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

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<