Synthesis and evaluation of heterocyclic catechol mimics as inhibitors of catechol-o-methyltransferase (COMT)

Scott T. Harrison, Michael S. Poslusney, James J. Mulhearn, Zhijian Zhao, Nathan R. Kett, Jeffrey W. Schubert, Jeffrey Y. Melamed, Timothy J. Allison, Sangita B. Patel, John M. Sanders, Sujata Sharma, Robert F. Smith, Dawn L. Hall, Ronald G. Robinson, Nancy A. Sachs, Pete H. Hutson, Scott E. Wolkenberg, James C. Barrow

Research output: Contribution to journalArticlepeer-review

Abstract

3-Hydroxy-4-pyridinones and 5-hydroxy-4-pyrimidinones were identified as inhibitors of catechol-O-methyltransferase (COMT) in a high-throughput screen. These heterocyclic catechol mimics exhibit potent inhibition of the enzyme and an improved toxicity profile versus the marketed nitrocatechol inhibitors tolcapone and entacapone. Optimization of the series was aided by X-ray cocrystal structures of the novel inhibitors in complex with COMT and cofactors SAM and Mg2+. The crystal structures suggest a mechanism of inhibition for these heterocyclic inhibitors distinct from previously disclosed COMT inhibitors.

Original languageEnglish (US)
Pages (from-to)318-323
Number of pages6
JournalACS Medicinal Chemistry Letters
Volume6
Issue number3
DOIs
StatePublished - Mar 12 2015

Keywords

  • Catechol O-methyl transferase
  • catechol mimic
  • cognition
  • schizophrenia

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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