Rational Design,\nSynthesis, and Structure–Activity\nRelationship of a Novel Isoquinolinone-Based Series of HBV Capsid\nAssembly Modulators Leading to the Identification of Clinical Candidate\nAB-836

Inhibition of Hepatitis B Virus (HBV) replication by\nsmall molecules\nthat modulate capsid assembly and the encapsidation of pgRNA and viral\npolymerase by HBV core protein is a clinically validated approach\ntoward the development of new antivirals. Through definition of a\nminimal pharmacophore, a series of isoquinolinone-based capsid assembly\nmodulators (CAMs) was identified. Structural biology analysis revealed\nthat lead molecules possess a unique binding mode, exploiting electrostatic\ninteractions with accessible phenylalanine and tyrosine residues.\nKey analogs demonstrated excellent primary potency, absorption, distribution,\nmetabolism, and excretion (ADME) and pharmacokinetic properties, and\nefficacy in a mouse model of HBV. The optimized lead also displayed\npotent inhibition of capsid uncoating in HBV-infected HepG2 cells\nexpressing the sodium-taurocholate cotransporting polypeptide (NTCP)\nreceptor, affecting the generation of HBsAg and cccDNA establishment.\nBased on these results, isoquinolinone derivative <b>AB-836</b> was advanced into clinical development. In Phase 1b trials, <b>AB-836</b> demonstrated >3 log<sub>10</sub> reduction in serum\nHBV DNA, however, further development was discontinued due to the\nobservation of incidental alanine aminotransferase (ALT) elevations.