2. Academic Validation
  3. Design, synthesis and FXR partial agonistic activity of anthranilic acid derivatives bearing aryloxy moiety as therapeutic agents for metabolic dysfunction-associated steatohepatitis

Design, synthesis and FXR partial agonistic activity of anthranilic acid derivatives bearing aryloxy moiety as therapeutic agents for metabolic dysfunction-associated steatohepatitis

  • Bioorg Chem. 2024 Dec:153:107940. doi: 10.1016/j.bioorg.2024.107940.
Cong Chen 1,  Xianghui Zhou 2,  Wa Cheng 3,  Xin Li 4,  Bing Zhang 3,  Jiaojiao Tu 3,  Jieyun Meng 3,  Yanfen Peng 3,  Xiaoqun Duan 5,  Qiming Yu 6,  Xiangduan Tan 7
Affiliations

Affiliations

  • 1 Guangxi Key Laboratory of Drug Discovery and Optimization, College of Pharmacy, Guilin Medical University, Guilin 541199, China; Guangxi Key Laboratory of Environmental Exposure Omics and Life Cycle Health, College of Public Health, Guilin Medical University, Guilin 541199, China.
  • 2 Guangxi Key Laboratory of Drug Discovery and Optimization, College of Pharmacy, Guilin Medical University, Guilin 541199, China; Department of Pharmacy, Yunfu People's Hospital, Yunfu 527300, China.
  • 3 Guangxi Key Laboratory of Drug Discovery and Optimization, College of Pharmacy, Guilin Medical University, Guilin 541199, China.
  • 4 School of Life Sciences, Guangzhou University, Guangzhou 510006, China.
  • 5 Guangxi Key Laboratory of Drug Discovery and Optimization, College of Pharmacy, Guilin Medical University, Guilin 541199, China. Electronic address: robortduan@163.com.
  • 6 Guangxi Key Laboratory of Environmental Exposure Omics and Life Cycle Health, College of Public Health, Guilin Medical University, Guilin 541199, China. Electronic address: qm_yu19@glmc.edu.cn.
  • 7 Guangxi Key Laboratory of Drug Discovery and Optimization, College of Pharmacy, Guilin Medical University, Guilin 541199, China. Electronic address: tandy@glmc.edu.cn.
PMID: 39515132 DOI: 10.1016/j.bioorg.2024.107940
Abstract

Farnesoid X receptor (FXR) is considered a promising therapeutic target for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). Increasing evidence suggests that targeting FXR with full agonists may lead to side effects. FXR partial agonists, which moderately activate FXR signaling, are emerging as a feasible approach to mitigate side effects and address MASH. Herein, a series of novel anthranilic acid derivatives bearing aryloxy moiety were designed and synthesized using a hybrid strategy from the previously identified FXR partial agonists DM175 and AIV-25. Particularly, compound 26 exhibited potent FXR partial agonistic activity in a dual-luciferase reporter gene assay with an EC50 value of 0.09 ± 0.02 µM (75.13 % maximum efficacy relative to OCA). In the MASH mice model, compound 26 significantly ameliorated the pathological features of the liver, including steatosis, inflammation, and fibrosis. In addition, compound 26 displayed high selectivity, good oral bioavailability, high liver distribution, as well as an acceptable safety profile. Molecular simulation studies showed that compound 26 fitted well with the binding site of FXR. Collectively, these findings demonstrated that compound 26 might serve as a promising candidate targeting FXR for MASH treatment.

Keywords

Anthranilic acid derivative; Bile acid; Farnesoid X receptor; Hybrid; MASH; Metabolic dysfunction-associated steatohepatitis; Partial agonists.

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