Details

Autor(en) / Beteiligte

• Zhang, Bei
• Huang, Yue
• Zhang, Si-Rui
• Huang, Meng-Xing
• Zhang, Chen
• Luo, Hai-Bin

Titel

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

Ist Teil von

• Bioorganic chemistry, 2021-09, Vol.114, p.105104-105104, Article 105104

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2021

Quelle

Elsevier ScienceDirect

Beschreibungen/Notizen

• [Display omitted] •We discovered novel pyrazolopyrimidone derivatives as PDE1 inhibitors.•Compound 2j exhibited excellent PDE1 inhibitory activity (IC50 of 21 nM).•Compound 2j showed good metabolic stability (T1/2 of 28.5 min) in RLMs.•Compound 2j showed good selectivity profile (>35-fold over other PDEs). 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.