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

Area of Science:

• Cardiovascular Research
• Pharmacology
• Drug Discovery

Background:

• Heart failure treatment options remain limited, contributing to significant patient morbidity and mortality.
• Modulating cyclic guanosine monophosphate (cGMP) via phosphodiesterase 9A (PDE9A) inhibition shows preclinical promise in heart failure models.
• The natriuretic peptide signaling pathway plays a crucial role in cardiovascular homeostasis.

Purpose of the Study:

• To identify and characterize novel, orally bioavailable PDE9A inhibitors for potential heart failure therapy.
• To optimize lead compounds for improved pharmacokinetic properties, specifically shifting metabolism from glucuronidation to oxidation.
• To validate the therapeutic relevance of PDE9A inhibition in a relevant preclinical model of heart disease.

Main Methods:

• High-throughput screening was employed to identify initial hits.
• Medicinal chemistry optimization focused on metabolic stability and pharmacokinetic profiling.
• BAY-7081, a potent and selective PDE9A inhibitor, was synthesized and characterized.
• Pharmacological studies were conducted using a transverse aortic constriction mouse model.

Main Results:

• BAY-7081 was identified as a potent, selective, orally bioavailable PDE9A inhibitor with excellent aqueous solubility.
• Metabolic optimization successfully shifted drug metabolism from glucuronidation to oxidation, improving pharmacokinetic profiles.
• A tool compound demonstrated the efficacy of PDE9A inhibition in a mouse model of cardiac disease.

Conclusions:

• BAY-7081 represents a promising drug candidate for heart failure treatment.
• Targeting PDE9A offers a viable therapeutic strategy for cardiovascular diseases.
• Optimizing drug metabolism is critical for developing effective cardiovascular therapeutics.