Synthesis and discovery of new compounds bearing coumarin scaffold for the treatment of pulmonary fibrosis

  • Eur J Med Chem. 2020 Jan 1;185:111790. doi: 10.1016/j.ejmech.2019.111790.
Dexin Deng  1 ,  Heying Pei  1 ,  Tingxuan Lan  1 ,  Jiali Zhu  1 ,  Minghai Tang  1 ,  Linlin Xue  1 ,  Zhuang Yang  1 ,  Shoujun Zheng  1 ,  Haoyu Ye  1 ,  Lijuan Chen  2
Affiliations
  • 1. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, 610041, China.
  • 2. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, 610041, China. Electronic address: [email protected].
PMID: 31699535 DOI: 10.1016/j.ejmech.2019.111790
Abstract

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-β-induced total Collagen accumulation in NRK-49F cell line and migration of macrophages. Compound 9d also suppressed the TGF-β-induced protein expression of COL1A1, α-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-β/SMAD3 pathway and anti-inflammation efficacy. In addition, 9d demonstrated decent bioavailability (F = 39.88%) and suitable eliminated half-life time (T1/2 = 13.09 h), suggesting that 9d could be a potential drug candidate for the treatment of fibrotic diseases.

Keywords
Anti-fibrosis; Anti-inflammatory; Collagen accumulation; Coumarins; Pulmonary fibrosis.
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