Vesatolimod, also known as GS-9620, is a potent and oral agonist of Toll-like receptor-7 developed for finite treatment of chronic hepatitis B viral (HBV) infection, with the goal of inducing a liver-targeted antiviral effect without inducing the adverse effects associated with current systemic interferon-α (IFN-α) therapies. GS-9620 demonstrate interferon-stimulated gene induction without detectable serum interferon at low oral doses. GS-9620 can induce a sustained antiviral response in the woodchuck model of CHB.(In Vitro):Vesatolimod (GS-9620) rapidly internalizes into cells and preferentially localizes to and signals from endo-lysosomal compartments. To test this hypothesis, the kinetics of cellular uptake of the compound in Daudi cells using tritiated Vesatolimod (3H-GS-9620) is measured. The kinetics of 3H-GS-9620 accumulation is rapid, reaching concentration-dependent steady-state equilibrium in approximately thirty minutes. Measured intracellular concentration of 3H-Vesatolimod is 5-fold higher than the extracellular concentration of 3H-GS-9620 used to treat cells. Increases in intracellular 3H-Vesatolimod concentrations are roughly proportional with increasing concentrations of 3H-GS-9620.(In Vivo):Single oral doses of Vesatolimod (GS-9620) at 0.3 and 1 mg/kg in uninfected chimpanzees demonstrates a dose- and exposure-related induction of serum IFN-α, select cytokines/chemokines, and IFN-stimulated genes (ISG) in the peripheral blood and liver. Following oral administration at 0.3 (n=3), and 1 mg/kg (n=3 and n=4), Vesatolimod (GS-9620) Cmax is 3.6±3.5, 36.8±34.5, and 55.4±81.0 nM, respectively. Peak serum IFN responses occur at 8 h post-dose. The mean peak levels of induced serum IFN-α are 66 and 479 pg/mL at doses of 0.3 and 1 mg/kg, respectively. Vesatolimod (GS-9620) treatment induces ISG transcripts including ISG15, OAS-1, MX1, IP-10 (CXCL10), and I-TAC (CXCL11) in peripheral blood mononuclear cells (PBMC) at 0.3 mg/kg and in both PBMC and the liver at 1 mg/kg.
Images & Validation
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Key Properties
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CAS Number
1228585-88-3
MW
410.51
Purity
>98% (HPLC)
Formula
C22H30N6O2
SMILES
CCCCOc1nc2c(c(n1)N)NC(=O)CN2Cc1cc(ccc1)CN1CCCC1
Target
TLR7
Solubility
DMSO : 4.8 mg/mL. 11.69 mM;
Bioactivity
−
In Vivo
Single oral doses of Vesatolimod (GS-9620) at 0.3 and 1 mg/kg in uninfected chimpanzees demonstrates a dose-and exposure-related induction of serum IFN-α, select cytokines/chemokines, and IFN-stimulated genes (ISG) in the peripheral blood and liver. Following oral administration at 0.3 (n = 3), and 1 mg/kg (n = 3 and n = 4), Vesatolimod (GS-9620) Cmax is 3.6±3.5, 36.8±34.5, and 55.4±81.0 nM, respectively. Peak serum IFN responses occur at 8 h post-dose. The mean peak levels of induced serum IFN-α are 66 and 479 pg/mL at doses of 0.3 and 1 mg/kg, respectively. Vesatolimod (GS-9620) treatment induces ISG transcripts including ISG15, OAS-1, MX1, IP-10 (CXCL10), and I-TAC (CXCL11) in peripheral blood mononuclear cells (PBMC) at 0.3 mg/kg and in both PBMC and the liver at 1 mg/kg.
In Vitro
Vesatolimod (GS-9620) rapidly internalizes into cells and preferentially localizes to and signals from endo-lysosomal compartments. To test this hypothesis, the kinetics of cellular uptake of the compound in Daudi cells using tritiated Vesatolimod (3H-GS-9620) is measured. The kinetics of 3H-GS-9620 accumulation is rapid, reaching concentration-dependent steady-state equilibrium in approximately thirty minutes. Measured intracellular concentration of 3H-Vesatolimod is 5-fold higher than the extracellular concentration of 3H-GS-9620 used to treat cells. Increases in intracellular 3H-Vesatolimod concentrations are roughly proportional with increasing concentrations of 3H-GS-9620.
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