Rational design, synthesis, and evaluations of HBV capsid assembly modulators featuring a core of 2-amino-5-(2-amino-2-oxoacetyl)-4-methylthiophene-3-carboxamide.

Hepatitis B virus (HBV) remains a major global health challenge, where current therapies offer limited functional cure rates and are often burdened by adverse effects. HBV capsid assembly modulators (CAMs) represent a promising therapeutic approach by targeting viral nucleocapsid formation. Compounds GLP-26 and b were reported as CAMs exhibiting potent antiviral activity. A series of HBV CAMs featuring the core of 2-amino-5-(2-amino-2-oxoacetyl)-4-methylthiophene-3-carboxamide were designed and synthesized by integrating the acetamide fragment of GLP-26 with the pentavalent aromatic amine of b. Among them, compound 14Bc exhibited potent inhibitory activity on HBV DNA replication in HepG2.2.15 cells, alongside notable metabolic stability. Further biological evaluations indicated that 14Bc is an effective regulatory factor for capsid assembly, exhibiting strong antiviral properties that surpasses that of a CAM currently undergoing advanced clinical evaluation for chronic hepatitis B treatment. Moreover, 14Bc showed improved metabolic and pharmacokinetic profiles and in vivo distribution relative to GLP-26, thereby augmenting its potential as a therapeutic candidate for managing chronic hepatitis B.