Abstract
The synthetic entry to new classes of dual fXa/thrombin and selective thrombin inhibitors with significant oral bioavailability is described. This was achieved through minor modifications to the sulfonamide group in our potent and selective fXa inhibitor (E)-2-(5-chlorothien-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-(morpholin-4-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide and these observed activity changes have been rationalised using structural studies.
MeSH terms
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Animals
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Dogs
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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 / pharmacology*
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Models, Molecular
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Molecular Structure
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Morpholines / chemical synthesis
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Morpholines / pharmacology*
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Rats
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Structure-Activity Relationship
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Sulfonamides / chemical synthesis
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Sulfonamides / pharmacology*
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Thrombin / antagonists & inhibitors*
Substances
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2-(5-chlorothien-2-yl)-N-((3S)-1-((1S)-1-methyl-2-(morpholin-4-yl)-2-oxoethyl)-2-oxopyrrolidin-3-yl)ethenesulfonamide
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Factor Xa Inhibitors
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Fibrinolytic Agents
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Morpholines
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Sulfonamides
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Thrombin