Key Laboratory of Tropical Biological Resources of Ministry of Education and Hainan Engineering Research Center for Drug Screening and Evaluation, School of Pharmaceutical Sciences, Hainan University, Haikou, Hainan 570228, China.
State Key Laboratory of Anti-Infective Drug Discovery and Development, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P. R. China.
J Med Chem. 2024 May 23;67(10):8309-8322. doi: 10.1021/acs.jmedchem.4c00461. Epub 2024 Apr 26.
Liver fibrosis is a common pathological feature of most chronic liver diseases with no effective drugs available. Phosphodiesterase 1 (PDE1), a subfamily of the PDE super enzyme, might work as a potent target for liver fibrosis by regulating the concentration of cAMP and cGMP. However, there are few PDE1 selective inhibitors, and none has been investigated for liver fibrosis treatment yet. Herein, compound with the dihydropyrimidine scaffold was selected as the hit by virtual screening. A hit-to-lead structural modification led to a series of dihydropyrimidine derivatives. Lead exhibited the IC of 10 nM against PDE1, high selectivity over other PDEs, as well as good safety properties. Administration of exerted significant anti-liver fibrotic effects in bile duct ligation-induced fibrosis rats, which also prevented TGF-β-induced myofibroblast differentiation in vitro, confirming that PDE1 could work as a potential target for liver fibrosis.
肝纤维化是大多数慢性肝病的一种常见病理特征，目前尚无有效的治疗药物。磷酸二酯酶 1（PDE1）是 PDE 超级酶的一个亚家族，通过调节 cAMP 和 cGMP 的浓度，可能成为肝纤维化的一个潜在有效靶点。然而，目前仅有少数 PDE1 选择性抑制剂，且尚无抑制剂被用于肝纤维化的治疗。在此，我们通过虚拟筛选选择了具有二氢嘧啶结构的化合物 作为命中物。通过对命中物的结构进行优化，得到了一系列二氢嘧啶衍生物。先导化合物 对 PDE1 的抑制活性为 10 nM，对其他 PDE 具有高选择性，且安全性良好。化合物 在胆管结扎诱导的肝纤维化大鼠模型中发挥了显著的抗肝纤维化作用，同时还能抑制 TGF-β诱导的肌成纤维细胞分化，证实 PDE1 可作为肝纤维化的一个潜在治疗靶点。
