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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...

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Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2022
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
Descripción
Sumario:[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.