State Key Laboratory of Anti-Infective Drug Discovery and Development, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China.
School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University, Zhongshan 528458, China.
J Med Chem. 2024 Nov 28;67(22):20203-20213. doi: 10.1021/acs.jmedchem.4c01533. Epub 2024 Nov 15.
Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with no ideal drugs. Our previous research demonstrated that phosphodiesterase 1 (PDE1) could be a promising target for the treatment of IPF. However, only a few selective PDE1 inhibitors are available, and the mechanism of recognition between inhibitors and the PDE1 protein is not fully understood. This study carried out a step-by-step optimization of a dihydropyrimidine hit . By targeting the metal pocket of PDE1, a lead compound was obtained, exhibiting an IC value of 11 nM against PDE1, moderate selectivity over other PDEs, and significant anti-fibrotic effects in bleomycin-induced pulmonary fibrosis rats. The structure-activity relationship study aided by molecular docking revealed that forming halogen bonds with water in the metal pocket greatly enhanced the PDE1 inhibition, providing a novel strategy for further rational design of PDE1 inhibitors.
特发性肺纤维化（IPF）是一种致命的肺部疾病，目前尚无理想的药物。我们之前的研究表明，磷酸二酯酶 1（PDE1）可能是治疗 IPF 的一个有前途的靶点。然而，目前只有少数几种选择性 PDE1 抑制剂可用，并且抑制剂与 PDE1 蛋白之间的识别机制尚不完全清楚。本研究对二氢嘧啶类化合物进行了逐步优化。通过靶向 PDE1 的金属口袋，获得了一个先导化合物 ，对 PDE1 的 IC 值为 11 nM，对其他 PDE 具有中等选择性，并且在博来霉素诱导的肺纤维化大鼠中具有显著的抗纤维化作用。分子对接辅助的构效关系研究表明，与金属口袋中的水形成卤键可显著增强 PDE1 的抑制作用，为进一步合理设计 PDE1 抑制剂提供了一种新策略。
