Discovery of 4-aminophenylacetamide derivatives as intestine-specific farnesoid X receptor antagonists for the potential treatment of nonalcoholic steatohepatitis

  • Eur J Med Chem. 2023 Nov 27:264:115992. doi: 10.1016/j.ejmech.2023.115992.
Cong Chen  1 ,  Bing Zhang  1 ,  Jiaojiao Tu  1 ,  Yanfen Peng  1 ,  Yihuan Zhou  1 ,  Xinping Yang  1 ,  Qiming Yu  2 ,  Xiangduan Tan  3
Affiliations
  • 1. Guangxi Key Laboratory of Drug Discovery and Optimization, College of Pharmacy, Guilin Medical University, Guilin 541199, China.
  • 2. Guangxi Key Laboratory of Environmental Exposure Omics and Life Cycle Health, College of Public Health, Guilin Medical University, Guilin 541199, China. Electronic address: [email protected].
  • 3. Guangxi Key Laboratory of Drug Discovery and Optimization, College of Pharmacy, Guilin Medical University, Guilin 541199, China. Electronic address: [email protected].
PMID: 38043493 DOI: 10.1016/j.ejmech.2023.115992
Abstract

Farnesoid X receptor (FXR) plays a key role in bile acid homeostasis, inflammation, fibrosis, lipid and glucose metabolism and is emerging as a promising therapeutic target for nonalcoholic steatohepatitis (NASH). Emerging evidence suggested that intestine-specific FXR antagonists exhibited remarkable metabolic improvements and slowed NASH progression. In this study, we discovered several potent FXR antagonists using a multistage ligand- and structure-based virtual screening approach. Notably, compound V023-9340, which possesses a 4-aminophenylacetamide scaffold, emerged as the most potent FXR antagonist with an IC50 value of 4.27 μM. In vivo, V023-9340 demonstrated selective accumulation in the intestine, substantially ameliorating high-fat diet (HFD)-induced NASH in mice by mitigating hepatic steatosis and inflammation. Mechanistic studies revealed that V023-9340 strongly inhibited intestinal FXR while concurrently feedback-activated hepatic FXR. Further structure-activity relationship optimization employing V023-9340 has resulted in the synthesis of a more efficacious compound V02-8 with an IC50 value of 0.89 μM, which exhibited a 4.8-fold increase in FXR antagonistic activity compared to V023-9340. In summary, 4-aminophenylacetamide derivative V023-9340 represented a novel intestine-specific FXR antagonist and showed improved effects against HFD-induced NASH in mice, which may serve as a promising lead in discovering potential therapeutic drugs for NASH treatment.

Keywords
4-Aminophenylacetamide; Farnesoid X receptor antagonists; Intestine-specific; Nonalcoholic steatohepatitis; Virtual screening.
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