1,5-Disubstituted indole derivatives as selective human neuronal nitric oxide synthase inhibitors

Bioorg Med Chem Lett. 2011 Sep 15;21(18):5301-4. doi: 10.1016/j.bmcl.2011.07.022. Epub 2011 Jul 14.

Abstract

A series of 1,5-disubstituted indole derivatives was designed, synthesized and evaluated as inhibitors of human nitric oxide synthase. A variety of flexible and restricted basic amine side chain substitutions was explored at the 1-position of the indole ring, while keeping the amidine group fixed at the 5-position. Compounds having N-(1-(2-(1-methylpyrrolidin-2-yl)ethyl)- (12, (R)-12, (S)-12 and 13) and N-(1-(1-methylazepan-4-yl)- side chains (14, 15, (-)-15 and (+)-15) showed increased inhibitory activity for the human nNOS isoform and selectivity over eNOS and iNOS isoforms. The most potent compound of the series for human nNOS (IC(50)=0.02 μM) (S)-12 showed very good selectivity over the eNOS (eNOS/nNOS=96-fold) and iNOS (iNOS/nNOS=850-fold) isoforms.

MeSH terms

  • Dose-Response Relationship, Drug
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Indoles / chemical synthesis
  • Indoles / chemistry
  • Indoles / pharmacology*
  • Molecular Structure
  • Nitric Oxide Synthase Type I
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Indoles
  • Nitric Oxide Synthase Type I