Novel nanomolar imidazo[4,5-b]pyridines as selective nitric oxide synthase (iNOS) inhibitors: SAR and structural insights

Bioorg Med Chem Lett. 2011 Jul 15;21(14):4228-32. doi: 10.1016/j.bmcl.2011.05.073. Epub 2011 May 30.

Abstract

Inducible arginine oxidation and subsequent NO production by correspondent synthase (iNOS) are important cellular answers to proinflammatory signals. Prolonged NO production has been proved in higher organisms to cause stroke or septic shock. Several classes of potent NOS inhibitors have been reported, most of them targeting the arginine binding site of the oxygenase domain. Here we disclose the SAR and the rational design of potent and selective iNOS inhibitors which may be useful as anti-inflammatory drugs.

MeSH terms

  • Animals
  • Binding Sites
  • Computer Simulation
  • Crystallography, X-Ray
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacokinetics
  • Humans
  • Imidazoles / chemistry*
  • Mice
  • Nitric Oxide Synthase Type II / antagonists & inhibitors*
  • Nitric Oxide Synthase Type II / metabolism
  • Protein Structure, Tertiary
  • Pyridines / chemical synthesis
  • Pyridines / chemistry*
  • Pyridines / pharmacokinetics
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Imidazoles
  • Pyridines
  • imidazole
  • Nitric Oxide Synthase Type II