title: Development of 2,3-dihydro-6-(3-phenoxypropyl)-2-(2-phenylethyl)-5-benzofuranol (L-670,630) as a potent and orally active inhibitor of 5-lipoxygenase.
abstract: Leukotrienes are potent biological mediators of allergic and inflammatory diseases and are derived from arachidonic acid through the action of the 5-lipoxygenase. In this study, the syntheses and comparative biological activities of three series of 2,3-dihydro-2,6-disubstituted-5-benzofuranols with various substituents on position 3 are described. Compounds from each series were evaluated for their ability to inhibit the production of leukotriene B4 (LTB4) in human peripheral blood polymorphonuclear (PMN) leukocytes and the 5-lipoxygenase reaction in cell-free preparations from rat PMN leukocytes. The structure-activity relationships of each series in vitro and in vivo are presented. The bioavailability, metabolism, and toxicity profile of each series are discussed. The series with no substituent at position 3 was the most potent and among the compounds in that series 2,3-dihydro-6-(3-phenoxypropyl)-2-(2-phenylethyl)-5-benzofuranol (46, L-670,630) was chosen for further development.
authors.affiliation: Department of Medicinal Chemistry, Merck Frosst Centre For Therapeutic Research, Pointe Claire-Dorval, Quebec, Canada.
authors.forename: C K
authors.initials: CK
authors.lastname: Lau
authors.forename: P C
authors.initials: PC
authors.lastname: Bélanger
authors.forename: C
authors.initials: C
authors.lastname: Dufresne
authors.forename: J
authors.initials: J
authors.lastname: Scheigetz
authors.forename: M
authors.initials: M
authors.lastname: Therien
authors.forename: B
authors.initials: B
authors.lastname: Fitzsimmons
authors.forename: R N
authors.initials: RN
authors.lastname: Young
authors.forename: A W
authors.initials: AW
authors.lastname: Ford-Hutchinson
authors.forename: D
authors.initials: D
authors.lastname: Riendeau
authors.forename: D
authors.initials: D
authors.lastname: Denis
mesh_terms: D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D001572:Benzofurans / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D016084:Bronchoconstriction / Q000187:drug effects; D004285:Dogs; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000201:enzymology; D007975:Leukotriene B4 / Q000096:biosynthesis; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D008297:Male; D008706:Methemoglobin / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism; D015394:Molecular Structure; D051381:Rats; D011919:Rats, Inbred Strains; D012453:Saimiri; D013329:Structure-Activity Relationship
chemical_list: D001572:Benzofurans; D016859:Lipoxygenase Inhibitors; C074028:L 670630; D007975:Leukotriene B4; D008706:Methemoglobin; D001094:Arachidonate 5-Lipoxygenase