Optimization of 8-Hydroxyquinolines as Inhibitors of Catechol O-Methyltransferase

Ingrid Buchler, Daniel Akuma, Vinh Au, Gregory Carr, Pablo De León, Michael Depasquale, Glen Ernst, Yifang Huang, Martha Kimos, Anna Kolobova, Michael Poslusney, Huijun Wei, Dominique Swinnen, Florian Montel, Florence Moureau, Emilie Jigorel, Monika Sarah E.D. Schulze, Martyn Wood, James Barrow

Research output: Contribution to journalArticle

Abstract

A series of 8-hydroxy quinolines were identified as potent inhibitors of catechol O-methyltransferase (COMT) with selectivity for the membrane-bound form of the enzyme. Small substituents at the 7-position of the quinoline were found to increase metabolic stability without sacrificing potency. Compounds with good pharmacokinetics and brain penetration were identified and demonstrated in vivo modulation of dopamine metabolites in the brain. An X-ray cocrystal structure of compound 21 in the S-COMT active site shows chelation of the active site magnesium similar to catechol-based inhibitors. These compounds should prove useful for treatment of many neurological and psychiatric conditions associated with compromised cortical dopamine signaling.

Original languageEnglish (US)
Pages (from-to)9647-9665
Number of pages19
JournalJournal of Medicinal Chemistry
Volume61
Issue number21
DOIs
StatePublished - Nov 8 2018

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Oxyquinoline
Dopamine
Catalytic Domain
Quinolines
Catechol O-Methyltransferase
Brain
Magnesium
Psychiatry
Pharmacokinetics
X-Rays
Membranes
Enzymes
Catechol O-Methyltransferase Inhibitors
catechol
quinoline

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Optimization of 8-Hydroxyquinolines as Inhibitors of Catechol O-Methyltransferase. / Buchler, Ingrid; Akuma, Daniel; Au, Vinh; Carr, Gregory; De León, Pablo; Depasquale, Michael; Ernst, Glen; Huang, Yifang; Kimos, Martha; Kolobova, Anna; Poslusney, Michael; Wei, Huijun; Swinnen, Dominique; Montel, Florian; Moureau, Florence; Jigorel, Emilie; Schulze, Monika Sarah E.D.; Wood, Martyn; Barrow, James.

In: Journal of Medicinal Chemistry, Vol. 61, No. 21, 08.11.2018, p. 9647-9665.

Research output: Contribution to journalArticle

Buchler, I, Akuma, D, Au, V, Carr, G, De León, P, Depasquale, M, Ernst, G, Huang, Y, Kimos, M, Kolobova, A, Poslusney, M, Wei, H, Swinnen, D, Montel, F, Moureau, F, Jigorel, E, Schulze, MSED, Wood, M & Barrow, J 2018, 'Optimization of 8-Hydroxyquinolines as Inhibitors of Catechol O-Methyltransferase', Journal of Medicinal Chemistry, vol. 61, no. 21, pp. 9647-9665. https://doi.org/10.1021/acs.jmedchem.8b01126
Buchler, Ingrid ; Akuma, Daniel ; Au, Vinh ; Carr, Gregory ; De León, Pablo ; Depasquale, Michael ; Ernst, Glen ; Huang, Yifang ; Kimos, Martha ; Kolobova, Anna ; Poslusney, Michael ; Wei, Huijun ; Swinnen, Dominique ; Montel, Florian ; Moureau, Florence ; Jigorel, Emilie ; Schulze, Monika Sarah E.D. ; Wood, Martyn ; Barrow, James. / Optimization of 8-Hydroxyquinolines as Inhibitors of Catechol O-Methyltransferase. In: Journal of Medicinal Chemistry. 2018 ; Vol. 61, No. 21. pp. 9647-9665.
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