Abstract
Monoamidine FXa inhibitors 3 were designed and synthesized. SAR studies and molecular modeling led to the design of conformationally constrained diaryl ethers 4 and 5, as well as benzopyrrolidinone 7 as potent FXa inhibitors. The monoamidines show high efficacy in a DVT model, but lack desirable oral bioavailability. The benzopyrrolidinone-based aminoisoquinolines 8 do not show significant improvement in oral bioavailability.
MeSH terms
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Administration, Oral
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Animals
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Benzamidines / chemical synthesis*
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Benzamidines / chemistry
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Benzamidines / pharmacokinetics
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Benzamidines / pharmacology*
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Biological Availability
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Drug Design
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Factor Xa Inhibitors*
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Isoquinolines / chemical synthesis*
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Isoquinolines / chemistry
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Isoquinolines / pharmacokinetics
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Isoquinolines / pharmacology*
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Rats
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Rats, Sprague-Dawley
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Serine Proteinase Inhibitors / chemical synthesis*
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Serine Proteinase Inhibitors / chemistry
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Serine Proteinase Inhibitors / pharmacokinetics
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Serine Proteinase Inhibitors / pharmacology*
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Structure-Activity Relationship
Substances
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Benzamidines
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Factor Xa Inhibitors
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Isoquinolines
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Serine Proteinase Inhibitors