BAY-7081: A Potent, Selective, and Orally Bioavailable Cyanopyridone-Based PDE9A Inhibitor

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.

Automated summary

Despite advancements in heart failure treatment, limited options exist for patients and the disease still carries significant morbidity and mortality risks. In this study, researchers identified a potent and selective oral PDE9A inhibitor named BAY-7081, which showed beneficial effects in preclinical heart failure models. The compound's optimization involved a switch in metabolism, leading to improved pharmacokinetic profiles. The relevance of PDE9A inhibition in heart diseases was substantiated through a mouse model study.