Discovery and Pre-Clinical Characterization of Third-Generation 4‑H Heteroaryldihydropyrimidine (HAP) Analogues as Hepatitis B Virus (HBV) Capsid Inhibitors

Described
herein are the discovery and structure–activity relationship
(SAR) studies of the third-generation 4-H heteroaryldihydropyrimidines
(4-H HAPs) featuring the introduction of a C6 carboxyl group as novel
HBV capsid inhibitors. This new series of 4-H HAPs showed improved
anti-HBV activity and better drug-like properties compared to the
first- and second-generation 4-H HAPs. X-ray crystallographic study
of analogue 12 (HAP_R01) with Cp149 Y132A mutant hexamer
clearly elucidated the role of C6 carboxyl group played for the increased
binding affinity, which formed strong hydrogen bonding interactions
with capsid protein and coordinated waters. The representative analogue 10 (HAP_R10) was extensively characterized in vitro (ADMET)
and in vivo (mouse PK and PD) and subsequently selected for further
development as oral anti-HBV infection agent.