N-Substituted acetamidines and 2-methylimidazole derivatives as selective inhibitors of neuronal nitric oxide synthase

Bioorg Med Chem Lett. 2010 Nov 15;20(22):6495-9. doi: 10.1016/j.bmcl.2010.09.059. Epub 2010 Sep 17.

Abstract

A series of N-substituted acetamidines and 2-methylimidazole derivatives structurally related to W1400 were synthesized and evaluated as Nitric Oxide Synthase (NOS) inhibitors. Analogs with sterically hindering isopropyl and phenyl substituents on the benzylic carbon connecting the aromatic core of W1400 to the acetamidine nitrogen, showed good inhibitory potency for nNOS (IC(50)=0.2 and 0.3 μM) and selectivity over eNOS (500 and 1166) and to a lesser extent over iNOS (50 and 100). A molecular modeling study allowed to shed light on the effects of the structural modifications on the selectivity of the designed inhibitors toward the different NOS isoforms.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetamides / chemistry
  • Acetamides / pharmacology*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Imidazoles / chemistry
  • Imidazoles / pharmacology*
  • Models, Molecular
  • Nitric Oxide Synthase Type I / antagonists & inhibitors*
  • Nitric Oxide Synthase Type II / antagonists & inhibitors

Substances

  • Acetamides
  • Enzyme Inhibitors
  • Imidazoles
  • Nitric Oxide Synthase Type I
  • Nitric Oxide Synthase Type II
  • 2-methylimidazole