title: 5-Lipoxygenase-activating protein (FLAP) inhibitors. Part 4: development of 3-[3-tert-butylsulfanyl-1-[4-(6-ethoxypyridin-3-yl)benzyl]-5-(5-methylpyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethylpropionic acid (AM803), a potent, oral, once daily FLAP inhibitor.
abstract: The potent 5-lipoxygenase-activating protein (FLAP) inhibitor 3-[3-tert-butylsulfanyl-1-[4-(6-ethoxypyridin-3-yl)benzyl]-5-(5-methylpyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethylpropionic acid 11cc is described (AM803, now GSK2190915). Building upon AM103 (1) (Hutchinson et al. J. Med Chem.2009, 52, 5803-5815; Stock et al. Bioorg. Med. Chem. Lett. 2010, 20, 213-217; Stock et al. Bioorg. Med. Chem. Lett.2010, 20, 4598-4601), SAR studies centering around the pyridine moiety led to the discovery of compounds that exhibit significantly increased potency in a human whole blood assay measuring LTB(4) inhibition with longer drug preincubation times (15 min vs 5 h). Further studies identified 11cc with a potency of 2.9 nM in FLAP binding, an IC(50) of 76 nM for inhibition of LTB(4) in human blood (5 h incubation) and excellent preclinical toxicology and pharmacokinetics in rat and dog. 11cc also demonstrated an extended pharmacodynamic effect in a rodent bronchoalveolar lavage (BAL) model. This compound has successfully completed phase 1 clinical studies in healthy volunteers and is currently undergoing phase 2 trials in asthmatic patients.
authors: Department of Chemistry, Amira Pharmaceuticals, San Diego, California 92121, United States. nstock@inceptionsci.com
authors: Nicholas S
authors: NS
authors: Stock
authors: Gretchen
authors: G
authors: Bain
authors: Jasmine
authors: J
authors: Zunic
authors: Yiwei
authors: Y
authors: Li
authors: Jeannie
authors: J
authors: Ziff
authors: Jeffrey
authors: J
authors: Roppe
authors: Angelina
authors: A
authors: Santini
authors: Janice
authors: J
authors: Darlington
authors: Pat
authors: P
authors: Prodanovich
authors: Christopher D
authors: CD
authors: King
authors: Christopher
authors: C
authors: Baccei
authors: Catherine
authors: C
authors: Lee
authors: Haojing
authors: H
authors: Rong
authors: Charles
authors: C
authors: Chapman
authors: Alex
authors: A
authors: Broadhead
authors: Dan
authors: D
authors: Lorrain
authors: Lucia
authors: L
authors: Correa
authors: John H
authors: JH
authors: Hutchinson
authors: Jilly F
authors: JF
authors: Evans
authors: Peppi
authors: P
authors: Prasit
mesh_terms: D058946:5-Lipoxygenase-Activating Protein Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D018893:Bronchoalveolar Lavage; D065607:Cytochrome P-450 Enzyme Inhibitors; D004285:Dogs; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D010421:Pentanoic Acids / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: C552410:3-(3-tert-butylsulfanyl-1-(4-(6-ethoxypyridin-3-yl)benzyl)-5-(5-methylpyridin-2-ylmethoxy)-1H-indol-2-yl)-2,2-dimethylpropionic acid; D058946:5-Lipoxygenase-Activating Protein Inhibitors; D018927:Anti-Asthmatic Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D007211:Indoles; D010421:Pentanoic Acids