Toll-like receptors (TLRs) recognize fragments of invading pathogens and subsequently initiate an immune response. TLR-7 is predominantly localized in endosomes and lysosomes of immune cells, particularly plasmacytoid dendritic cells and B lymphocytes, where it recognizes viral single-stranded RNA as its native ligand. Signaling from the receptor in dendritic cells leads to the secretion of high levels of interferon-alpha, with subsequent activation of these cells for antigen presentation. Substantial published data suggests that TLR-7 agonists could be used for the treatment of chronic infection with hepatitis B and C viruses. The SAR leading to the discovery of GS-9620, an orally available small-molecule TLR-7 agonist, will be described. Additionally, a summary of in vivo animal pharmacodynamics and efficacy models as well as Phase 1 clinical data will be presented.

Discovery of GS-9620, an oral agonist of Toll-like receptor 7 for the treatment of chronic hepatitis B and C infection

243rd National Meeting (2012)

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