Discovery of potent anti-idiopathic pulmonary fibrosis (IPF) agents based on an o-aminopyridinyl alkynyl scaffold
文献类型：期刊论文
| 作者 | Wang, Yang4,6; Fan, Wenhui5,6; Guo, Yihao3; Sun, Li5,6; Hu, Youhong1,3,4,6 ; Chen, Jing4,5,6; Gong, Likun2,4,5,6; Xie, Zhicheng6
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| 刊名 | EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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| 出版日期 | 2025-09-15 |
| 卷号 | 294页码:15 |
| 关键词 | IPF EMT Key kinases Inhibitors |
| ISSN号 | 0223-5234 |
| DOI | 10.1016/j.ejmech.2025.117768 |
| 英文摘要 | Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with high mortality and limited treatment options. Targeting multiple kinase-driven pathological processes offers a promising strategy. Using epithelial-mesenchymal transition (EMT) phenotypic screening, we optimized a series of o-aminopyridinyl alkynyl compounds derived from CSF-1R relatively selective inhibitor, compound 1, through a structure-activity relationship (SAR) study, integrating liver and kidney cytotoxicity evaluations. Compound 22, emerged as the potent antifibrotic candidate, exhibiting low cytotoxic effects against human kidney (HEK293) and hepatocyte (L02) cell lines, and minimal hERG inhibition. In addition, 22 showed significant inhibition against other IPFrelated processes, including fibroblast-to-myofibroblast transition (FMT)-driven fibrosis in both human fetal lung fibroblasts cell line (HFL1) and primary human lung fibroblasts (HLFs), as well as pro-fibrotic M2 polarization. In vivo, compound 22 exhibited the acceptable PK properties and low toxicity profiles. In addition, oral administration of 22 demonstrated superior anti-fibrotic efficacy compared to Nintedanib, significantly attenuating bleomycin-induced lung fibrosis, reducing inflammation and pro-fibrotic M2-associated cytokine levels, and improving lung function. Preliminary kinase profiling indicates that compound 22 likely targets CSF-1R, PDGFR-alpha and Src family kinases to inhibit IPF progression, while sparing VEGFRs, FGFRs and Abl to minimize off-target toxicity commonly associated with multi-kinase inhibitor treatment. These findings highlight the advantages and therapeutic potential of a multi-kinase targeting strategy, enabling selective inhibition key IPFassociated kinases to develop more effective and safer anti-IPF agents. |
| WOS关键词 | TYROSINE KINASE INHIBITOR ; GROWTH-FACTOR ; SRC KINASE ; EFFICACY ; PATHOGENESIS ; NINTEDANIB ; PATHWAY ; SAFETY ; ADULTS ; TRIAL |
| 资助项目 | Commission of Shanghai Municipality[23YF1456900] ; National Natural Science Foundation of China[82273760] ; Department of Science and Technology of Guangdong Province (High-level Innovative Research Institute)[2021B0909050003] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:001498993500001 |
| 出版者 | ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/318261]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Hu, Youhong; Chen, Jing; Gong, Likun; Xie, Zhicheng |
| 作者单位 | 1.Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, 1 Xiangshanzhi Rd, Hangzhou 310024, Peoples R China 2.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Peoples R China 3.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Shandong, Peoples R China 4.Univ Chinese Acad Sci, 19 Yuquan Rd, Beijing 110039, Peoples R China 5.Nanjing Univ Chinese Med, Sch Chinese Mat Med, 138 Xianlin Rd, Nanjing 210046, Peoples R China 6.Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Wang, Yang,Fan, Wenhui,Guo, Yihao,et al. Discovery of potent anti-idiopathic pulmonary fibrosis (IPF) agents based on an o-aminopyridinyl alkynyl scaffold[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2025,294:15. |
| APA | Wang, Yang.,Fan, Wenhui.,Guo, Yihao.,Sun, Li.,Hu, Youhong.,...&Xie, Zhicheng.(2025).Discovery of potent anti-idiopathic pulmonary fibrosis (IPF) agents based on an o-aminopyridinyl alkynyl scaffold.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,294,15. |
| MLA | Wang, Yang,et al."Discovery of potent anti-idiopathic pulmonary fibrosis (IPF) agents based on an o-aminopyridinyl alkynyl scaffold".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 294(2025):15. |
入库方式： OAI收割
来源：上海药物研究所
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