title: 5-lipoxygenase-activating protein inhibitors: development of 3-[3-tert-butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (AM103).
abstract: The potent and selective 5-lipoxygenase-activating protein leukotriene synthesis inhibitor 3-[3-tert-butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (11j) is described. Lead optimization was designed to afford compounds with superior in vitro and in vivo inhibition of leukotriene synthesis in addition to having excellent pharmacokinetics and safety in rats and dogs. The key structural features of these new compounds are incorporation of heterocycles on the indole N-benzyl substituent and replacement of the quinoline group resulting in compounds with excellent in vitro and in vivo activities, superior pharmacokinetics, and improved physical properties. The methoxypyridine derivative 11j has an IC(50) of 4.2 nM in a 5-lipoxygenase-activating protein (FLAP) binding assay, an IC(50) of 349 nM in the human blood LTB(4) inhibition assay, and is efficacious in a murine ovalbumin model of allergen-induced asthma. Compound 11j was selected for clinical development and has successfully completed phase 1 trials in healthy volunteers.
authors.affiliation: Departments of Chemistry, Amira Pharmaceuticals, San Diego, California 92121, USA. john.hutchinson@amirapharm.com
authors.forename: John H
authors.initials: JH
authors.lastname: Hutchinson
authors.forename: Yiwei
authors.initials: Y
authors.lastname: Li
authors.forename: Jeannie M
authors.initials: JM
authors.lastname: Arruda
authors.forename: Christopher
authors.initials: C
authors.lastname: Baccei
authors.forename: Gretchen
authors.initials: G
authors.lastname: Bain
authors.forename: Charles
authors.initials: C
authors.lastname: Chapman
authors.forename: Lucia
authors.initials: L
authors.lastname: Correa
authors.forename: Janice
authors.initials: J
authors.lastname: Darlington
authors.forename: Christopher D
authors.initials: CD
authors.lastname: King
authors.forename: Catherine
authors.initials: C
authors.lastname: Lee
authors.forename: Dan
authors.initials: D
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: Nicholas
authors.initials: N
authors.lastname: Stock
authors.forename: Peppi
authors.initials: P
authors.lastname: Prasit
authors.forename: Jilly F
authors.initials: JF
authors.lastname: Evans
mesh_terms: D058927:5-Lipoxygenase-Activating Proteins; D000818:Animals; D001249:Asthma / Q000188:drug therapy; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D004285:Dogs; D064420:Drug-Related Side Effects and Adverse Reactions; D006571:Heterocyclic Compounds / Q000737:chemistry; D006801:Humans; D007211:Indoles / Q000493:pharmacokinetics*; D020128:Inhibitory Concentration 50; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D051379:Mice; D011422:Propionates / Q000493:pharmacokinetics*; D011485:Protein Binding; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: C544814:3-(3-tert-butylsulfanyl-1-(4-(6-methoxypyridin-3-yl)benzyl)-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl)-2,2-dimethylpropionic acid; D058927:5-Lipoxygenase-Activating Proteins; C548592:ALOX5AP protein, human; C548593:Alox5ap protein, mouse; D002352:Carrier Proteins; D006571:Heterocyclic Compounds; D007211:Indoles; D008565:Membrane Proteins; D011422:Propionates; D007975:Leukotriene B4