Synthesis and discovery of new compounds bearing coumarin scaffold for the treatment of pulmonary fibrosis
Synthesis and discovery of new compounds bearing coumarin scaffold for the treatment of pulmonary fibrosis
复制标题
用于治疗肺纤维化的香豆素支架新化合物的合成与发现
DOI：
10.1016/j.ejmech.2019.111790
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发表时间：
2020-01-01
影响因子：
6.7
通讯作者：
Chen, Lijuan
中科院分区：
文献类型：
--
作者：
Deng, Dexin;Pei, Heying;Chen, Lijuan
特发性肺纤维化以细胞外基质过度积累为特征，涉及多种慢性疾病或损伤，严重威胁人类健康。我们报道了一系列带有香豆素支架的化合物，它们能有效抑制 TGF-β 诱导的 NRK-49F 细胞系中总胶原蛋白的积累和巨噬细胞的迁移。化合物 9d 还在体外抑制 TGF-β 诱导的 COL1A1、α-SMA 和 p-Smad3 蛋白表达。同时，口服100 mg/kg/天剂量9d，连续4周，可有效减轻博来霉素诱导的肺纤维化模型中肺组织炎症细胞浸润和纤维化程度，这可能与其抑制TGF-β/Smad3通路和抗炎功效有关。此外，9d表现出良好的生物利用度（T-1/2 = 39.88%）和适当的消除半衰期alp = 13.09 h），表明9d可能是治疗纤维化疾病的潜在候选药物。 (C) 2019 年由 Elsevier Masson SAS 出版。
Idiopathic pulmonary fibrosis, characterized by excess accumulation of extracellular matrix, involved in many chronic diseases or injuries, threatens human health greatly. We have reported a series of compounds bearing coumarin scaffold which potently inhibited TGF-beta-induced total collagen accumulation in NRK-49F cell line and migration of macrophages. Compound 9d also suppressed the TGF-beta-induced protein expression of COL1A1, alpha-SMA, and p-Smad3 in vitro. Meanwhile, 9d at a dose of 100 mg/kg/day through oral administrations for 4 weeks effectively alleviated infiltration of inflammatory cells in lung tissue and fibrotic degree in bleomycin-induced pulmonary fibrosis model, which may related to its inhibition of TGF-beta/Smad3 pathway and anti-inflammation efficacy. In addition, 9d demonstrated decent bioavailability (T-1/2 = 39.88%) and suitable eliminated half-life time alp =13.09 h), suggesting that 9d could be a potential drug candidate for the treatment of fibrotic diseases. (C) 2019 Published by Elsevier Masson SAS.