Discovery of Non-Carboxylic Steroidal FXR Agonist as a Promising Preclinical Candidate for Metabolic Dysfunction-Associated Steatohepatitis

  • J Med Chem. 2026 May 28;69(10):11872-11899. doi: 10.1021/acs.jmedchem.5c03220.
Zhe Zhang  1  2  3 ,  Xiaomin Zheng  3 ,  Chuyu Dong  3 ,  Pengru Li  3 ,  Yi Lin  3 ,  Zhenzhu Sun  3 ,  Wenjing Li  3 ,  Xiaoxiao Liu  2 ,  Jing Li  3 ,  Shan Li  3 ,  Bing Gu  2 ,  Lei Zhang  3
Affiliations
  • 1. Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), South China University of Technology, Guangzhou 510000, China.
  • 2. Department of Clinical Laboratory Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510000, China.
  • 3. MOE International Joint Lab for Synthetic Biology and Medicines, School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510000, China.
PMID: 42102281 DOI: 10.1021/acs.jmedchem.5c03220
Abstract

Metabolic dysfunction-associated steatohepatitis (MASH) presents a growing global health challenge, underscoring the need for effective therapies. Farnesoid X receptor (FXR) represents a promising therapeutic target against MASH. This study reported the rational design of a novel non-carboxylic steroidal FXR Agonist, compound 27, which demonstrated effective FXR agonistic activity (TR-FRET: EC50 = 10 ± 3 nM; Luciferase Reporter: EC50 = 128 ± 9 nM) alongside reduced activation of the off-target receptor MRGPRX4 compared to OCA. Compound 27 exhibited high oral bioavailability in rats (F = 70.30%) and activation of hTGR5 (HTRF: EC50 = 1360 nM). In vivo studies confirmed its efficacy: attenuated Collagen deposition in the CCl4-induced liver fibrosis model and improved steatosis and inflammatory foci in the MASH model. In summary, compound 27 achieves its promising efficacy and safety profile by the dual-path strategy that enhances FXR/TGR5 activity while suppressing MRGPRX4, supporting its further development as a novel therapeutic agent for MASH.

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