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

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.