Azabenzthiazole inhibitors of leukotriene A₄ hydrolase

Bioorg Med Chem Lett. 2012 Dec 15;22(24):7504-11. doi: 10.1016/j.bmcl.2012.10.036. Epub 2012 Oct 17.

Abstract

Previously, benzthiazole containing LTA(4)H inhibitors were discovered that were potent (1-3), but were associated with the potential for a hERG liability. Utilizing medicinal chemistry first principles (e.g., introducing rigidity, lowering cLogD) a new benzthiazole series was designed, congeners of 1-3, which led to compounds 7a, 7c, 12a-d which exhibited LTA(4)H IC(50)=3-6 nM and hERG Dofetilide Binding IC(50)=8.9-> >10 μM.

MeSH terms

  • Animals
  • Aza Compounds / chemical synthesis
  • Aza Compounds / chemistry
  • Aza Compounds / pharmacology*
  • Benzothiazoles / chemical synthesis
  • Benzothiazoles / chemistry
  • Benzothiazoles / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Epoxide Hydrolases / antagonists & inhibitors*
  • Epoxide Hydrolases / metabolism
  • Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
  • Humans
  • Mice
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Aza Compounds
  • Benzothiazoles
  • Enzyme Inhibitors
  • Ether-A-Go-Go Potassium Channels
  • azabenzthiazole
  • Epoxide Hydrolases
  • leukotriene A4 hydrolase