Discovery of GS-9688 (Selgantolimod) as a Potent and Selective Oral Toll-Like Receptor 8 Agonist for the Treatment of Chronic Hepatitis B

Toll-like receptor 8 (TLR8) recognizes
pathogen-derived single-stranded
RNA fragments to trigger innate and adaptive immune responses. Chronic
hepatitis B (CHB) is associated with a dysfunctional immune response,
and therefore a selective TLR8 agonist may be an effective treatment
option. Structure-based optimization of a dual TLR7/8 agonist led
to the identification of the selective TLR8 clinical candidate (R)-2-((2-amino-7-fluoropyrido­[3,2-d]­pyrimidin-4-yl)­amino)-2-methylhexan-1-ol
(GS-9688, (R)-7). Potent TLR8 agonism
(IL-12p40 EC50 = 220 nM) and >100-fold TLR7 selectivity
(IFN-α EC50 > 50 μM) was observed in human
peripheral blood mononuclear cells (PBMCs). The TLR8-ectodomain:(R)-7 complex confirmed TLR8 binding and a direct
ligand interaction with TLR8 residue Asp545. Oral (R)-7 had good absorption and high first pass clearance
in preclinical species. A reduction in viral markers was observed
in HBV-infected primary human hepatocytes treated with media from
PBMCs stimulated with (R)-7, supporting
the clinical development of (R)-7 for
the treatment of CHB.