Development of dihydroquinolizinone (DHQ)-based inhibitors for suppression of hepatitis B viral infections

Chronic hepatitis B virus (HBV) infection is a serious public health burden, and current treatments fail to achieve satisfactory cure rates. RG7834 is a novel therapeutic agent with a differentiated mechanism of action (MOA) compared to current standard treatments. However, its Phase I clinical trial was terminated due to neurotoxicity issues. Furthermore, the pharmacokinetic performances of RG7834 are unsatisfactory, leaving significant room for improvement. This article reports some attempts and efforts based on the RG7834 molecule, including enhancing antiviral activity, improving pharmacokinetic performance in various genera. Ultimately, we obtained a preferred molecule 42 that, compared with RG7834, exhibited stronger in-vitro antiviral activity and significantly better pharmacokinetic performance in dogs, and cynomolgus monkeys. 42 demonstrated strong in vivo anti-HBV activity in an AAV/HBV mouse model, warranting further investigation.