2. Academic Validation
  3. Discovery of novel capsaicin analogs as TRPV1 inhibitors for the treatment of idiopathic pulmonary fibrosis

Discovery of novel capsaicin analogs as TRPV1 inhibitors for the treatment of idiopathic pulmonary fibrosis

  • Eur J Med Chem. 2025 Feb 15:284:117229. doi: 10.1016/j.ejmech.2024.117229.
Yu Cao 1,  Yongju Wen 2,  Zongyuan Zhou 3,  Ruiying Xi 3,  Wen Shuai 4,  Jichao Zhang 3,  Apichart Suksamrarn 5,  Guolin Zhang 6,  Xiao-Xia Lu 7,  Fei Wang 8
Affiliations

Affiliations

  • 1 Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, 610041, PR China; State Key Laboratory of Biotherapy and Cancer Center, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, National Clinical Research Center for Geriatrics, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, 610041, PR China; University of Chinese Academy of Sciences, Beijing, 100049, PR China.
  • 2 Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, 610041, PR China; College of Chemistry and Bioengineering Yichun University, Yichun, 336000, PR China; University of Chinese Academy of Sciences, Beijing, 100049, PR China.
  • 3 Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, 610041, PR China; University of Chinese Academy of Sciences, Beijing, 100049, PR China.
  • 4 State Key Laboratory of Biotherapy and Cancer Center, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, National Clinical Research Center for Geriatrics, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, 610041, PR China.
  • 5 Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Ramkhamhaeng University, Bangkok, 10240, Thailand.
  • 6 Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, 610041, PR China.
  • 7 Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, 610041, PR China. Electronic address: luxx@cib.ac.cn.
  • 8 Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, 610041, PR China. Electronic address: wangfei@cib.ac.cn.
PMID: 39826937 DOI: 10.1016/j.ejmech.2024.117229
Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease for which few drugs are available in clinical practice. Here, we identified novel capsaicin analogs by combining in-house chemical library screening and further structural optimization. (E)-1-(3,4-dihydroxyphenyl)-7-phenylhept-1-en-3-one (Compound 14) was found to be the most potent in inhibiting TGF-β-induced collagen accumulation, proliferation and migration in fibroblast cells. Furthermore, compound 14 (IC50 = 0.51 ± 0.06 μM) showed over 100-fold increasing antifibrotic activity compared to capsaicin (IC50 = 53.71 ± 4.78 μM). Notably, compound 14 could target TRPV1, thereby affecting the expression of the fibrosis markers Collagen Ⅰ and α-SMA by inhibiting the TGF-β/Smads and MAPK pathways to exert antifibrotic activity in vitro. Compound 14 significantly inhibited collagen deposition in lung tissues, ameliorated alveolar structures, and increased survival rates in mice with bleomycin-induced pulmonary fibrosis. In addition, compound 14 possessed lower cytotoxicity (compared to nitedanib) and no toxicity in mice. Overall, compound 14 promise as a potential drug candidate for the treatment of IPF.

Keywords

Capsaicin analogs; Idiopathic pulmonary fibrosis; MAPK pathway; TGF-β/Smads pathway; TRPV1 inhibitors.

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