title: Effect of structure on potency and selectivity in 2,6-disubstituted 4-(2-arylethenyl)phenol lipoxygenase inhibitors.
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.
authors.affiliation: Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut 06877.
authors.forename: E S
authors.initials: ES
authors.lastname: Lazer
authors.forename: H C
authors.initials: HC
authors.lastname: Wong
authors.forename: C D
authors.initials: CD
authors.lastname: Wegner
authors.forename: A G
authors.initials: AG
authors.lastname: Graham
authors.forename: P R
authors.initials: PR
authors.lastname: Farina
mesh_terms: D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000097:blood; D001091:Arachidonate Lipoxygenases / Q000037:antagonists & inhibitors*; D001792:Blood Platelets / Q000201:enzymology; D001993:Bronchodilator Agents / Q000138:chemical synthesis*; D016861:Cyclooxygenase Inhibitors; D006168:Guinea Pigs; D006801:Humans; D007202:Indicators and Reagents; D007213:Indomethacin / Q000494:pharmacology; D007700:Kinetics; D007962:Leukocytes / Q000201:enzymology; D015289:Leukotrienes / Q000502:physiology; D016859:Lipoxygenase Inhibitors; D008168:Lung / Q000187:drug effects / Q000502:physiology*; D015394:Molecular Structure; D010636:Phenols / Q000138:chemical synthesis* / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000097:blood; D011738:Pyrilamine / Q000494:pharmacology; D012129:Respiratory Function Tests; D013329:Structure-Activity Relationship
chemical_list: D001993:Bronchodilator Agents; D016861:Cyclooxygenase Inhibitors; D007202:Indicators and Reagents; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D010636:Phenols; D001091:Arachidonate Lipoxygenases; D001094:Arachidonate 5-Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases; D011738:Pyrilamine; D007213:Indomethacin