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Synthesis and Evaluation of Bicyclic Hydroxypyridones as Inhibitors of Catechol O-Methyltransferase
[Image: see text] 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...
| Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , |
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| Formato: | Online Artículo Texto |
| Lenguaje: | English |
| Publicado: |
American Chemical
Society
2019
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| Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003998/ https://www.ncbi.nlm.nih.gov/pubmed/32038769 http://dx.doi.org/10.1021/acsmedchemlett.9b00345 |
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| author | Ernst, Glen Akuma, Daniel Au, Vinh Buchler, Ingrid P. Byers, Spencer Carr, Gregory V. Defays, Sabine de León, Pablo Demaude, Thierry DePasquale, Michael Durieu, Véronique Huang, Yifang Jigorel, Emilie Kimos, Martha Kolobova, Anna Montel, Florian Moureau, Florence Poslusney, Michael Swinnen, Dominique Vandergeten, Marie-Christine Van houtvin, Nathalie Wei, Huijun White, Noelle Wood, Martyn Barrow, James C. |
| author_facet | Ernst, Glen Akuma, Daniel Au, Vinh Buchler, Ingrid P. Byers, Spencer Carr, Gregory V. Defays, Sabine de León, Pablo Demaude, Thierry DePasquale, Michael Durieu, Véronique Huang, Yifang Jigorel, Emilie Kimos, Martha Kolobova, Anna Montel, Florian Moureau, Florence Poslusney, Michael Swinnen, Dominique Vandergeten, Marie-Christine Van houtvin, Nathalie Wei, Huijun White, Noelle Wood, Martyn Barrow, James C. |
| author_sort | Ernst, Glen |
| collection | PubMed |
| description | [Image: see text] 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 IC(50)s, leading to changes in the levels of dopamine metabolites in a manner consistent with COMT inhibition. |
| format | Online Article Text |
| id | pubmed-7003998 |
| institution | National Center for Biotechnology Information |
| language | English |
| publishDate | 2019 |
| publisher | American Chemical
Society |
| record_format | MEDLINE/PubMed |
| spelling | pubmed-70039982020-02-07 Synthesis and Evaluation of Bicyclic Hydroxypyridones as Inhibitors of Catechol O-Methyltransferase Ernst, Glen Akuma, Daniel Au, Vinh Buchler, Ingrid P. Byers, Spencer Carr, Gregory V. Defays, Sabine de León, Pablo Demaude, Thierry DePasquale, Michael Durieu, Véronique Huang, Yifang Jigorel, Emilie Kimos, Martha Kolobova, Anna Montel, Florian Moureau, Florence Poslusney, Michael Swinnen, Dominique Vandergeten, Marie-Christine Van houtvin, Nathalie Wei, Huijun White, Noelle Wood, Martyn Barrow, James C. ACS Med Chem Lett [Image: see text] 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 IC(50)s, leading to changes in the levels of dopamine metabolites in a manner consistent with COMT inhibition. American Chemical Society 2019-10-22 /pmc/articles/PMC7003998/ /pubmed/32038769 http://dx.doi.org/10.1021/acsmedchemlett.9b00345 Text en Copyright © 2019 American Chemical Society This is an open access article published under an ACS AuthorChoice License (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) , which permits copying and redistribution of the article or any adaptations for non-commercial purposes. |
| spellingShingle | Ernst, Glen Akuma, Daniel Au, Vinh Buchler, Ingrid P. Byers, Spencer Carr, Gregory V. Defays, Sabine de León, Pablo Demaude, Thierry DePasquale, Michael Durieu, Véronique Huang, Yifang Jigorel, Emilie Kimos, Martha Kolobova, Anna Montel, Florian Moureau, Florence Poslusney, Michael Swinnen, Dominique Vandergeten, Marie-Christine Van houtvin, Nathalie Wei, Huijun White, Noelle Wood, Martyn Barrow, James C. Synthesis and Evaluation of Bicyclic Hydroxypyridones as Inhibitors of Catechol O-Methyltransferase |
| title | Synthesis and Evaluation of Bicyclic Hydroxypyridones
as Inhibitors of Catechol O-Methyltransferase |
| title_full | Synthesis and Evaluation of Bicyclic Hydroxypyridones
as Inhibitors of Catechol O-Methyltransferase |
| title_fullStr | Synthesis and Evaluation of Bicyclic Hydroxypyridones
as Inhibitors of Catechol O-Methyltransferase |
| title_full_unstemmed | Synthesis and Evaluation of Bicyclic Hydroxypyridones
as Inhibitors of Catechol O-Methyltransferase |
| title_short | Synthesis and Evaluation of Bicyclic Hydroxypyridones
as Inhibitors of Catechol O-Methyltransferase |
| title_sort | synthesis and evaluation of bicyclic hydroxypyridones
as inhibitors of catechol o-methyltransferase |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003998/ https://www.ncbi.nlm.nih.gov/pubmed/32038769 http://dx.doi.org/10.1021/acsmedchemlett.9b00345 |
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