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

Bioorg Med Chem Lett. 2010 Jan 1;20(1):213-7. doi: 10.1016/j.bmcl.2009.10.131. Epub 2009 Oct 31.

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.

MeSH terms

  • 5-Lipoxygenase-Activating Proteins
  • Animals
  • Carrier Proteins / antagonists & inhibitors*
  • Carrier Proteins / metabolism
  • Humans
  • Indoles / chemical synthesis
  • Indoles / chemistry*
  • Indoles / pharmacology
  • Leukotrienes / blood
  • Leukotrienes / metabolism
  • Lipoxygenase Inhibitors / chemical synthesis
  • Lipoxygenase Inhibitors / chemistry*
  • Lipoxygenase Inhibitors / pharmacology
  • Membrane Proteins / antagonists & inhibitors*
  • Membrane Proteins / metabolism
  • Mice
  • Models, Animal
  • Pentanoic Acids / chemical synthesis
  • Pentanoic Acids / chemistry*
  • Pentanoic Acids / pharmacology
  • Rats
  • Structure-Activity Relationship

Substances

  • 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
  • 5-Lipoxygenase-Activating Proteins
  • ALOX5AP protein, human
  • Alox5ap protein, mouse
  • Carrier Proteins
  • Indoles
  • Leukotrienes
  • Lipoxygenase Inhibitors
  • Membrane Proteins
  • Pentanoic Acids
  • indole