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Synthesis and Biological Evaluation of N-(5-(2,5-dimethyl-phenoxy)-2,2-dimethylpentyl)-benzamide Derivatives as Novel Farnesoid X Receptor (FXR) Antagonist

[ Vol. 15 , Issue. 9 ]

Author(s):

Siyun Nian, Zhenpeng Yu, Xiangduan Tan, Xia Gan, Mohan Huang, Yihuan Zhou and Guoping Wang*   Pages 923 - 936 ( 14 )

Abstract:


Background: Dyslipidemia is a serious threat to human health. The objective of our research was to develop effective FXR antagonists against dyslipidemia.

Methods: Herein we describe the design, synthesis of 37 N-(5-(2,5-dimethylphenoxy)-2,2- dimethylpentyl)-benzamide derivatives and evaluated for their FXR inhibition ability compared to GS and SIPI-7623.

Results: Structure–activity relationship analyses indicated that compounds containing hydroxyl on the right side of the phenyl were more effective than those without hydroxyl. Compound BI-24 was identified to have the most potent antagonic activity with an IC50 value of 10.8 µM for FXR, exhibited no cytotoxicity on HepG2 cells and reduced levels of TC, TG, LDL-C for 36%, 69%, and 32% on serum, respectively.

Conclusion: Compound BI-24 may be developed to a potential agent for the treatment of dyslipidemia.

Keywords:

Hypolipidemic activity, FXR antagonists, synthesis, structure activity relationship, gugglesterone, molecular docking.

Affiliation:

Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai 201203, YangZhou Aurisco Pharmaceutical Co., Ltd, Yangzhou, 225100, College of Pharmacy, Guilin Medical University, Guilin 541004, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai 201203, College of Pharmacy, Guilin Medical University, Guilin 541004, College of Pharmacy, Guilin Medical University, Guilin 541004, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai 201203

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