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Identification and Optimization of Pyrrolo[3,2-d]pyrimidine Toll-like Receptor 7 (TLR7) Selective Agonists for the Treatment of Hepatitis B.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2017 Jul 27; Vol. 60 (14), pp. 6137-6151. Date of Electronic Publication: 2017 Jul 14. - Publication Year :
- 2017
-
Abstract
- Pyrrolo[3,2-d]pyrimidines were identified as a new series of potent and selective TLR7 agonists. Compounds were optimized for their activity and selectivity over TLR8. This presents an advantage over recently described scaffolds that have residual TLR8 activity, which may be detrimental to the tolerability of the candidate drug. Oral administration of the lead compound 54 effectively induced a transient interferon stimulated gene (ISG) response in mice and cynomolgus monkeys. We aimed for a high first pass effect, limiting cytokine induction systemically, and demonstrated the potential for the immunotherapy of viral hepatitis.
- Subjects :
- Administration, Oral
Animals
Antiviral Agents pharmacokinetics
Antiviral Agents pharmacology
Dendritic Cells drug effects
Dendritic Cells metabolism
Dogs
Female
Genes, Reporter
HEK293 Cells
Hepatitis B immunology
Humans
Immunotherapy
Interferons biosynthesis
Macaca fascicularis
Madin Darby Canine Kidney Cells
Mice, Inbred C57BL
Molecular Docking Simulation
Pyrimidines pharmacokinetics
Pyrimidines pharmacology
Pyrroles pharmacokinetics
Pyrroles pharmacology
Rats
Structure-Activity Relationship
Toll-Like Receptor 7 genetics
Toll-Like Receptor 8 agonists
Toll-Like Receptor 8 genetics
Antiviral Agents chemical synthesis
Hepatitis B drug therapy
Pyrimidines chemical synthesis
Pyrroles chemical synthesis
Toll-Like Receptor 7 agonists
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 60
- Issue :
- 14
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 28671847
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.7b00365