Design, synthesis and biological evaluation of novel pyrazolopyrimidone derivatives as potent PDE1 inhibitors
Design, synthesis and biological evaluation of novel pyrazolopyrimidone derivatives as potent PDE1 inhibitors
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作为有效 PDE1 抑制剂的新型吡唑并嘧啶酮衍生物的设计、合成和生物学评价
DOI：
10.1016/j.bioorg.2021.105104
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发表时间：
2021-06-27
影响因子：
5.1
通讯作者：
Luo, Hai-Bin
中科院分区：
文献类型：
--
作者：
Zhang, Bei;Huang, Yue;Luo, Hai-Bin
磷酸二酯酶-1（PDE 1）是一个与中枢和外周疾病密切相关的有前途的药物靶点。借助分子对接和动力学模拟，我们设计并合成了一系列新的吡唑并嘧啶酮衍生物，作为有效的和代谢稳定的PDE 1抑制剂。大多数化合物在20 nM浓度下对PDE 1具有良好的抑制活性。化合物2 j对PDE 1B的IC 50为21 nM，在大鼠肝微粒体（RLM）中显示出良好的代谢稳定性（t1/2为28.5 min），表明化合物2 j可用作探索抑制剂与靶蛋白PDE 1之间的分子识别机制的工具。
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.