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 AG-205/1186117 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 13h exhibited the IC₅₀ of 10 nM against PDE1, high selectivity over other PDEs, as well as good safety properties. Administration of 13h 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.

中文翻译：

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二氢嘧啶衍生物作为选择性 PDE1 抑制剂治疗肝纤维化的设计、合成和评价


肝纤维化是大多数慢性肝病的共同病理特征，目前尚无有效药物。磷酸二酯酶 1 (PDE1) 是 PDE 超级酶的一个亚家族，可能通过调节 cAMP 和 cGMP 的浓度作为肝纤维化的有效靶标。然而，PDE1选择性抑制剂很少，并且尚未研究用于肝纤维化治疗。在此，通过虚拟筛选，选择具有二氢嘧啶支架的化合物AG-205/1186117作为命中。命中先导结构修饰产生了一系列二氢嘧啶衍生物。 Lead 13h 对 PDE1 的 IC ₅₀ 为 10 nM，比其他 PDE 具有高选择性，并且具有良好的安全性。给药13小时对胆管结扎诱导的纤维化大鼠产生显着的抗肝纤维化作用，同时还可以在体外阻止TGF-β诱导的肌成纤维细胞分化，证实PDE1可以作为肝纤维化的潜在靶点。