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

doi:10.1021/ml500502d

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

School of Medicine

Research output: Contribution to journal › Article › peer-review

21 Scopus citations

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 language	English (US)
Pages (from-to)	318-323
Number of pages	6
Journal	ACS Medicinal Chemistry Letters
Volume	6
Issue number	3
DOIs	https://doi.org/10.1021/ml500502d
State	Published - 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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10.1021/ml500502d

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Harrison, S. T., Poslusney, M. S., Mulhearn, J. J., Zhao, Z., Kett, N. R., Schubert, J. W., Melamed, J. Y., Allison, T. J., Patel, S. B., Sanders, J. M., Sharma, S., Smith, R. F., Hall, D. L., Robinson, R. G., Sachs, N. A., Hutson, P. H., Wolkenberg, S. E., & Barrow, J. C. (2015). Synthesis and evaluation of heterocyclic catechol mimics as inhibitors of catechol-o-methyltransferase (COMT). ACS Medicinal Chemistry Letters, 6(3), 318-323. https://doi.org/10.1021/ml500502d

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, JC 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

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title = "Synthesis and evaluation of heterocyclic catechol mimics as inhibitors of catechol-o-methyltransferase (COMT)",

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.",

keywords = "Catechol O-methyl transferase, catechol mimic, cognition, schizophrenia",

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

note = "Publisher Copyright: {\textcopyright} 2015 American Chemical Society.",

year = "2015",

month = mar,

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doi = "10.1021/ml500502d",

language = "English (US)",

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AU - Harrison, Scott T.

AU - Poslusney, Michael S.

AU - Mulhearn, James J.

AU - Zhao, Zhijian

AU - Kett, Nathan R.

AU - Schubert, Jeffrey W.

AU - Melamed, Jeffrey Y.

AU - Allison, Timothy J.

AU - Patel, Sangita B.

AU - Sanders, John M.

AU - Sharma, Sujata

AU - Smith, Robert F.

AU - Hall, Dawn L.

AU - Robinson, Ronald G.

AU - Sachs, Nancy A.

AU - Hutson, Pete H.

AU - Wolkenberg, Scott E.

AU - Barrow, James C.

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AB - 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.

KW - Catechol O-methyl transferase

KW - catechol mimic

KW - cognition

KW - schizophrenia

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

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Keywords

ASJC Scopus subject areas

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