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TitleDiscovery of a highly potent series of TLR7 agonists
Publication TypeJournal Article
Year of Publication2011
AuthorsJones, P., Pryde D.C., Tran T.-D., Adam F.M., Bish G., Calo F., Ciaramella G., Dixon R., Duckworth J., Fox D.N.A., Hay D.A., Hitchin J., Horscroft N., Howard M., Laxton C., Parkinson T., Parsons G., Proctor K., Smith M.C., Smith N., and Thomas A.
JournalBioorganic and Medicinal Chemistry Letters
Pagination5939 - 5943
Date Published2011
ISSN0960894X (ISSN)
Keywordsaldehyde oxidase, animal experiment, Animals, Antiviral Agents, area under the curve, article, distribution volume, Dose-Response Relationship, Drug, drug clearance, Drug Discovery, Drug Evaluation, Preclinical, drug half life, drug potency, drug receptor binding, Hepacivirus, hepatitis C, Hepatitis C virus, Humans, Injections, Intravenous, Interferon Inducers, Interferons, Microsomes, Liver, Molecular Targeted Therapy, Molecular weight, nonhuman, Oxidation, purine derivative, Purines, pyridine derivative, rat, Rats, Rattus, Solubility, Stereoisomerism, structure activity relation, Structure-Activity Relationship, toll like receptor 7, toll like receptor 7 agonist, toll like receptor agonist, Toll-Like Receptor 7, unclassified drug
AbstractThe discovery of a series of highly potent and novel TLR7 agonist interferon inducers is described. Structure-activity relationships are presented, along with pharmacokinetic studies of a lead molecule from this series of N9-pyridylmethyl-8-oxo-3-deazapurine analogues. A rationale for the very high potency observed is offered. An investigation of the clearance mechanism of this class of compounds in rat was carried out, resulting in aldehyde oxidase mediated oxidation being identified as a key component of the high clearance observed. A possible solution to this problem is discussed. © 2011 Elsevier Ltd. All rights reserved.

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