leukotriene-b4 and Constriction--Pathologic

The synthesis of a series of 2-(phenylmethyl)-4-hydroxy-3,5-dialkylbenzofurans and their inhibitory effects against leukotriene biosynthesis and 5-lipoxygenase activity in vitro are described. Many compounds in this series were found to be potent inhibitors of LTB4 production by human polymorphonuclear leukocytes with IC50 values ranging from 7 to 100 nM. Structure-activity relationships of the series are presented. Within this series, 2-[(4'-methoxyphenyl)methyl]-4-hydroxy-3-methyl-5-propyl-7-chlorobenz ofuran (L-656,224) showed extremely potent activity, inhibiting leukotriene biosynthesis in intact human leukocytes (IC50 = 11 nM), as well as the 5-lipoxygenase reaction catalyzed by cell-free preparations from rat leukocytes (IC50 = 36 nM), human leukocytes (IC50 = 0.4 microM), and the purified enzyme from porcine leukocytes (IC50 = 0.4 microM). The compound also shows oral activity in a number of animal models in vivo.

Topics: Adult; Animals; Arachidonate Lipoxygenases; Benzofurans; Bronchi; Chemical Phenomena; Chemistry; Constriction, Pathologic; Humans; Immunoglobulin E; Leukocytes; Leukotriene B4; Lipoxygenase Inhibitors; Molecular Structure; Neutrophils; Rats; Rats, Inbred Strains; Structure-Activity Relationship

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Airway Obstruction; Animals; Arachidonic Acids; Capillary Permeability; Chemotactic Factors; Constriction, Pathologic; Eosinophils; Guinea Pigs; Humans; Hypersensitivity, Immediate; Inflammation; Leukotriene B4; Lipoxygenase; Muscle Contraction; Muscle, Smooth; Neutrophils; Rats; Skin; SRS-A; Trachea