Acta Pharmaceutica Sinica B (Apr 2022)
Discovery of 4-cyclopropyl-3-(2-((1-cyclopropyl-1H-pyrazol-4-yl) amino) quinazolin-6-yl)-N-(3-(trifluoromethyl) phenyl) benzamides as potent discoidin domain receptor inhibitors for the treatment of idiopathic pulmonary fibrosis
- Qi Wang,
- Bixi Tang,
- Dandan Sun,
- Ying Dong,
- Yinchun Ji,
- Huanyu Shi,
- Liwei Zhou,
- Yueyue Yang,
- Menglan Luo,
- Qian Tan,
- Lin Chen,
- Yue Dong,
- Cong Li,
- Rongrong Xie,
- Yi Zang,
- Jingkang Shen,
- Bing Xiong,
- Jia Li,
- Danqi Chen
Affiliations
- Qi Wang
- Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China
- Bixi Tang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China
- Dandan Sun
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China
- Ying Dong
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China
- Yinchun Ji
- Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- Huanyu Shi
- Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China
- Liwei Zhou
- Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Center for Supramolecular Chemistry and Catalysis and Department of Chemistry, College of Sciences, Shanghai University, Shanghai 200444, China
- Yueyue Yang
- Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China
- Menglan Luo
- Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Department of Chemistry, College of Sciences, Shanghai University, Shanghai 200444, China
- Qian Tan
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- Lin Chen
- Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- Yue Dong
- Department of Pulmonary and Critical Care Medicine, Shanghai Fifth People's Hospital, Fudan University, Shanghai 200240, China
- Cong Li
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- Rongrong Xie
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- Yi Zang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, UCAS, Hangzhou 310024, China
- Jingkang Shen
- Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- Bing Xiong
- Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; Corresponding authors. Tel: +86 21 50806600 5412, fax: +86 21 50807088.
- Jia Li
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, UCAS, Hangzhou 310024, China; Corresponding authors. Tel: +86 21 50806600 5412, fax: +86 21 50807088.
- Danqi Chen
- Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Corresponding authors. Tel: +86 21 50806600 5412, fax: +86 21 50807088.
- Journal volume & issue
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Vol. 12,
no. 4
pp. 1943 – 1962
Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic fatal lung disease with a median survival time of 3–5 years. Inaccurate diagnosis, limited clinical therapy and high mortality together indicate that the development of effective therapeutics for IPF is an urgent need. In recent years, it was reported that DDRs are potential targets in anti-fibrosis treatment. Based on previous work we carried out further structure modifications and led to a more selective inhibitor 47 by averting some fibrosis-unrelated kinases, such as RET, AXL and ALK. Extensive profiling of compound 47 has demonstrated that it has potent DDR1/2 inhibitory activities, low toxicity, good pharmacokinetic properties and reliable in vivo anti-fibrosis efficacy. Therefore, we confirmed that discoidin domain receptors are promising drug targets for IPF, and compound 47 would be a promising candidate for further drug development.
