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Sanderson PE, Cutrona KJ, Savage KL, Naylor-Olsen AM, Bickel DJ, Bohn DL, Clayton FC, Krueger JA, Lewis SD, Lucas BJ, Lyle EA, Wallace AA, Welsh DC, and Yan Y
- Subjects
- Acetamides pharmacokinetics, Administration, Oral, Animals, Disease Models, Animal, Dogs, Ferric Compounds toxicity, Humans, Models, Molecular, Pyridones pharmacokinetics, Rats, Structure-Activity Relationship, Sulfones chemistry, Sulfones pharmacokinetics, Sulfones pharmacology, Thiadiazines pharmacokinetics, Thrombosis chemically induced, Trypsin Inhibitors chemistry, Trypsin Inhibitors pharmacokinetics, Trypsin Inhibitors pharmacology, Acetamides chemistry, Acetamides pharmacology, Pyridones chemistry, Pyridones pharmacology, Thiadiazines chemistry, Thiadiazines pharmacology, Thrombin antagonists & inhibitors
- 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.
- Published
- 2003
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