Effect of structure on potency and selectivity in 2,6-disubstituted-4-(2-arylethenyl)phenol lipoxygenase inhibitors

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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 range) is described. This series evolved from the chemical modification of an inflammatory 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-medited bronchoconstriction and cell influx in guinea pigs is presented. Representatives of the series are active when administered at 30 mg/kg ip.

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