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-5H-chromeno­[4,3-b]­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.