Abstract
A series of substituted omega-[2-(1H-imidazol-1-yl)ethoxy]alkanoic acid derivatives were synthesized and evaluated for their ability to inhibit thromboxane synthase both in vitro and in vivo. Compound 13 was identified as a potent and selective competitive inhibitor of human platelet thromboxane synthase having a Ki value of 9.6 X 10(-8) M. In collagen-treated human whole blood, 13 potentiated levels of 6-keto PGF1 alpha. Enantiospecific syntheses afforded the R and S enantiomers of 13, of which the S enantiomer 13b was the more potent. Compounds 13 and 13b were potent in vivo inhibitors of thromboxane synthase with good oral activity and duration of action.
MeSH terms
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6-Ketoprostaglandin F1 alpha / blood
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Administration, Oral
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Animals
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Caproates / chemical synthesis*
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Caproates / pharmacology
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Collagen / pharmacology
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / pharmacology
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Guinea Pigs
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Humans
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Imidazoles / chemical synthesis*
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Imidazoles / pharmacology
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Kinetics
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Prostaglandin Endoperoxides, Synthetic / metabolism
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Prostaglandin H2
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Prostaglandins H / metabolism
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Stereoisomerism
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Thromboxane B2 / blood
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Thromboxane-A Synthase / antagonists & inhibitors*
Substances
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Caproates
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Enzyme Inhibitors
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Imidazoles
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Prostaglandin Endoperoxides, Synthetic
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Prostaglandins H
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Prostaglandin H2
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Thromboxane B2
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6-Ketoprostaglandin F1 alpha
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Collagen
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Thromboxane-A Synthase