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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Design, synthesis and discovery of 2(1H)-quinolone derivatives for the treatment of pulmonary fibrosis through inhibition of TGF-beta/smad dependent and independent pathway
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Design, synthesis and discovery of 2(1H)-quinolone derivatives for the treatment of pulmonary fibrosis through inhibition of TGF-beta/smad dependent and independent pathway

机译：2（1H）-Qquinolone衍生物的设计，合成和发现用于治疗TGF-β/ Smad依赖性和独立途径的抑制作用肺纤维化

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Idiopathic pulmonary fibrosis (IPF) is a progressive, life-threatening and interstitial lung disease with the median survival of only 3-5 years. However, due to the unclear etiology and problems in accurate diagnosis, up to now only two drugs were approved by FDA for the treatment of IPF and their outcome responses are limited. Numerous studies have shown that TGF-beta is the most important cytokine in the development of pulmonary fibrosis and plays a role through its downstream signaling molecule TGF-binding receptor Smads protein. In this paper, compounds bearing 2(1H)-quinolone scaffold were designed and their anti-fibrosis effects were evaluated. Of these compounds, 20f was identified as the most active one and could inhibit TGF-beta-induced collagen deposition of NRK-49F cells and mouse fibroblasts migration with comparable activity and lower cytotoxicity than nintedanib in vitro. Further mechanism studies indicated that 20f reduced the expression of fibrogenic phenotypic protein alpha-SMA and collagen I by inhibiting the TGF-beta/Smad dependent pathways and ERK1/2 and p38 pathways. Moreover, compared with the nintedanib, 20f (100 mg/kg/day, p.o) more effectively alleviated collagen deposition in lung tissue and delayed the destruction of lung tissue structure both in bleomycin-induced prevention and treatment mice pulmonary fibrosis models. The immunohistochemical experiments further showed that 20f could block the expression level of phosphorylated Smad3 in the lung tissue cells, which resulted in its anti-fibrosis effects in vivo. In addition, 20f demonstrated good bioavailability (F = 41.55% vs 12%, compare with nintedanib) and an appropriate elimination half-life (T-1/2 = 3.5 h), suggesting that 20f may be a potential drug candidate for the treatment of pulmonary fibrosis. (C) 2020 Published by Elsevier Masson SAS.
机译：特发性肺纤维化（IPF）是一种进步，危及生命和间质肺病，中位存活仅为3 - 5年。然而，由于在准确诊断中的病因和问题上不清楚，直到现为仅有两种药物被FDA批准用于治疗IPF，其结果响应有限。许多研究表明，TGF-β是肺纤维化发育中最重要的细胞因子，并通过其下游信号分子TGF结合受体Smads蛋白发挥作用。在本文中，设计了化合物2（1H） - 喹啉支架，评价其抗纤维化作用。在这些化合物中，将20°F被鉴定为最活跃的，可以抑制NRK-49F细胞的TGF-β诱导的胶原沉积，并在体外比尼德尼布迁移到比目毒性的小鼠成纤维细胞迁移。进一步的机制研究表明，20F通过抑制TGF-β/ Smad依赖性途径和ERK1 / 2和P38途径来降低纤维型表型蛋白α-SMA和胶原I的表达。此外，与尼丁尼，20F（100mg / kg /天，P.O）相比，在肺组织中更有效地缓解胶原沉积，并延迟了肺组织结构的破坏，无论是博莱霉素诱导的预防和治疗小鼠肺纤维化模型。免疫组织化学实验进一步表明20F可以阻断肺组织细胞中磷酸化Smad3的表达水平，这导致其在体内抗纤维化作用。此外，20F证明了良好的生物利用度（F = 41.55％与12％，与尼林尼布相比）和适当的消除半衰期（T-1/2 = 3.5小时），表明20F可能是治疗的潜在药物候选者肺纤维化。 （c）2020由Elsevier Masson SA发表。

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