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

• Main Authors: Qi Wang (Author), Bixi Tang (Author), Dandan Sun (Author), Ying Dong (Author), Yinchun Ji (Author), Huanyu Shi (Author), Liwei Zhou (Author), Yueyue Yang (Author), Menglan Luo (Author), Qian Tan (Author), Lin Chen (Author), Yue Dong (Author), Cong Li (Author), Rongrong Xie (Author), Yi Zang (Author), Jingkang Shen (Author), Bing Xiong (Author), Jia Li (Author), Danqi Chen (Author)
• Format: Book
• Published: Elsevier, 2022-04-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

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.

Item Description

2211-3835
10.1016/j.apsb.2021.11.012