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

Zhijian Zhao, Scott T. Harrison, Jeffrey W. Schubert, John M. Sanders, Stacey Polsky-Fisher, Nanyan Rena Zhang, Debra McLoughlin, Christopher R. Gibson, Ronald G. Robinson, Nancy A. Sachs, Monika Kandebo, Lihang Yao, Sean M. Smith, Pete H. Hutson, Scott E. Wolkenberg, James C. Barrow

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


A series of N-heterocyclic pyridinone catechol-O-methyltransferase (COMT) inhibitors were synthesized. Physicochemical properties, including ligand lipophilic efficiency (LLE) and c log P, 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.

Original languageEnglish (US)
Pages (from-to)2952-2956
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Issue number12
StatePublished - Jun 15 2016


  • Catechol O-methyl transferase
  • Cognition
  • Schizophrenia

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry


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