Synthesis and optimization of N-heterocyclic pyridinones as catechol-O-methyltransferase (COMT) inhibitors

Bioorg Med Chem Lett. 2016 Jun 15;26(12):2952-2956. doi: 10.1016/j.bmcl.2016.03.095. Epub 2016 Apr 7.


A series of N-heterocyclic pyridinone catechol-O-methyltransferase (COMT) inhibitors were synthesized. Physicochemical properties, including ligand lipophilic efficiency (LLE) and clogP, were used to guide compound design and attempt to improve inhibitor pharmacokinetics. Incorporation of heterocyclic central rings provided improvements in physicochemical parameters but did not significantly reduce in vitro or in vivo clearance. Nevertheless, compound 11 was identified as a potent inhibitor with sufficient in vivo exposure to significantly affect the dopamine metabolites homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC), and indicate central COMT inhibition.

Keywords: Catechol O-methyl transferase; Cognition; Schizophrenia.

MeSH terms

  • Animals
  • Catechol O-Methyltransferase / metabolism*
  • Catechol O-Methyltransferase Inhibitors / chemical synthesis
  • Catechol O-Methyltransferase Inhibitors / chemistry
  • Catechol O-Methyltransferase Inhibitors / pharmacology*
  • Dose-Response Relationship, Drug
  • Heterocyclic Compounds / chemical synthesis
  • Heterocyclic Compounds / chemistry
  • Heterocyclic Compounds / pharmacology*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Pyridones / chemical synthesis
  • Pyridones / chemistry
  • Pyridones / pharmacology*
  • Rats
  • Structure-Activity Relationship


  • Catechol O-Methyltransferase Inhibitors
  • Heterocyclic Compounds
  • Pyridones
  • Catechol O-Methyltransferase