Identification of dihydroquinolizinone derivatives with cyclic ether moieties as new anti-HBV agents

RG7834, a dihydroquinolizinone (DHQ) candidate developed by Roche Pharma, was expected to realize the "functional cure of HBV". However, it was dismissed in phase I clinical trial due to its neurotoxicity. In this study, a series of new DHQ derivatives containing a cyclic ether or benzo-fused (cyclic) ether moiety were designed, synthesized and evaluated for their in vitro activity. Many of them exhibited potent inhibition activity against HBsAg, HBeAg and HBV DNA. More importantly, in the in vitro neurotoxicity evaluation, most of the PC12 cells treated with RG7834 became round and even shrunken with the disappearance of neurites; in contrast, most of the cells treated by (2'S, 6S)-1a, showed similar morphological structures to the control group with clearly visible neurites, indicating that (2'S, 6S)-1a could have improved neurotoxicity. The first study of the structure-neurotoxicity relationship of DHQs paves the way for the future development of DHQs.