Identification of a potent, selective, and orally active leukotriene a4 hydrolase inhibitor with anti-inflammatory activity

J Med Chem. 2008 Jul 24;51(14):4150-69. doi: 10.1021/jm701575k. Epub 2008 Jun 28.


LTA 4H is a ubiquitously distributed 69 kDa zinc-containing cytosolic enzyme with both hydrolase and aminopeptidase activity. As a hydrolase, LTA 4H stereospecifically catalyzes the transformation of the unstable epoxide LTA 4 to the diol LTB 4, a potent chemoattractant and activator of neutrophils and a chemoattractant of eosinophils, macrophages, mast cells, and T cells. Inhibiting the formation of LTB 4 is expected to be beneficial in the treatment of inflammatory diseases such as inflammatory bowel disease (IBD), asthma, and atherosclerosis. We developed a pharmacophore model using a known inhibitor manually docked into the active site of LTA 4H to identify a subset of compounds for screening. From this work we identified a series of benzoxazole, benzthiazole, and benzimidazole inhibitors. SAR studies resulted in the identification of several potent inhibitors with an appropriate cross-reactivity profile and excellent PK/PD properties. Our efforts focused on further profiling JNJ 27265732, which showed encouraging efficacy in a disease model relevant to IBD.

MeSH terms

  • Administration, Oral
  • Animals
  • Anti-Inflammatory Agents / administration & dosage
  • Anti-Inflammatory Agents / chemistry
  • Anti-Inflammatory Agents / pharmacology*
  • Catalysis
  • Dogs
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Epoxide Hydrolases / antagonists & inhibitors*
  • Humans
  • Magnetic Resonance Spectroscopy
  • Mice
  • Structure-Activity Relationship


  • Anti-Inflammatory Agents
  • Enzyme Inhibitors
  • Epoxide Hydrolases
  • leukotriene A4 hydrolase