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.
MeSH terms
-
Animals
-
Antiviral Agents / chemical synthesis
-
Antiviral Agents / chemistry*
-
Antiviral Agents / pharmacokinetics
-
Antiviral Agents / pharmacology
-
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
-
Macaca fascicularis
-
Mice
-
Mice, Inbred C57BL
-
Molecular Docking Simulation
-
Pyrimidines / chemical synthesis
-
Pyrimidines / chemistry*
-
Pyrimidines / pharmacokinetics
-
Pyrimidines / pharmacology
-
Rats, Sprague-Dawley
-
Stereoisomerism
-
Structure-Activity Relationship
-
Toll-Like Receptor 7 / agonists*
-
Toll-Like Receptor 8 / agonists*
-
Virus Replication / drug effects
Substances
-
Antiviral Agents
-
Cytokines
-
Pyrimidines
-
Toll-Like Receptor 7
-
Toll-Like Receptor 8