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

  • J Med Chem. 2026 Feb 12;69(3):2006-2024. doi: 10.1021/acs.jmedchem.5c01703.
Oscar Mammoliti  1 ,  Adeline Palisse  1 ,  Ann De Blieck  1 ,  Caroline Joannesse  1 ,  Brigitte Allart  1 ,  Chris Laruelle  1 ,  Alex Jaunet  1 ,  Tom De Munck  1 ,  Steven Van der Plas  1 ,  Béranger Duthion  2 ,  Cornel Catana  1 ,  Thierry Christophe  1 ,  Nicolas Houvenaghel  1 ,  Vincent Porte  1 ,  Juan-Miguel Jimenez  1 ,  Filip Beirinckx  1 ,  Annelies Iwens  1 ,  Melanie Chypre  1 ,  Kim De Rijck  1 ,  Nele Vandervoort  1 ,  Luc Nelles  1 ,  Philippe Clément-Lacroix  2 ,  Carole Delachaume  2 ,  Cécile Belleville  2 ,  Line Oste  1 ,  Monica Borgonovi  2 ,  Emanuelle Wakselman  2 ,  Mia Jans  1 ,  Josee Hue-Perron  2 ,  Laurent Saniere  2 ,  Reginald Brys  1 ,  Martin Andrews  1
Affiliations
  • 1. Galapagos NV, Generaal De Wittelaan L11 A3, 2800 Mechelen, Belgium.
  • 2. Galapagos SASU, 102 avenue Gaston Roussel, 93230 Romainville, France.
PMID: 41557942 DOI: 10.1021/acs.jmedchem.5c01703
Abstract

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.

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