Abstract
The synthesis of novel 1-thio-substituted butadienes, designed as mechanism-based 5-lipoxygenase inhibitors, is described. The structure of these compounds closely resembles a proposed high-energy intermediate during the lipoxygenation of arachidonic acid. They demonstrate 5-lipoxygenase inhibition in vitro and in vivo. The most potent compound is 15a with an IC50 of 1.8 microM in vitro. LTC4 release was inhibited by 80% after intraperitoneal administration of 15c at a dose of 2 mg/kg.
MeSH terms
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Animals
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Arachidonate Lipoxygenases / antagonists & inhibitors*
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Arachidonic Acids / chemical synthesis*
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Arachidonic Acids / pharmacology
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Butadienes / chemical synthesis*
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Butadienes / pharmacology
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Chemical Phenomena
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Chemistry
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Lipoxygenase Inhibitors*
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Male
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Mice
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Structure-Activity Relationship
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Sulfhydryl Compounds / chemical synthesis*
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Sulfhydryl Compounds / pharmacology
Substances
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Arachidonic Acids
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Butadienes
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Lipoxygenase Inhibitors
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Sulfhydryl Compounds
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methyl 5-thia-6,8,11,14-eicosatetraenoate
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Arachidonate Lipoxygenases