Identification and optimization of pteridinone Toll-like receptor 7 (TLR7) agonists for the oral treatment of viral hepatitis.

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.

• Authors: Paul A Roethle, Ryan M McFadden, Hong Yang, Paul Hrvatin, Hon Hui, Michael Graupe, Brian Gallagher, Jessica Chao, Joseph Hesselgesser, Paul Duatschek, Jim Zheng, Bing Lu, Daniel B Tumas, Jason Perry, Randall L Halcomb
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 56 Issue 18 Pg. 7324-33 (Sep 26 2013) ISSN: 1520-4804 [Electronic] United States
• PMID: 23961878 (Publication Type: Journal Article)

Chemical References

• Antiviral Agents
• Pteridines
• Toll-Like Receptor 7

Topics

• Administration, Oral
• Animals
• Antiviral Agents (chemistry, metabolism, pharmacokinetics, pharmacology)
• Dogs
• Drug Evaluation, Preclinical
• Female
• Hepatitis B, Chronic (drug therapy)
• Humans
• Male
• Mice
• Microsomes, Liver (metabolism)
• Models, Molecular
• Protein Conformation
• Pteridines (chemistry, metabolism, pharmacokinetics, pharmacology)
• Rats
• Structure-Activity Relationship
• Substrate Specificity
• Toll-Like Receptor 7 (agonists, chemistry, metabolism)