Abstract
To overcome the low bioavailability of our substituted acrylamide P1 benzamidine factor Xa inhibitors reported previously, neutral and less basic groups were used to replace the benzamidine. As a result, a series of P1 aminoisoquinoline substituted acrylamide Xa inhibitors was identified to be potent, selective, and orally bioavailable. Modification of P4 moiety of these compounds further improved their pharmacokinetic properties.
MeSH terms
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Acrylamides / chemistry*
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Acrylamides / pharmacokinetics*
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Animals
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Antithrombin III / chemical synthesis*
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Antithrombin III / pharmacokinetics*
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Asparagine / chemistry
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Benzamidines / chemistry
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Biological Availability
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Dogs
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Factor Xa Inhibitors*
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Half-Life
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Hydrocarbons, Halogenated / chemistry
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Inhibitory Concentration 50
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Isoquinolines / chemical synthesis
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Isoquinolines / chemistry
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Isoquinolines / pharmacokinetics
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Prothrombin Time
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Rabbits
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Rats
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Stereoisomerism
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Structure-Activity Relationship
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Thrombin / antagonists & inhibitors
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Trypsin / drug effects
Substances
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Acrylamides
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Benzamidines
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Factor Xa Inhibitors
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Hydrocarbons, Halogenated
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Isoquinolines
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Asparagine
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Antithrombin III
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Trypsin
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Thrombin