Design and optimisation of orally active TLR7 agonists for the treatment of hepatitis C virus infection

The synthesis and structure–activity relationships of a series of novel interferon inducers are described. Pharmacokinetic studies and efficacy assessment of a series of 8-oxo-3-deazapurine analogues led to the identification of compound 33, a potent and selective agonist of the TLR7 receptor with a...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2011-04, Vol.21 (8), p.2389-2393
Main Authors: Tran, Thien-Duc, Pryde, David C., Jones, Peter, Adam, Fiona M., Benson, Neil, Bish, Gerwyn, Calo, Frederick, Ciaramella, Guiseppe, Dixon, Rachel, Duckworth, Jonathan, Fox, David N.A., Hay, Duncan A., Hitchin, James, Horscroft, Nigel, Howard, Martin, Gardner, Iain, Jones, Hannah M., Laxton, Carl, Parkinson, Tanya, Parsons, Gemma, Proctor, Katie, Smith, Mya C., Smith, Nicholas, Thomas, Amy
Format: Article
Language:English
Subjects:
Administration, Oral
agonists
Aldehyde oxidase
animal models
Animals
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antiviral agents
Antiviral Agents - chemical synthesis
Antiviral Agents - chemistry
Antiviral Agents - therapeutic use
Biological and medical sciences
Drug Design
HCV
Hepacivirus - drug effects
Hepatitis C virus
Interferon inducer
interferons
Medical sciences
Mice
Models, Animal
pharmacokinetics
Pharmacology. Drug treatments
Purines - chemistry
Purines - pharmacokinetics
Purines - therapeutic use
Rats
RNA Virus Infections - drug therapy
Structure-Activity Relationship
structure-activity relationships
TLR7 agonist
Toll-like receptor 7
Toll-Like Receptor 7 - agonists
Toll-Like Receptor 7 - metabolism
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Summary:The synthesis and structure–activity relationships of a series of novel interferon inducers are described. Pharmacokinetic studies and efficacy assessment of a series of 8-oxo-3-deazapurine analogues led to the identification of compound 33, a potent and selective agonist of the TLR7 receptor with an excellent in vivo efficacy profile in a mouse model. The synthesis and structure–activity relationships of a series of novel interferon inducers are described. Pharmacokinetic studies and efficacy assessment of a series of 8-oxo-3-deazapurine analogues led to the identification of compound 33, a potent and selective agonist of the TLR7 receptor with an excellent in vivo efficacy profile in a mouse model.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2011.02.092