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

• Published in: Journal of medicinal chemistry Vol. 59; no. 17; pp. 7936 - 7949
• Main Authors: McGowan, David, Herschke, Florence, Pauwels, Frederik, Stoops, Bart, Last, Stefaan, Pieters, Serge, Scholliers, Annick, Thoné, Tine, Van Schoubroeck, Bertrand, De Pooter, Dorien, Mostmans, Wendy, Khamlichi, Mourad Daoubi, Embrechts, Werner, Dhuyvetter, Deborah, Smyej, Ilham, Arnoult, Eric, Demin, Samuël, Borghys, Herman, Fanning, Gregory, Vlach, Jaromir, Raboisson, Pierre
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 08.09.2016; Amer Chemical Soc
• Subjects: Animals; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacokinetics; Antiviral Agents - pharmacology; Chemistry, Medicinal; Computer Simulation; Cytokines - biosynthesis; Dogs; Hepatitis B - drug therapy; Hepatitis B - virology; Hepatitis B virus - drug effects; Hepatitis B virus - physiology; High-Throughput Screening Assays; Humans; Life Sciences & Biomedicine; Macaca fascicularis; Mice; Mice, Inbred C57BL; Molecular Docking Simulation; Pharmacology & Pharmacy; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacokinetics; Pyrimidines - pharmacology; Rats, Sprague-Dawley; Science & Technology; Stereoisomerism; Structure-Activity Relationship; Toll-Like Receptor 7 - agonists; Toll-Like Receptor 8 - agonists; Virus Replication - drug effects; IMMUNITY; DENDRITIC CELLS; POTENT INTERFERON INDUCERS; SINGLE-STRANDED RNA; BIOLOGICAL EVALUATION; INFECTION; TOLL-LIKE-RECEPTOR-7; LINKING INNATE; CD8(+) T-CELLS; VIRAL CLEARANCE
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.6b00747

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.