Isoquinolinone-based HBV capsid assembly modulators that
bind at
the dimer:dimer interface of HBV core protein have been shown to suppress
viral replication in chronic hepatitis B patients. Analysis of their
binding mode by protein X-ray crystallography has identified a region
of the small molecule where the application of a constraint can lock
the preferred binding conformation and has allowed for further optimization
of this class of compounds. Key analogues demonstrated single digit
nM EC50 values in reducing HBV DNA in a HepDE19 cellular
assay in addition to favorable ADME and pharmacokinetic properties,
leading to a high degree of oral efficacy in a relevant in
vivo hydrodynamic injection mouse model of HBV infection,
with 12e effecting a 3 log10 decline in serum
HBV DNA levels at a once daily dose of 1 mg/kg. Additionally, maintenance
of activity was observed in clinically relevant HBV core protein variants
T33N and I105T.