Abstract
The 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.
Copyright © 2011 Elsevier Ltd. All rights reserved.
MeSH terms
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Aldehyde Oxidase / metabolism
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Animals
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Antiviral Agents / chemical synthesis*
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Antiviral Agents / chemistry
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Antiviral Agents / pharmacokinetics
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Antiviral Agents / pharmacology*
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Dose-Response Relationship, Drug
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Drug Discovery
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Drug Evaluation, Preclinical
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Hepacivirus / drug effects*
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Hepacivirus / physiology
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Hepatitis C / drug therapy*
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Hepatitis C / virology
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Humans
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Injections, Intravenous
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Interferon Inducers / chemical synthesis
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Interferon Inducers / chemistry
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Interferon Inducers / pharmacokinetics
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Interferon Inducers / pharmacology
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Interferons / agonists*
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Microsomes, Liver / metabolism
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Molecular Targeted Therapy
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Molecular Weight
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Purines / chemical synthesis
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Purines / metabolism
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Rats
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Solubility
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Stereoisomerism
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Structure-Activity Relationship
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Toll-Like Receptor 7 / agonists*
Substances
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Antiviral Agents
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Interferon Inducers
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Purines
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Toll-Like Receptor 7
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Interferons
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Aldehyde Oxidase