1,2-Dihydro-4-quinazolinamines: potent, highly selective inhibitors of inducible nitric oxide synthase which show antiinflammatory activity in vivo

J Med Chem. 2003 Mar 13;46(6):913-6. doi: 10.1021/jm0255926.

Abstract

The discovery of a novel class of nitric oxide synthase (NOS) inhibitors, 2-substituted 1,2-dihydro-4-quinazolinamines, and the related 4'-aminospiro[piperidine-4,2'(1'H)-quinazolin]-4'-amines is described. Members of both series exhibit nanomolar potency and high selectivity for the inducible isoform of the enzyme (i-NOS) relative to the constitutive isoforms in vitro. Efficacy in acute and chronic animal models of inflammatory disease following oral administration has also been demonstrated using these compounds.

MeSH terms

  • Acute Disease
  • Administration, Oral
  • Amines / chemical synthesis
  • Amines / chemistry
  • Amines / pharmacology
  • Animals
  • Arthritis, Experimental / drug therapy
  • Cell Line
  • Chronic Disease
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Injections, Intravenous
  • Isoenzymes / antagonists & inhibitors
  • Nitric Oxide Synthase / antagonists & inhibitors*
  • Nitric Oxide Synthase Type II
  • Quinazolines / chemical synthesis*
  • Quinazolines / chemistry
  • Quinazolines / pharmacology
  • Rats
  • Spiro Compounds / chemical synthesis
  • Spiro Compounds / chemistry
  • Spiro Compounds / pharmacology
  • Structure-Activity Relationship

Substances

  • Amines
  • Enzyme Inhibitors
  • Isoenzymes
  • Quinazolines
  • Spiro Compounds
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nos2 protein, rat