2-(4-acetylpiperazin-1-yl)-N-(3-fluoro-4-((2-oxo-1,2-dihydroquinolin-4-yl)oxy)phenyl)acetamide

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: 2-(4-acetylpiperazin-1-yl)-N-(3-fluoro-4-((2-oxo-1,2-dihydroquinolin-4-yl)oxy)phenyl)acetamide
• 英文别名: 2-(4-acetylpiperazin-1-yl)-N-[3-fluoro-4-[(2-oxo-1H-quinolin-4-yl)oxy]phenyl]acetamide
• 化学式: C₂₃H₂₃FN₄O₄
• 分子量: 438.458
• InChiKey: DUOZBCWRHWIJIK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  32
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  91
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  2,4-喹啉二醇 在 盐酸 、 铁粉 、 potassium carbonate 、 三乙胺 、 potassium iodide 作用下， 以 甲醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 11.83h， 生成 2-(4-acetylpiperazin-1-yl)-N-(3-fluoro-4-((2-oxo-1,2-dihydroquinolin-4-yl)oxy)phenyl)acetamide
  参考文献：
  名称：

  Design, synthesis and discovery of 2(1H)-quinolone derivatives for the treatment of pulmonary fibrosis through inhibition of TGF-β/smad dependent and independent pathway

  摘要：

  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.

  DOI：

  10.1016/j.ejmech.2020.112259

文献信息

• Design, synthesis and discovery of 2(1H)-quinolone derivatives for the treatment of pulmonary fibrosis through inhibition of TGF-β/smad dependent and independent pathway
  作者：Linlin Xue、Dexin Deng、Shoujun Zheng、Minghai Tang、Zhuang Yang、Heying Pei、Yong Chen、Tao Yang、Kongjun Liu、Haoyu Ye、Lijuan Chen

  DOI：10.1016/j.ejmech.2020.112259

  日期：2020.7

  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.