Discovery and Characterization of GLPG3808, a PAPD5/7 Inhibitor for Suppression of Hepatitis B Viral Infections

Hepatitis B virus (HBV) is the most common and severe liver infection, and approximately 260 million people suffer from chronic hepatitis B infection, which can lead to life-threatening conditions such as cirrhosis and hepatocellular carcinoma. Treatment of the infection resulting in sustained clearance of hepatitis B surface antigen (HBsAg) is considered as "functional cure". Although current treatments effectively reduce the viral load, few agents have achieved HBsAg reduction. In this context, we focused on PAPD5/7 inhibitors as effective HBsAg suppressors. Leveraging a 2-oxo-5<i>H</i>-chromeno[4,3-<i>b</i>]pyridine template, we exploited a chemical enablement strategy for broad combinatorial explorations. This rapidly led to the identification of optimal groups not seen in other PAPD5/7 inhibitors. The effort culminated with the extremely potent preclinical candidate GLPG3808, which was active in an animal model of HBV infection. Progression was halted after neurological findings in a 13-week toxicological study in rat.