Discovery of carboxyl-containing heteroaryldihydropyrimidine derivatives as novel HBV capsid assembly modulators with significantly improved metabolic stability.

ABSTRACT: Interfering with the assembly of hepatitis B virus (HBV) capsid is a promising approach for treating chronic hepatitis B (CHB). In order to enhance the metabolic stability and reduce the strong hERG inhibitory effect of HBV capsid assembly modulator (CAM) GLS4, we rationally designed a series of carboxyl-containing heteroaryldihydropyrimidine (HAP) derivatives based on structural biology information combined with medicinal chemistry strategies. The results from biological evaluation demonstrated that compound 6a-25 (EC₅₀ = 0.020 μM) exhibited greater potency than the positive drug lamivudine (EC₅₀ = 0.09 μM), and was comparable to the lead compound GLS4 (EC₅₀ = 0.007 μM). Furthermore, it was observed that 6a-25 reduced levels of core protein (Cp) and capsid

SUBMITTER: Zhao S 

PROVIDER: S-EPMC10650354 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature