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J Med Chem. 2013 Sep 26;56(18):7324-33. doi: 10.1021/jm400815m. Epub 2013 Sep 9.

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

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1
Departments of †Medicinal Chemistry, ‡Clinical Virology, §Drug Metabolism, ∥Biology, and ⊥Structural Chemistry, Gilead Sciences , 333 Lakeside Drive, Foster City, California 94404, United States.

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.

PMID:
23961878
DOI:
10.1021/jm400815m
[Indexed for MEDLINE]
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