Discovery and SAR Study of Boronic Acid-Based Selective PDE3B Inhibitors from a Novel DNA-Encoded Library.

Area of Science:

• Biochemistry
• Pharmacology
• Genetics

Background:

• Phosphodiesterase 3B (PDE3B) is genetically linked to metabolic and dyslipidemia phenotypes.
• Existing PDE3 inhibitors face challenges due to proarrhythmic effects, necessitating PDE3B-selective agents.
• High homology between PDE3A and PDE3B active sites complicates selective inhibition.

Purpose of the Study:

• To identify potent and selective inhibitors of PDE3B.
• To overcome the challenge of active site homology between PDE3A and PDE3B.
• To discover novel chemical matter for PDE3B-targeted therapeutics.

Main Methods:

• Utilized a DNA-encoded library (DEL) screen for high-throughput screening.
• Employed a screening strategy to identify compounds with selectivity for PDE3B over PDE3A.
• Characterized identified compounds for their inhibitory activity and selectivity.

Main Results:

• Successfully identified potent and selective PDE3B inhibitors through the DEL screen.
• Discovered novel boronic acid compounds that bind to the PDE3B active site.
• Demonstrated the feasibility of achieving PDE3B selectivity despite high active site homology.

Conclusions:

• DNA-encoded library screening is an effective approach for discovering selective enzyme inhibitors.
• The identified boronic acid compounds represent promising leads for PDE3B-targeted drug development.
• Achieving PDE3B selectivity is critical for mitigating cardiovascular risks associated with PDE3 inhibition.