Design, Synthesis, and Identification of an Orally Bioavailable Small-Molecule HBsAg Production Inhibitor with High Hepatoselectivity and Reduced Neurotoxic Potential

  • J Med Chem. 2026 May 14;69(9):11146-11166. doi: 10.1021/acs.jmedchem.6c00264.
Ruoyu Dong  1  2 ,  Liqin Zhou  1  2 ,  Haiqiao Wang  1  2 ,  Shanghan Ruan  1  3 ,  Xin Meng  1 ,  Jing Feng  1  2 ,  Yushe Yang  1  2  3
Affiliations
  • 1. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 2. School of Pharmacy, University of Chinese Academy of Sciences, Beijing 100049, China.
  • 3. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
PMID: 42028788 DOI: 10.1021/acs.jmedchem.6c00264
Abstract

Hepatitis B surface antigen (HBsAg) is overproduced in chronic HBV Infection, causing immune tolerance and hindering a functional cure. The first HBsAg production inhibitor RG7834 demonstrated potent anti-HBV activity and advanced to Phase I clinical trials but was discontinued due to neurotoxicity concerns. Systematic structure optimization was performed based on RG7834, ultimately leading to the identification of a tetracyclic dihydroquinolizinone (6S,10S)-57, which showed potent HBsAg production inhibition (EC50 = 0.63 nM), no neurite outgrowth inhibition in SH-SY5Y cells at 90 μM for 24 h, and displayed pronounced hepatoselectivity in mice (liver-to-blood ratio = 13.4). In an AAV-HBV mouse model, once-daily oral administration of (6S,10S)-57 produced efficacy comparable to that of RG7834, reducing serum HBsAg by 0.78 and 0.97 log10 at doses of 8 and 24 mg/kg, respectively. These results demonstrate that (6S,10S)-57 can decouple neurite outgrowth inhibition from Antiviral efficacy, supporting the further development of (6S,10S)-57 as a safer, orally available HBsAg production inhibitor.

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