Design, Synthesis, and Identification of an Orally Bioavailable Small-Molecule HBsAg Production Inhibitor with High...

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.