2. Academic Validation
  3. Discovery of novel potent indazole-based FXR agonists via scaffold hopping for MASH treatment

Discovery of novel potent indazole-based FXR agonists via scaffold hopping for MASH treatment

  • Eur J Med Chem. 2026 Jan 5:301:118203. doi: 10.1016/j.ejmech.2025.118203.
Da-Yu Shi 1,  Xin-Wei Shi 1,  Hang Shi 2,  Jing Yu 2,  Qing-Hua Li 3,  Ping Tian 4,  Cheng Huang 5,  Dingding Gao 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, China; School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, China.
  • 2 School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, China.
  • 3 State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, China. Electronic address: qinghuali@shutcm.edu.cn.
  • 4 State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, China. Electronic address: tianping@shutcm.edu.cn.
  • 5 School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, China. Electronic address: chuang@shutcm.edu.cn.
  • 6 State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, China. Electronic address: gaodingding@shutcm.edu.cn.
PMID: 41027177 DOI: 10.1016/j.ejmech.2025.118203
Abstract

The farnesoid X receptor (FXR) plays a crucial role in regulating bile acid homeostasis, inflammation, fibrosis, as well as glucose and lipid metabolism, positioning it as a promising target for the treatment of Metabolic Associated Steatohepatitis (MASH). LMB763 (Nidufexor), a clinical-stage FXR Agonist developed by Novartis, has demonstrated efficacy in alleviating hepatic steatosis, inflammation, and fibrosis in preclinical MASH models. Using LMB763 as a lead compound, a series of novel compounds were designed and synthesized via a scaffold hopping strategy. The lead compound E2 exhibited potent FXR Agonist activity with an EC50 value of 0.097 ± 0.009 μM and favorable hepatic microsomal metabolic stability. Additionally, compound E2 displayed good selectivity against related nuclear receptors, including LXRα/β, PPARα/γ/δ, PXR, and TGR5. In vivo evaluation confirmed that compound E2 improved hepatic steatosis in high-fat diet (HFD)-induced MASH mouse model. These findings highlight E2 as a promising candidate for further development and provide valuable insights into the design of selective FXR agonists for MASH treatment.

Keywords

FXR; Indazole scaffold; MASH; Scaffold hopping strategy; Structure-activity relationships.

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