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.