European Journal of Medicinal Chemistry (2020)
Update date:2022-08-15
Topics: Synthesis Design Discovery Inhibition 2(1H)-quinolone derivatives Pulmonary fibrosis TGF-β Smad Dependent pathway Independent pathway
Chen, Lijuan
Chen, Yong
Deng, Dexin
Liu, Kongjun
Pei, Heying
Tang, Minghai
Xue, Linlin
Yang, Tao
Yang, Zhuang
Ye, Haoyu
Zheng, Shoujun
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-β 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-β-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 α-SMA and collagen Ⅰ by inhibiting the TGF-β/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 (T1/2 = 3.5 h), suggesting that 20f may be a potential drug candidate for the treatment of pulmonary fibrosis.
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Doi:10.1021/jo00042a003
(1992)Doi:10.1021/ol100183s
(2010)Doi:10.1007/BF00959918
(1988)Doi:10.1016/j.bmcl.2009.12.007
(2010)Doi:10.1016/j.tetlet.2010.01.003
(2010)Doi:10.3987/COM-09-11868
(2010)