Abstract
To develop a novel and effective anticoagulant with potent and selective factor Xa (FXa) inhibitory activity, a new series of cinnamyl derivatives with enhanced lipophilicity and prodrug forms were synthesized and their biological activities were evaluated. As a result, we found that cinnamyl derivative (N-[4-[1-(acetimidoyl)piperidin-4-yloxy]-3-carbamoylphenyl]-N-[(Z)-3-(3-amidinophenyl)-2-fluoro-2-propenyl]sulfamoyl)acetic acid dihydrochloride (26d, R-142086) with a fluorine atom on the double bond exhibited potent anticoagulant activity and no mutagenic potential. Moreover, orally administered R-142086 exhibited potent anti-FXa activity and anticoagulant activity in dogs.
MeSH terms
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Administration, Oral
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Amidines* / chemical synthesis
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Amidines* / chemistry
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Amidines* / pharmacology
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Animals
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Anticoagulants* / chemical synthesis
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Anticoagulants* / chemistry
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Anticoagulants* / pharmacology
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Antithrombin III* / chemical synthesis
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Antithrombin III* / chemistry
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Antithrombin III* / pharmacology
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Cinnamates / chemistry*
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Cricetinae
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Dogs
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Factor Xa Inhibitors*
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Humans
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Male
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Molecular Structure
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Structure-Activity Relationship
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Sulfonamides* / chemical synthesis
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Sulfonamides* / chemistry
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Sulfonamides* / pharmacology
Substances
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Amidines
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Anticoagulants
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Cinnamates
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Factor Xa Inhibitors
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N-(4-(1-(acetimidoyl)piperidin-4-yloxy)-3-carbamoylphenyl)-N-(3-(3-amidinophenyl)-2-fluoro-2-propenyl)sulfamoylacetic acid
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Sulfonamides
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Antithrombin III