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

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

Zhang Guoning; Liu Shuainan; Tan Wenjuan; Verma Ruchi; Chen Yuan; Sun Deyang; Huan Yi; Jiang Qian; Wang Xing; Wang Na; Xu Yang; Wong Chiwai; Shen Zhufang; Deng Ruitang; Liu Jinsong; Zhang Yanqiao; Fang Weishuo

European journal of medicinal chemistry

2017

2017-03

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.

Animals; Antagonist; Benzopyrans/chemical synthesis/*pharmacology; Chalcones; Chalcones/chemical synthesis/*pharmacology; Chromenes; Cytoplasmic and Nuclear/*antagonists & inhibitors; Farnesoid X receptor; Flavones/chemical synthesis/*pharmacology; Liver Diseases/drug therapy; Liver/chemistry/*drug effects/metabolism; Mice; Receptors; Triglycerides/analysis

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