title: 5-Lipoxygenase-activating protein inhibitors. Part 2: 3-{5-((S)-1-Acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-3-tert-butylsulfanyl-1-[4-(5-methoxy-pyrimidin-2-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionic acid (AM679)--a potent FLAP inhibitor.
abstract: A series of potent 5-lipoxygenase-activating protein (FLAP) inhibitors are herein described. SAR studies focused on the discovery of novel alicyclic moieties appended to an indole core to optimize potency, physical properties and off-target activities. Subsequent SAR on the N-benzyl substituent of the indole led to the discovery of compound 39 (AM679) which showed potent inhibition of leukotrienes in human blood and in a rodent bronchoalvelolar lavage (BAL) challenge model.
authors.affiliation: Amira Pharmaceuticals, 9535 Waples St., Suite 100, San Diego, CA 92121, USA. nick.stock@amirapharm.com
authors.forename: Nicholas
authors.initials: N
authors.lastname: Stock
authors.forename: Christopher
authors.initials: C
authors.lastname: Baccei
authors.forename: Gretchen
authors.initials: G
authors.lastname: Bain
authors.forename: Alex
authors.initials: A
authors.lastname: Broadhead
authors.forename: Charles
authors.initials: C
authors.lastname: Chapman
authors.forename: Janice
authors.initials: J
authors.lastname: Darlington
authors.forename: Christopher
authors.initials: C
authors.lastname: King
authors.forename: Catherine
authors.initials: C
authors.lastname: Lee
authors.forename: Yiwei
authors.initials: Y
authors.lastname: Li
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Lorrain
authors.forename: Pat
authors.initials: P
authors.lastname: Prodanovich
authors.forename: Haojing
authors.initials: H
authors.lastname: Rong
authors.forename: Angelina
authors.initials: A
authors.lastname: Santini
authors.forename: Jasmine
authors.initials: J
authors.lastname: Zunic
authors.forename: Jilly F
authors.initials: JF
authors.lastname: Evans
authors.forename: John H
authors.initials: JH
authors.lastname: Hutchinson
authors.forename: Peppi
authors.initials: P
authors.lastname: Prasit
mesh_terms: D058927:5-Lipoxygenase-Activating Proteins; D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015289:Leukotrienes / Q000097:blood / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D023421:Models, Animal; D010421:Pentanoic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: C549133:3-(5-(-1-acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-3-tert-butylsulfanyl-1-(4-(5-methoxypyrimidin-2-yl)-benzyl)-1H-indol-2-yl)-2,2-dimethyl-propionic acid; D058927:5-Lipoxygenase-Activating Proteins; C548592:ALOX5AP protein, human; C548593:Alox5ap protein, mouse; D002352:Carrier Proteins; D007211:Indoles; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D008565:Membrane Proteins; D010421:Pentanoic Acids; C030374:indole