Synthesis and biological evaluations of chalcones, flavones and chromenes as farnesoid x receptor (FXR) antagonists

Authors

Guoning Zhang, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College
Shuainan Liu, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College
Wenjuan Tan, NeuMed Pharmaceuticals Limited
Ruchi Verma, University of Rhode Island
Yuan Chen, University of Rhode Island
Deyang Sun, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College
Yi Huan, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College
Qian Jiang, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College
Xing Wang, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College
Na Wang, University of Science and Technology of China
Yang Xu, Northeast Ohio Medical University (NEOMED)
Chiwai Wong, NeuMed Pharmaceuticals Limited
Zhufang Shen, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College
Ruitang Deng, University of Rhode Island
Jinsong Liu, University of Science and Technology of China
Yanqiao Zhang, Northeast Ohio Medical University (NEOMED)
Weishuo Fang, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College

Document Type

Article

Date of Original Version

1-1-2017

Abstract

Farnesoid X receptor (FXR), a nuclear receptor mainly distributed in liver and intestine, has been regarded as a potential target for the treatment of various metabolic diseases, cancer and infectious diseases related to liver. Starting from two previously identified chalcone-based FXR antagonists, we tried to increase the activity through the design and synthesis of a library containing chalcones, flavones and chromenes, based on substitution manipulation and conformation (ring closure) restriction strategy. Many chalcones and four chromenes were identified as microM potent FXR antagonists, among which chromene 11c significantly decreased the plasma and hepatic triglyceride level in KKay mice.

Publication Title, e.g., Journal

European Journal of Medicinal Chemistry

Volume

129

Citation/Publisher Attribution

Zhang, Guoning, Shuainan Liu, Wenjuan Tan, Ruchi Verma, Yuan Chen, Deyang Sun, Yi Huan, Qian Jiang, Xing Wang, Na Wang, Yang Xu, Chiwai Wong, Zhufang Shen, Ruitang Deng, Jinsong Liu, Yanqiao Zhang, and Weishuo Fang. "Synthesis and biological evaluations of chalcones, flavones and chromenes as farnesoid x receptor (FXR) antagonists." European Journal of Medicinal Chemistry 129, (2017): 303-309. doi: 10.1016/j.ejmech.2017.02.037.