Abstract
A series of 2,6-disubstituted 4-(2-arylethenyl)phenols with potent human neutrophil 5-lipoxygenase (5-LO) inhibiting activity (IC50S in the 10(-7) M range) and weaker human platelet cyclooxygenase (CO) inhibiting activity (IC50S in the 10(-6) M range) is described. This series evolved from the chemical modification of an antiinflammatory dual CO/5-LO inhibitor, 2,6-di-tert-butyl-4-[2-(3-pyridyl)ethenyl]phenol (BI-L-93 BS). The potency and selectivity for 5-LO inhibition is greatly influenced by the nature of the substituents in the 2- and 6-positions. Other structure-activity relationships that determine relative 5-LO and CO potency are discussed. In vivo activity against antigen-induced leukotriene-mediated bronchoconstriction and cell influx in guinea pigs is presented. Representatives of the series are active when administered at 30 mg/kg ip.
MeSH terms
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Animals
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Arachidonate 5-Lipoxygenase / blood
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Arachidonate Lipoxygenases / antagonists & inhibitors*
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Blood Platelets / enzymology
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Bronchodilator Agents / chemical synthesis*
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Cyclooxygenase Inhibitors
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Guinea Pigs
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Humans
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Indicators and Reagents
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Indomethacin / pharmacology
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Kinetics
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Leukocytes / enzymology
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Leukotrienes / physiology
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Lipoxygenase Inhibitors*
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Lung / drug effects
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Lung / physiology*
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Molecular Structure
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Phenols / chemical synthesis*
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Phenols / pharmacology
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Prostaglandin-Endoperoxide Synthases / blood
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Pyrilamine / pharmacology
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Respiratory Function Tests
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Structure-Activity Relationship
Substances
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Bronchodilator Agents
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Cyclooxygenase Inhibitors
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Indicators and Reagents
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Leukotrienes
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Lipoxygenase Inhibitors
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Phenols
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Arachidonate Lipoxygenases
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Arachidonate 5-Lipoxygenase
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Prostaglandin-Endoperoxide Synthases
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Pyrilamine
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Indomethacin