2-Aminonicotinic acid 1-oxides are chemically stable inhibitors of quinolinic acid synthesis in the mammalian brain: a step toward new antiexcitotoxic agents

J Med Chem. 2013 Dec 12;56(23):9482-95. doi: 10.1021/jm401249c. Epub 2013 Dec 3.


3-Hydroxyanthranilic acid 3,4-dioxygenase (3-HAO) is the enzyme responsible for the production of the neurotoxic tryptophan metabolite quinolinic acid (QUIN). Elevated brain levels of QUIN are observed in several neurodegenerative diseases, but pharmacological investigation on its role in the pathogenesis of these conditions is difficult because only one class of substrate-analogue 3-HAO inhibitors, with poor chemical stability, has been reported so far. Here we describe the design, synthesis, and biological evaluation of a novel class of chemically stable inhibitors based on the 2-aminonicotinic acid 1-oxide nucleus. After the preliminary in vitro evaluation of newly synthesized compounds using brain tissue homogenate, we selected the most active inhibitor and showed its ability to acutely reduce the production of QUIN in the rat brain in vivo. These findings provide a novel pharmacological tool for the study of the mechanisms underlying the onset and propagation of neurodegenerative diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-Hydroxyanthranilate 3,4-Dioxygenase / antagonists & inhibitors*
  • Animals
  • Brain / drug effects
  • Brain / metabolism*
  • Cyclic N-Oxides / chemical synthesis*
  • Cyclic N-Oxides / pharmacology
  • Disease Models, Animal
  • Drug Stability
  • Enzyme Inhibitors / chemical synthesis*
  • Humans
  • Neurodegenerative Diseases / drug therapy
  • Nicotinic Acids / pharmacology
  • Quinolinic Acid / metabolism*
  • Rats


  • Cyclic N-Oxides
  • Enzyme Inhibitors
  • Nicotinic Acids
  • 2-aminonicotinic acid
  • 3-Hydroxyanthranilate 3,4-Dioxygenase
  • Quinolinic Acid