@article{ad32bbfd1ea14613a91f2e7d4f156f4c,
title = "Synthesis and Evaluation of Bicyclic Hydroxypyridones as Inhibitors of Catechol O-Methyltransferase",
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.",
keywords = "Catechol O-methyl transferase, catechol mimic, dopamine metabolism, enzyme inhibitors",
author = "Glen Ernst and Daniel Akuma and Vinh Au and Buchler, {Ingrid P.} and Spencer Byers and Carr, {Gregory V.} and Sabine Defays and {De Le{\'o}n}, Pablo and Thierry Demaude and Michael Depasquale and V{\'e}ronique Durieu and Yifang Huang and Emilie Jigorel and Martha Kimos and Anna Kolobova and Florian Montel and Florence Moureau and Michael Poslusney and Dominique Swinnen and Vandergeten, {Marie Christine} and {Van Houtvin}, Nathalie and Huijun Wei and Noelle White and Martyn Wood and Barrow, {James C.}",
note = "Funding Information: I.B., S.D., P.d.L., T.D., V.D., G.E., Y.H., M.P., D.S., F.M., M.-C.V., N.V., and J.C.B. designed and synthesized compounds. M.K., H.W., M.W., E.J., and J.C.B. developed the in vitro assays. D.A., V.A., S.B., G.C., M.D., A.K., E.J., D.S., N.W., and J.C.B. developed and analyzed the in vivo assays. The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Funding of parts of this work from the National Institutes of Mental Health NIMH R01 MH107126 is gratefully acknowledged. The authors declare no competing financial interest. Funding Information: We gratefully acknowledge Yves Lamberty (UCB) for the design of in vivo experiments and for constructive pharmacology discussions, and David Boucaut (UCB) for assistance with in vivo studies. We also gratefully acknowledge Eric Gillent (UCB) and Benoi?t Culot (UCB) for bioanalysis assistance, and Benoi?t Mathieu (UCB), Geraldine Longfils (UCB), and Ariane Descamps (UCB) for analytical chemistry support. Publisher Copyright: Copyright {\textcopyright} 2019 American Chemical Society.",
year = "2019",
month = nov,
day = "14",
doi = "10.1021/acsmedchemlett.9b00345",
language = "English (US)",
volume = "10",
pages = "1573--1578",
journal = "ACS Medicinal Chemistry Letters",
issn = "1948-5875",
publisher = "American Chemical Society",
number = "11",
}