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BAY-7081: A Potent, Selective, and Orally Bioavailable Cyanopyridone-Based PDE9A Inhibitor
[Image: see text] Despite advances in the treatment of heart failure in recent years, options for patients are still limited and the disease is associated with considerable morbidity and mortality. Modulating cyclic guanosine monophosphate levels within the natriuretic peptide signaling pathway by i...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9791655/ https://www.ncbi.nlm.nih.gov/pubmed/36475653 http://dx.doi.org/10.1021/acs.jmedchem.2c01267 |
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author | Meibom, Daniel Micus, Sina Andreevski, Anna Lena Anlauf, Sonja Bogner, Pamela von Buehler, Clemens-Jeremias Dieskau, André P. Dreher, Jan Eitner, Frank Fliegner, Daniela Follmann, Markus Gericke, Kersten Matthias Maassen, Stefanie Meyer, Jutta Schlemmer, Karl-Heinz Steuber, Holger Tersteegen, Adrian Wunder, Frank |
author_facet | Meibom, Daniel Micus, Sina Andreevski, Anna Lena Anlauf, Sonja Bogner, Pamela von Buehler, Clemens-Jeremias Dieskau, André P. Dreher, Jan Eitner, Frank Fliegner, Daniela Follmann, Markus Gericke, Kersten Matthias Maassen, Stefanie Meyer, Jutta Schlemmer, Karl-Heinz Steuber, Holger Tersteegen, Adrian Wunder, Frank |
author_sort | Meibom, Daniel |
collection | PubMed |
description | [Image: see text] Despite advances in the treatment of heart failure in recent years, options for patients are still limited and the disease is associated with considerable morbidity and mortality. Modulating cyclic guanosine monophosphate levels within the natriuretic peptide signaling pathway by inhibiting PDE9A has been associated with beneficial effects in preclinical heart failure models. We herein report the identification of BAY-7081, a potent, selective, and orally bioavailable PDE9A inhibitor with very good aqueous solubility starting from a high-throughput screening hit. Key aspect of the optimization was a switch in metabolism of our lead structures from glucuronidation to oxidation. The switch proved being essential for the identification of compounds with improved pharmacokinetic profiles. By studying a tool compound in a transverse aortic constriction mouse model, we were able to substantiate the relevance of PDE9A inhibition in heart diseases. |
format | Online Article Text |
id | pubmed-9791655 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-97916552022-12-27 BAY-7081: A Potent, Selective, and Orally Bioavailable Cyanopyridone-Based PDE9A Inhibitor Meibom, Daniel Micus, Sina Andreevski, Anna Lena Anlauf, Sonja Bogner, Pamela von Buehler, Clemens-Jeremias Dieskau, André P. Dreher, Jan Eitner, Frank Fliegner, Daniela Follmann, Markus Gericke, Kersten Matthias Maassen, Stefanie Meyer, Jutta Schlemmer, Karl-Heinz Steuber, Holger Tersteegen, Adrian Wunder, Frank J Med Chem [Image: see text] Despite advances in the treatment of heart failure in recent years, options for patients are still limited and the disease is associated with considerable morbidity and mortality. Modulating cyclic guanosine monophosphate levels within the natriuretic peptide signaling pathway by inhibiting PDE9A has been associated with beneficial effects in preclinical heart failure models. We herein report the identification of BAY-7081, a potent, selective, and orally bioavailable PDE9A inhibitor with very good aqueous solubility starting from a high-throughput screening hit. Key aspect of the optimization was a switch in metabolism of our lead structures from glucuronidation to oxidation. The switch proved being essential for the identification of compounds with improved pharmacokinetic profiles. By studying a tool compound in a transverse aortic constriction mouse model, we were able to substantiate the relevance of PDE9A inhibition in heart diseases. American Chemical Society 2022-12-07 2022-12-22 /pmc/articles/PMC9791655/ /pubmed/36475653 http://dx.doi.org/10.1021/acs.jmedchem.2c01267 Text en © 2022 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by-nc-nd/4.0/Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Meibom, Daniel Micus, Sina Andreevski, Anna Lena Anlauf, Sonja Bogner, Pamela von Buehler, Clemens-Jeremias Dieskau, André P. Dreher, Jan Eitner, Frank Fliegner, Daniela Follmann, Markus Gericke, Kersten Matthias Maassen, Stefanie Meyer, Jutta Schlemmer, Karl-Heinz Steuber, Holger Tersteegen, Adrian Wunder, Frank BAY-7081: A Potent, Selective, and Orally Bioavailable Cyanopyridone-Based PDE9A Inhibitor |
title | BAY-7081: A
Potent, Selective, and Orally Bioavailable
Cyanopyridone-Based PDE9A Inhibitor |
title_full | BAY-7081: A
Potent, Selective, and Orally Bioavailable
Cyanopyridone-Based PDE9A Inhibitor |
title_fullStr | BAY-7081: A
Potent, Selective, and Orally Bioavailable
Cyanopyridone-Based PDE9A Inhibitor |
title_full_unstemmed | BAY-7081: A
Potent, Selective, and Orally Bioavailable
Cyanopyridone-Based PDE9A Inhibitor |
title_short | BAY-7081: A
Potent, Selective, and Orally Bioavailable
Cyanopyridone-Based PDE9A Inhibitor |
title_sort | bay-7081: a
potent, selective, and orally bioavailable
cyanopyridone-based pde9a inhibitor |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9791655/ https://www.ncbi.nlm.nih.gov/pubmed/36475653 http://dx.doi.org/10.1021/acs.jmedchem.2c01267 |
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