title: Synthesis and structure-activity relationships of a novel class of 5-lipoxygenase inhibitors. 2-(Phenylmethyl)-4-hydroxy-3,5-dialkylbenzofurans: the development of L-656,224.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Merck Frosst Canada Inc., Pointe Claire-Dorval, Québec, Canada.
authors.forename: C K
authors.initials: CK
authors.lastname: Lau
authors.forename: P C
authors.initials: PC
authors.lastname: Bélanger
authors.forename: J
authors.initials: J
authors.lastname: Scheigetz
authors.forename: C
authors.initials: C
authors.lastname: Dufresne
authors.forename: H W
authors.initials: HW
authors.lastname: Williams
authors.forename: A L
authors.initials: AL
authors.lastname: Maycock
authors.forename: Y
authors.initials: Y
authors.lastname: Guindon
authors.forename: T
authors.initials: T
authors.lastname: Bach
authors.forename: A L
authors.initials: AL
authors.lastname: Dallob
authors.forename: D
authors.initials: D
authors.lastname: Denis
mesh_terms: D000328:Adult; D000818:Animals; D001091:Arachidonate Lipoxygenases / Q000037:antagonists & inhibitors*; D001572:Benzofurans / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D001980:Bronchi; D055598:Chemical Phenomena; D002621:Chemistry; D003251:Constriction, Pathologic / Q000188:drug therapy / Q000276:immunology; D006801:Humans; D007073:Immunoglobulin E; D007962:Leukocytes / Q000201:enzymology; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors / Q000097:blood; D016859:Lipoxygenase Inhibitors; D015394:Molecular Structure; D009504:Neutrophils / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
chemical_list: D001572:Benzofurans; D016859:Lipoxygenase Inhibitors; C055868:L 656224; D007975:Leukotriene B4; D007073:Immunoglobulin E; D001091:Arachidonate Lipoxygenases