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

J Med Chem. 2011 Dec 8;54(23):8013-29. doi: 10.1021/jm2008369. Epub 2011 Nov 7.

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.

MeSH terms

  • 5-Lipoxygenase-Activating Protein Inhibitors / chemical synthesis*
  • 5-Lipoxygenase-Activating Protein Inhibitors / pharmacokinetics
  • 5-Lipoxygenase-Activating Protein Inhibitors / pharmacology
  • Administration, Oral
  • Animals
  • Anti-Asthmatic Agents / chemical synthesis*
  • Anti-Asthmatic Agents / pharmacokinetics
  • Anti-Asthmatic Agents / pharmacology
  • Bronchoalveolar Lavage
  • Cytochrome P-450 Enzyme Inhibitors
  • Dogs
  • Female
  • Humans
  • In Vitro Techniques
  • Indoles / chemical synthesis*
  • Indoles / pharmacokinetics
  • Indoles / pharmacology
  • Male
  • Pentanoic Acids / chemical synthesis*
  • Pentanoic Acids / pharmacokinetics
  • Pentanoic Acids / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship

Substances

  • 3-(3-tert-butylsulfanyl-1-(4-(6-ethoxypyridin-3-yl)benzyl)-5-(5-methylpyridin-2-ylmethoxy)-1H-indol-2-yl)-2,2-dimethylpropionic acid
  • 5-Lipoxygenase-Activating Protein Inhibitors
  • Anti-Asthmatic Agents
  • Cytochrome P-450 Enzyme Inhibitors
  • Indoles
  • Pentanoic Acids