2. Academic Validation
  3. Synthesis and Evaluation of Bicyclic Hydroxypyridones as Inhibitors of Catechol O-Methyltransferase

Synthesis and Evaluation of Bicyclic Hydroxypyridones as Inhibitors of Catechol O-Methyltransferase

  • ACS Med Chem Lett. 2019 Oct 22;10(11):1573-1578. doi: 10.1021/acsmedchemlett.9b00345.
Glen Ernst 1,  Daniel Akuma 1,  Vinh Au 1,  Ingrid P Buchler 1,  Spencer Byers 1,  Gregory V Carr 1 2,  Sabine Defays 3,  Pablo de León 1,  Thierry Demaude 3,  Michael DePasquale 1,  Véronique Durieu 3,  Yifang Huang 1,  Emilie Jigorel 3,  Martha Kimos 1,  Anna Kolobova 1,  Florian Montel 3,  Florence Moureau 3,  Michael Poslusney 1,  Dominique Swinnen 3,  Marie-Christine Vandergeten 3,  Nathalie Van Houtvin 3,  Huijun Wei 1 2,  Noelle White 1,  Martyn Wood 3,  James C Barrow 1 2
Affiliations

Affiliations

  • 1 Lieber Institute for Brain Development, 855 North Wolfe Street, Baltimore, Maryland 21205, United States.
  • 2 Department of Pharmacology, Johns Hopkins University School of Medicine, 855 North Wolfe Street, Baltimore, Maryland 21287, United States.
  • 3 UCB Biopharma, SPRL, B-1420 Braine-L'Alleud, Belgium.
PMID: 32038769 DOI: 10.1021/acsmedchemlett.9b00345
Abstract

A series of bicyclic pyridones were identified as potent inhibitors of catechol O-methyltransferase (COMT). Substituted benzyl groups attached to the basic nitrogen of the core scaffold gave the most potent inhibitors within this series. Rat pharmacokinetic studies showed medium to high levels of clearance for this series, but with high free fraction due to remarkably low levels of protein and tissue binding. In rat biomarker studies, levels of unbound drug exposure are seen in the brain, which exceed their respective IC50s, leading to changes in the levels of dopamine metabolites in a manner consistent with COMT inhibition.

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