title: Substituted indoles as potent and orally active 5-lipoxygenase activating protein (FLAP) inhibitors.
abstract: This paper reports on the SAR investigation of inhibitors of 5-lipoxygenase activating protein (FLAP) based on MK-0591. Emphasis was made on modifications to the nature of the link between the indole and the quinoline moieties, to the substitution pattern around the two heterocycles and to possible replacements of the quinoline moiety. Lead optimization culminated in (3-[1-(4-chlorobenzyl)-3-(t-butylthio)-5-(pyridin-2-ylmethoxy)-ind ol-2-yl]-2,2-dimethylpropanoic acid (18k), as a potent inhibitor of leukotriene biosynthesis that is well absorbed and active in functional models.
authors.affiliation: Merck Frosst Center for Therapeutic Research, Pointe-Claire - Dorval, Québec, Canada.
authors.forename: R
authors.initials: R
authors.lastname: Frenette
authors.forename: J H
authors.initials: JH
authors.lastname: Hutchinson
authors.forename: S
authors.initials: S
authors.lastname: Léger
authors.forename: M
authors.initials: M
authors.lastname: Thérien
authors.forename: C
authors.initials: C
authors.lastname: Brideau
authors.forename: C C
authors.initials: CC
authors.lastname: Chan
authors.forename: S
authors.initials: S
authors.lastname: Charleson
authors.forename: D
authors.initials: D
authors.lastname: Ethier
authors.forename: J
authors.initials: J
authors.lastname: Guay
authors.forename: T R
authors.initials: TR
authors.lastname: Jones
authors.forename: M
authors.initials: M
authors.lastname: McAuliffe
authors.forename: H
authors.initials: H
authors.lastname: Piechuta
authors.forename: D
authors.initials: D
authors.lastname: Riendeau
authors.forename: P
authors.initials: P
authors.lastname: Tagari
authors.forename: Y
authors.initials: Y
authors.lastname: Girard
mesh_terms: D058927:5-Lipoxygenase-Activating Proteins; D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D004285:Dogs; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D016859:Lipoxygenase Inhibitors / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D011804:Quinolines / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D058927:5-Lipoxygenase-Activating Proteins; C548592:ALOX5AP protein, human; D002352:Carrier Proteins; D007211:Indoles; D016859:Lipoxygenase Inhibitors; D008565:Membrane Proteins; D011804:Quinolines; C078266:MK 0591