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

Disruption of the HBV viral life cycle with small molecules that prevent the encapsidation of pregenomic RNA and viral polymerase through binding to HBV core protein is a clinically validated approach to inhibiting HBV viral replication. Herein we report the further optimisation of clinical candidate AB-506 through core modification with a focus on increasing oral exposure and oral half-life. Maintenance of high levels of anti-HBV cellular potency in conjunction with improvements in pharmacokinetic properties led to multi-log 10 reductions in serum HBV DNA following low, once-daily oral dosing for key analogues in a preclinical animal model of HBV replication. Pharmacokinetic optimisation of the clinical candidate HBV capsid inhibitor AB-506 resulted in dramatic improvements in oral exposure and half-life providing compound 17 which demonstrated low dose QD efficacy in a mouse model of HBV replication.