2. Academic Validation
  3. Design, synthesis, and biological evaluation of novel FXR agonists based on auraptene

Design, synthesis, and biological evaluation of novel FXR agonists based on auraptene

  • Bioorg Chem. 2021 Oct:115:105198. doi: 10.1016/j.bioorg.2021.105198.
Qianqian Qiu 1,  Yanjuan Wang 1,  Guolong Gu 1,  Fan Yu 1,  Shichao Zhang 1,  Yining Zhao 2,  Bai Ling 3
Affiliations

Affiliations

  • 1 School of Pharmacy, Yancheng Teachers' University, Yancheng, PR China.
  • 2 School of Pharmacy, Yancheng Teachers' University, Yancheng, PR China. Electronic address: zhaoyn@yctu.edu.cn.
  • 3 Department of Pharmacy, Affiliated Hospital 4 of Nantong University, The First People's Hospital of Yancheng City, Yancheng, PR China. Electronic address: 1079014431@qq.com.
PMID: 34333419 DOI: 10.1016/j.bioorg.2021.105198
Abstract

Farnesoid X receptor (FXR) has been considered as an attractive target for metabolic disorder and liver injury, while many current FXR agonists suffer from undesirable side effects, such as pruritus. Therefore, it is urgent to develop new structure types different from current FXR agonists. In this study, a series of structural optimizations were introduced to displace the unstable coumarin and geraniol scaffolds of auraptene (AUR), a novel and safe FXR Agonist. All of these efforts led to the identification of compound 14, a potent FXR Agonist with nearly fourfold higher activity than AUR. Molecular modeling study suggested that compound 14 fitted well with binding pocket, and formed the key ionic bond with His291 and Arg328. In acetaminophen-induced acute liver injury model, compound 14 exerts better therapeutic effect than that of AUR, which highlighting its pharmacological potential in the treatment of drug-induced liver injury.

Keywords

FXR; N-acetyl-p-aminophenol.

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