Abstract
Pteridinone-based Toll-like receptor 7 (TLR7) agonists were identified as potent and selective alternatives to the previously reported adenine-based agonists, leading to the discovery of GS-9620. Analogues were optimized for the immunomodulatory activity and selectivity versus other TLRs, based on differential induction of key cytokines including interferon α (IFN-α) and tumor necrosis factor α (TNF-α). In addition, physicochemical properties were adjusted to achieve desirable in vivo pharmacokinetic and pharmacodynamic properties. GS-9620 is currently in clinical evaluation for the treatment of chronic hepatitis B (HBV) infection.
MeSH terms
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Administration, Oral
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Animals
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Antiviral Agents / chemistry
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Antiviral Agents / metabolism
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Antiviral Agents / pharmacokinetics
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Antiviral Agents / pharmacology*
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Dogs
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Drug Evaluation, Preclinical
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Female
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Hepatitis B, Chronic / drug therapy*
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Humans
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Male
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Mice
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Microsomes, Liver / metabolism
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Models, Molecular
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Protein Conformation
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Pteridines / chemistry
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Pteridines / metabolism
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Pteridines / pharmacokinetics
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Pteridines / pharmacology*
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Rats
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Structure-Activity Relationship
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Substrate Specificity
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Toll-Like Receptor 7 / agonists*
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Toll-Like Receptor 7 / chemistry
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Toll-Like Receptor 7 / metabolism
Substances
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Antiviral Agents
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Pteridines
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Toll-Like Receptor 7