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 Barrow

Research output: Contribution to journalArticle

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

Fingerprint

Catechol O-Methyltransferase
Methyltransferases
Pyrimidinones
Pyridones
X-Rays
Toxicity
Enzymes
Crystal structure
Throughput
X rays
catechol
entacapone
tolcapone
nitrocatechol
Catechol O-Methyltransferase Inhibitors

Keywords

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

ASJC Scopus subject areas

  • Organic Chemistry
  • Drug Discovery
  • Biochemistry

Cite this

Synthesis and evaluation of heterocyclic catechol mimics as inhibitors of catechol-o-methyltransferase (COMT). / Harrison, Scott T.; Poslusney, Michael S.; Mulhearn, James J.; Zhao, Zhijian; Kett, Nathan R.; Schubert, Jeffrey W.; Melamed, Jeffrey Y.; Allison, Timothy J.; Patel, Sangita B.; Sanders, John M.; Sharma, Sujata; Smith, Robert F.; Hall, Dawn L.; Robinson, Ronald G.; Sachs, Nancy A.; Hutson, Pete H.; Wolkenberg, Scott E.; Barrow, James.

In: ACS Medicinal Chemistry Letters, Vol. 6, No. 3, 12.03.2015, p. 318-323.

Research output: Contribution to journalArticle

Harrison, ST, Poslusney, MS, Mulhearn, JJ, Zhao, Z, Kett, NR, Schubert, JW, Melamed, JY, Allison, TJ, Patel, SB, Sanders, JM, Sharma, S, Smith, RF, Hall, DL, Robinson, RG, Sachs, NA, Hutson, PH, Wolkenberg, SE & Barrow, J 2015, 'Synthesis and evaluation of heterocyclic catechol mimics as inhibitors of catechol-o-methyltransferase (COMT)', ACS Medicinal Chemistry Letters, vol. 6, no. 3, pp. 318-323. https://doi.org/10.1021/ml500502d
Harrison, Scott T. ; Poslusney, Michael S. ; Mulhearn, James J. ; Zhao, Zhijian ; Kett, Nathan R. ; Schubert, Jeffrey W. ; Melamed, Jeffrey Y. ; Allison, Timothy J. ; Patel, Sangita B. ; Sanders, John M. ; Sharma, Sujata ; Smith, Robert F. ; Hall, Dawn L. ; Robinson, Ronald G. ; Sachs, Nancy A. ; Hutson, Pete H. ; Wolkenberg, Scott E. ; Barrow, James. / Synthesis and evaluation of heterocyclic catechol mimics as inhibitors of catechol-o-methyltransferase (COMT). In: ACS Medicinal Chemistry Letters. 2015 ; Vol. 6, No. 3. pp. 318-323.
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