Novel Pyrimidine Toll-like Receptor 7 and 8 Dual Agonists to Treat Hepatitis B Virus

  • J Med Chem. 2016 Sep 8;59(17):7936-49. doi: 10.1021/acs.jmedchem.6b00747.
David McGowan  1 ,  Florence Herschke  1 ,  Frederik Pauwels  1 ,  Bart Stoops  1 ,  Stefaan Last  1 ,  Serge Pieters  1 ,  Annick Scholliers  1 ,  Tine Thoné  1 ,  Bertrand Van Schoubroeck  1 ,  Dorien De Pooter  1 ,  Wendy Mostmans  1 ,  Mourad Daoubi Khamlichi  2 ,  Werner Embrechts  1 ,  Deborah Dhuyvetter  1 ,  Ilham Smyej  1 ,  Eric Arnoult  1 ,  Samuël Demin  1 ,  Herman Borghys  1 ,  Gregory Fanning  1 ,  Jaromir Vlach  1 ,  Pierre Raboisson  1
Affiliations
  • 1. Janssen Infectious Diseases Diagnostics BVBA , Turnhoutseweg 30, 2340 Beerse, Belgium.
  • 2. Villapharma Research S.L. , Parque Tecnológico de Fuente Álamo. Ctra. El Estrecho-Lobosillo, Km. 2.5, Av. Azul 30320 Fuente Álamo de Murcia, Murcia, Spain.
PMID: 27513093 DOI: 10.1021/acs.jmedchem.6b00747
Abstract

Toll-like Receptor (TLR) 7 and 8 agonists can potentially be used in the treatment of viral infections and are particularly promising for chronic hepatitis B virus (HBV) Infection. An internal screening effort identified a pyrimidine Toll-like Receptor 7 and 8 dual agonist. This provided a novel alternative over the previously reported adenine and pteridone type of agonists. Structure-activity relationship, lead optimization, in silico docking, pharmacokinetics, and demonstration of ex vivo and in vivo cytokine production of the lead compound are presented.

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