2. Academic Validation
  3. Identification of dihydroquinolizinone derivatives with cyclic ether moieties as new anti-HBV agents

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

  • Eur J Med Chem. 2022 Aug 5;238:114518. doi: 10.1016/j.ejmech.2022.114518.
Xiaoyu Qin 1,  Lu Yang 1,  Xican Ma 1,  Bin Jiang 2,  Shuo Wu 1,  Apeng Wang 1,  Shijie Xu 1,  Wenhao Wu 2,  Huijuan Song 1,  Na Du 1,  Kai Lv 3,  Yuhuan Li 4,  Mingliang Liu 5
Affiliations

Affiliations

  • 1 CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
  • 2 CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China; Department of Pharmaceutical Chemistry, School of Pharmacy, Hebei Medical University, Shijiazhuang, 050017, China.
  • 3 CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: lvkailk@hotmail.com.
  • 4 CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: yuhuanlibj@126.com.
  • 5 CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: lmllyx@126.com.
PMID: 35700597 DOI: 10.1016/j.ejmech.2022.114518
Abstract

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.

Keywords

Anti-HBV; HBeAg; HBsAg; Neurotoxicity; RG7834.

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