Endothelial and Cardiomyocyte Dysfunction in Heart Failure with Preserved Ejection Fraction Is Attenuated via PDE9A Inhibition

Hamdani, Nazha; Kolijn, Detmar; Lódi, Mária; Herwig, Melissa; Kovács, Attila; Linthout, S. Van; Bagi, Zsolt; Mügge, Andreas; Strauch, J; Haldenwang, PL

doi:10.1055/s-0040-1705428

Cited by 1 publication

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“…PDE9A expression has been reported for various tissues including those of the kidney − and the heart. , Furthermore, the recent literature suggests that inhibiting PDE9A might be beneficial for the treatment of renal dysfunction, HFrEF , and HFpEF. , We therefore studied urinary cGMP in rats and functional parameters in a rat heart failure model after PDE9A inhibition.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2022

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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.

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