Our previous research demonstrated that phosphodiesterase-1 (PDE1) could work as a potential target against idiopathic pulmonary fibrosis. Nimodipine, a calcium antagonist commonly used to improve hypertension, was reported to have inhibition against PDE1. Herein, a series of nimodipine analogues were discovered as novel selective and potent PDE1 inhibitors after structural modifications. Compound 2g exhibited excellent inhibitory activity against PDE1C (IC₅₀ = 10 nM), high selectivity over other PDEs except for PDE4, and weak calcium channel antagonistic activity. Administration of compound 2g exhibited remarkable therapeutic effects in a rat model of pulmonary fibrosis induced by bleomycin and prevented myofibroblast differentiation induced by TGF-β1. The expressions of PDE1B and PDE1C were found to be increased and concentrated in the focus of fibrosis. Compound 2g increased the levels of 3′,5′-cyclic adenosine monophosphate (cAMP) and 3′,5′-cyclic guanosine monophosphate (cGMP) in the lungs of rats with pulmonary fibrosis, supporting the fact that the anti-fibrosis effects of 2g were through the regulation of cAMP and cGMP.

中文翻译：

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尼莫地平的结构修饰导致具有抗肺纤维化作用的新型 PDE1 抑制剂

我们之前的研究表明，磷酸二酯酶 1 (PDE1) 可以作为对抗特发性肺纤维化的潜在靶点。据报道，尼莫地平是一种常用于改善高血压的钙拮抗剂，对 PDE1 有抑制作用。在此，一系列尼莫地平类似物被发现是经过结构修饰后的新型选择性和有效的 PDE1 抑制剂。化合物2g对 PDE1C 表现出优异的抑制活性 (IC ₅₀ = 10 nM)，对除 PDE4 之外的其他 PDE 具有高选择性，并且具有较弱的钙通道拮抗活性。复方2g给药在博莱霉素诱导的肺纤维化大鼠模型中表现出显着的治疗作用，并阻止了TGF-β1诱导的肌成纤维细胞分化。发现PDE1B和PDE1C的表达增加并集中在纤维化病灶。化合物2g增加了肺纤维化大鼠肺中 3',5'-环磷酸腺苷 (cAMP) 和 3',5'-环磷酸鸟苷 (cGMP) 的水平, 支持了抗纤维化作用的事实。2g均通过cAMP和cGMP的调节。