Discovery and optimization of selective FGFR4 inhibitors via scaffold hopping

作者：Wang Yikai; Chen Zhengxia; Dai Meibi; Sun Peipei; Wang Chunqiu; Gao Yang; Zhao Haixia; Zeng Wenqin; Shen Liang; Mao Weifeng; Wang Tian; Hu Guoping; Li Jian; Chen Shuhui; Long Chaofeng; Chen Xiaoxin; Liu Junhua; Zhang Yang

来源：Bioorganic & Medicinal Chemistry Letters, 2017, 27(11): 2420-2423.

DOI：10.1016/j.bmcl.2017.04.014

• Hepatocellular carcinoma
• Fibroblast growth factor 19
• Fibroblast growth factor receptor 4
• Covalent inhibitor
• Isoform selective

Introduction of a Michael acceptor on a flexible scaffold derived from pan-FGFR inhibitors has successfully yielded a novel series of highly potent FGFR4 inhibitors with selectivity over FGFR1. Due to reduced lipophilicity and aromatic ring count, this series demonstrated improved solubility and permeability. However, plasma instability and fast metabolism limited its potential for in vivo studies. Efforts have been made to address these problems, which led to the discovery of compound (−)-11 with improved stability, CYP inhibition, and good activity/selectivity for further optimization.

• 出版日期2017-6-1