Discovery of Novel Pyrimidine-Based Capsid Assembly Modulators as Potent Anti-HBV Agents

Core
assembly modulators of viral capsid proteins have been developed
as an effective treatment of chronic hepatitis B virus (HBV) infection.
In this study, we synthesized novel potent pyrimidine derivatives
as core assembly modulators, and their antiviral effects were evaluated
in in vitro and in vivo biological experiments. One of the synthesized
derivatives, compound 23h (R1 = MeSO2, R2 = 1-piperidin-4-amine, R3 = 3-Cl-4-F-aniline)
displayed potent inhibitory effects in the in vitro assays (52% inhibition
in the protein-based assay at 100 nM and an IC50 value
of 181 nM in the serum HBV DNA quantification assay). Moreover, treatment
with compound 23h for 5 weeks significantly decreased
serum levels of HBV DNA levels (3.35 log reduction) in a human liver-chimeric
uPA/SCID mouse model, and these effects were significantly increased
when 23h was combined with tenofovir, a nucleotide analogue
inhibitor of reverse transcriptase used for the treatment of HBV infection.