Preclinical characterization of AB-506, an inhibitor of HBV replication targeting the viral core protein

The identification of highly efficacious functionalised tetrahydrocyclopenta[c]pyrroles as inhibitors of HBV viral replication through modulation of HBV capsid assembly

“…These data are consistent with the aminoindane analogues where the ( S )-enantiomer of AB-506 was markedly more potent than its ( R )-enantiomer. 25 As with AB-506, neither 10a nor 10b showed any significant cytotoxicity in the HepDE19 cell line at concentrations up to 25 μM. The observed anti-HBV activity of this initial example supports the hypothesis that the N -methyl pyrrole is a suitable replacement for the phenyl group within the aminoindane and provides a comparative level of potency.…”

“…We have previously reported the pre-clinical antiviral profile of the potent class II capsid inhibitor AB-506 (ref. 25 and 27) (Fig. 1).…”

“…23 and 24) and AB-506 (ref. 25) are representative class II capsid assembly modulators and disrupt the viral life cycle through accelerating the formation of nucleocapsids which cannot produce rcDNA and subsequently cannot produce infectious virions capable of infecting other hepatocytes. NVR 3-778, representing the well-studied sulfamoyl benzamide chemotype, 9,19,26 was the first capsid assembly modulator to enter clinical studies and provided proof of concept for this class of antiviral agent.…”

Safety, pharmacokinetics and antiviral activity of ABI‐H2158, a hepatitis B virus core inhibitor: A randomized, placebo‐controlled phase 1 study

“…Core inhibitors have demonstrated pangenotypic antiviral activity 16 . In addition, resistance has not been observed when core inhibitors are combined with NrtIs 17 . Vebicorvir—a novel, pangenotypic, first‐generation, investigational core inhibitor—was safe, well tolerated and decreased serum HBV nucleic acids in patients with cHBV as a monotherapy in a Phase 1b study 18 and in combination with NrtIs in two Phase 2 studies 19,20 .…”

“…16 In addition, resistance has not been observed when core inhibitors are combined with NrtIs. 17 Vebicorvir-a novel, pangenotypic, first-generation, investigational core inhibitor-was safe, well tolerated and decreased serum HBV nucleic acids in patients with cHBV as a monotherapy in a Phase 1b study 18 and in combination with NrtIs in two Phase 2 studies. 19,20 Interference with multiple steps of viral replication distinct from existing treatments make HBV core inhibitors important candidates for therapeutic evaluation.…”