Discovery of Linvencorvir (RG7907), a Hepatitis B Virus Core Protein Allosteric Modulator, for the Treatment of Chronic HBV Infection

Described herein is the first-time disclosure of Linvencorvir
(RG7907),
a clinical compound and a hepatitis B virus (HBV) core protein allosteric
modulator, for the treatment of chronic HBV infection. Built upon
the core structure of hetero aryl dihydropyrimidine, RG7907 was rationally
designed by combining all the drug-like features of low CYP3A4 induction,
potent anti-HBV activity, high metabolic stability, low hERG liability,
and favorable animal pharmacokinetic (PK) profiles. In particular,
the chemistry strategy to mitigate CYP3A4 induction through introducing
a large, rigid, and polar substituent at the position that has less
interaction with the therapeutic biological target (HBV core proteins
herein) is of general interest to the medicinal chemistry community.
RG7907 demonstrated favorable animal PK, pharmacodynamics, and safety
profiles with sufficient safety margins supporting its clinical development
in healthy volunteers and HBV-infected patients.