Pteridinone-based TLR-7 agonists were identified as potent and selective alternatives to the previously reported adenine-based agonists, leading to the discovery of GS-9620. Analogs were optimized for the immunomodulatory activity and selectivity versus other toll-like receptors (TLRs), based on induction of key cytokines including interferon-alpha (IFN-a) and tumor necrosis factor-alpha (TNF-a). In addition, physicochemical properties were adjusted to achieve desirable pharmacokinetic and pharmacodynamic properties in vivo. GS-9620 is currently in clinical evaluation for the treatment of chronic hepatitis B (HBV) infection.

Identification and optimization of a pteridinone toll-like receptor-7 (TLR-7) agonist

246th National Meeting (2013)

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