Design, synthesis and biological evaluation of novel pyrazolopyrimidone derivatives as potent PDE1 inhibitors

Phosphodiesterase-1 (PDE1) is a promising drug target closely related to central and peripheral diseases. With the assistance of molecular docking and dynamics simulations, we designed and synthesized a novel series of pyrazolopyrimidone derivatives as effective and metabolically stable inhibitors against PDE1. Most compounds have good inhibitory activities against PDE1 at the concentration of 20 nM. Compound 2j with the IC50 of 21 nM against PDE1B, shows good metabolic stability in the rat liver microsomes (RLM) (t1/2 of 28.5 min), indicating that compound 2j can be used as a tool to explore the molecular recognition mechanism between inhibitors and the target protein PDE1.

Automated summary

Phosphodiesterase-1 (PDE1) is a promising drug target for central and peripheral diseases. Through molecular docking and dynamics simulations, a series of pyrazolopyrimidone derivatives were designed as effective PDE1 inhibitors, with most compounds showing good inhibitory activities and compound 2j demonstrating good metabolic stability. This compound can be utilized as a tool to explore the molecular recognition mechanism between inhibitors and the target protein PDE1.