School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China.
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China.
Bioorg Chem. 2021 Sep;114:105104. doi: 10.1016/j.bioorg.2021.105104. Epub 2021 Jun 18.
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 IC of 21 nM against PDE1B, shows good metabolic stability in the rat liver microsomes (RLM) (t 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.
磷酸二酯酶-1（PDE1）是一个有前景的药物靶点，与中枢和外周疾病密切相关。借助分子对接和动力学模拟，我们设计并合成了一系列新型吡唑并嘧啶酮衍生物，作为针对 PDE1 的有效且代谢稳定的抑制剂。大多数化合物在 20 nM 的浓度下对 PDE1 具有良好的抑制活性。化合物 2j 对 PDE1B 的抑制活性为 21 nM，在大鼠肝微粒体（RLM）中具有良好的代谢稳定性（t 为 28.5 分钟），表明化合物 2j 可用作工具来探索抑制剂与靶蛋白 PDE1 之间的分子识别机制。
