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)

• Published in: Journal of medicinal chemistry 2009-10, Vol.52 (19), p.5803-5815
• Main Authors: Hutchinson, John H, Li, Yiwei, Arruda, Jeannie M, Baccei, Christopher, Bain, Gretchen, Chapman, Charles, Correa, Lucia, Darlington, Janice, King, Christopher D, Lee, Catherine, Lorrain, Dan, Prodanovich, Pat, Rong, Haojing, Santini, Angelina, Stock, Nicholas, Prasit, Peppi, Evans, Jilly F
• Format: Article
• Language: English
• Subjects: 5-Lipoxygenase-Activating Proteins; Animals; Asthma - drug therapy; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Carrier Proteins - antagonists & inhibitors; Dogs; Drug-Related Side Effects and Adverse Reactions; Heterocyclic Compounds - chemistry; Humans; Indoles - pharmacokinetics; Inhibitory Concentration 50; Leukotriene B4 - antagonists & inhibitors; Leukotriene B4 - biosynthesis; Medical sciences; Membrane Proteins - antagonists & inhibitors; Mice; Pharmacology. Drug treatments; Propionates - pharmacokinetics; Protein Binding; Rats; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm900945d

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 IC50 of 4.2 nM in a 5-lipoxygenase-activating protein (FLAP) binding assay, an IC50 of 349 nM in the human blood LTB4 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.