HBsAg Suppression by a New Series of HBV RNA Destabilizers: Discovery and Effects on In Vitro Neurite Outgrowth

Chronic hepatitis B virus (HBV) infection remains a major global health burden. Despite the widespread availability of effective prophylactic vaccines, millions of people are at risk for complications of chronic HBV infection. Nucleoside polymerase inhibitors are highly effective at suppressing the production of infectious viral particles and decreasing the risk of cirrhosis; however, viral clearance remains very rare, which means that treatment is often lifelong. Alternative therapeutic agents with a new mode of action giving sustained activity of treatment are needed. We report a new thiochromeno[4,3- b ]pyridine-based scaffold, which targets hepatitis B surface antigen (HBsAg). Suppression of HBsAg in patients is currently thought to be critical for immune reactivation, allowing durable response in patients. We describe the medicinal chemistry approach taken to advance the series, including the in vitro neurite outgrowth assay used to evaluate the risk of neurotoxicity seen in other clinical candidates.