Discovery of RG7834:
The First-in-Class Selective
and Orally Available Small Molecule Hepatitis B Virus Expression Inhibitor
with Novel Mechanism of Action

Han, Xingchun; Zhou, Chengang; Jiang, Min; Wang, Yongguang; Wang, Jianhua; Cheng, Zhanling; Wang, Min; Liu, Yongqiang; Liang, Chungen; Wang, Jianping; Wang, Zhanguo; Weikert, Robert; Lv, Wenzhe; Xie, Jianxun; Yu, Xin; Zhou, Xue; Luangsay, Souphalone; Shen, Hong C.; Mayweg, Alexander V.; Javanbakht, Hassan; Yang, Song

doi:10.1021/acs.jmedchem.8b01245.s001

jm8b01245_si_001.pdf (615.95 kB)

Discovery of RG7834: The First-in-Class Selective and Orally Available Small Molecule Hepatitis B Virus Expression Inhibitor with Novel Mechanism of Action

journal contribution

posted on 2018-10-04, 00:00 authored by Xingchun Han, Chengang Zhou, Min Jiang, Yongguang Wang, Jianhua Wang, Zhanling Cheng, Min Wang, Yongqiang Liu, Chungen Liang, Jianping Wang, Zhanguo Wang, Robert Weikert, Wenzhe Lv, Jianxun Xie, Xin Yu, Xue Zhou, Souphalone Luangsay, Hong C. Shen, Alexander V. Mayweg, Hassan Javanbakht, Song Yang

Chronic hepatitis B virus (HBV) infection is a serious public health burden, and current therapies cannot achieve satisfactory cure rate. There are high unmet medical needs of novel therapeutic agents with differentiated mechanism of action (MOA) from the current standard of care. RG7834, a compound from the dihydroquinolizinone (DHQ) chemical series, is a first-in-class highly selective and orally bioavailable HBV inhibitor which can reduce both viral antigens and viral DNA with a novel mechanism of action. Here we report the discovery of RG7834 from a phenotypic screening and the structure–activity relationship (SAR) of the DHQ chemical series. RG7834 can selectively inhibit HBV but not other DNA or RNA viruses in a virus panel screening. Both in vitro and in vivo profiles of RG7834 are described herein, and the data support further development of this compound as a chronic HBV therapy.