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

  • J Med Chem. 2013 Sep 26;56(18):7324-33. doi: 10.1021/jm400815m.
Paul A Roethle  1 ,  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
Affiliations
  • 1. Departments of †Medicinal Chemistry, ‡Clinical Virology, §Drug Metabolism, ∥Biology, and ⊥Structural Chemistry, Gilead Sciences , 333 Lakeside Drive, Foster City, California 94404, United States.
PMID: 23961878 DOI: 10.1021/jm400815m
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.