Rational Design, Synthesis, and Structure–Activity Relationship of a Novel Isoquinolinone-Based Series of HBV Capsid Assembly Modulators Leading to the Identification of Clinical Candidate AB-836

Inhibition of Hepatitis B Virus (HBV) replication by
small molecules
that modulate capsid assembly and the encapsidation of pgRNA and viral
polymerase by HBV core protein is a clinically validated approach
toward the development of new antivirals. Through definition of a
minimal pharmacophore, a series of isoquinolinone-based capsid assembly
modulators (CAMs) was identified. Structural biology analysis revealed
that lead molecules possess a unique binding mode, exploiting electrostatic
interactions with accessible phenylalanine and tyrosine residues.
Key analogs demonstrated excellent primary potency, absorption, distribution,
metabolism, and excretion (ADME) and pharmacokinetic properties, and
efficacy in a mouse model of HBV. The optimized lead also displayed
potent inhibition of capsid uncoating in HBV-infected HepG2 cells
expressing the sodium-taurocholate cotransporting polypeptide (NTCP)
receptor, affecting the generation of HBsAg and cccDNA establishment.
Based on these results, isoquinolinone derivative AB-836 was advanced into clinical development. In Phase 1b trials, AB-836 demonstrated >3 log10 reduction in serum
HBV DNA, however, further development was discontinued due to the
observation of incidental alanine aminotransferase (ALT) elevations.