Design, synthesis and characterization of a novel class of coumarin-based inhibitors of inducible nitric oxide synthase

Bioorg Med Chem. 2005 Apr 15;13(8):2723-39. doi: 10.1016/j.bmc.2005.02.036.

Abstract

Inducible nitric oxide synthase (iNOS) has been implicated in various central and peripheral pathophysiological diseases. Our high throughput screening initially identified a weak inhibitor of iNOS, thiocoumarin 13. From this lead, a number of potent derivatives were prepared that demonstrate favorable potency, selectivity and kinetics. Compound 30 has an IC50 of 60 nM for mouse iNOS and 185-fold and 9-fold selectivity for bovine eNOS and rat nNOS, respectively. In cellular assays for iNOS, this compound has micromolar potency. Furthermore, two compounds (16 and 30) demonstrate a reasonable pharmacokinetic profile in rodents. The synthesis, SAR, and biological activity of this novel class of compounds is described.

MeSH terms

  • Animals
  • Coumarins / chemistry*
  • Drug Design
  • Enzyme Inhibitors* / chemical synthesis
  • Enzyme Inhibitors* / classification
  • Enzyme Inhibitors* / pharmacology
  • Humans
  • Kinetics
  • Mice
  • Microsomes / drug effects
  • Microsomes / metabolism
  • Molecular Structure
  • Nitric Oxide Synthase / antagonists & inhibitors*
  • Nitric Oxide Synthase Type II
  • Protein Binding / drug effects
  • Protein Conformation
  • Rats
  • Structure-Activity Relationship
  • Tissue Distribution

Substances

  • Coumarins
  • Enzyme Inhibitors
  • NOS2 protein, human
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse
  • Nos2 protein, rat