Structural Modifications of Nimodipine Lead to Novel PDE1 Inhibitors with Anti-pulmonary Fibrosis Effects
Structural Modifications of Nimodipine Lead to Novel PDE1 Inhibitors with Anti-pulmonary Fibrosis Effects
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DOI：
10.1021/acs.jmedchem.2c00458
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发表时间：
2022-06-23
影响因子：
7.3
通讯作者：
Wu, Yinuo
中科院分区：
文献类型：
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作者：
Huang, Meng-Xing;Tian, Yi-Jing;Wu, Yinuo
我们前期的研究表明，磷酸二酯酶-1（PDE 1）可能是治疗特发性肺纤维化的潜在靶点。尼莫地平是一种常用于改善高血压的钙拮抗剂，据报道对PDE 1有抑制作用。在此，一系列尼莫地平类似物被发现作为新的选择性和有效的PDE 1抑制剂后，结构修饰。化合物2g表现出对PDE 1C的优异抑制活性（IC 50 = 10 nM），对除PDE 4之外的其它PDE的高选择性，以及弱的钙通道拮抗活性。化合物2g的给药在由博来霉素诱导的肺纤维化的大鼠模型中表现出显著的治疗效果，并且防止了由TGF-β 1诱导的肌成纤维细胞分化。PDE 1B和PDE 1C在纤维化灶中表达增强并集中。化合物2g增加肺纤维化大鼠肺中3 '，5'-环腺苷酸（cAMP）和3 '，5'-环鸟苷酸（cGMP）的水平，支持2g的抗纤维化作用是通过调节cAMP和cGMP的事实。
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-beta 1. 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.