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

J Med Chem. 2018 Dec 13;61(23):10619-10634. doi: 10.1021/acs.jmedchem.8b01245. Epub 2018 Oct 17.


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.

MeSH terms

  • Administration, Oral
  • Animals
  • Biological Availability
  • Caco-2 Cells
  • Gene Expression Regulation, Viral / drug effects*
  • Hep G2 Cells
  • Hepatitis B Surface Antigens / metabolism
  • Hepatitis B virus / drug effects*
  • Hepatitis B virus / metabolism
  • Humans
  • Male
  • Mice
  • Phenotype
  • Quinolines / administration & dosage
  • Quinolines / chemistry
  • Quinolines / pharmacokinetics*
  • Quinolines / pharmacology*
  • Structure-Activity Relationship


  • Hepatitis B Surface Antigens
  • Quinolines
  • quinoline