GS-9620

Names

[ Name ]:
GS-9620

[Synonym ]:
6(5H)-Pteridinone, 4-amino-2-butoxy-7,8-dihydro-8-[[3-(1-pyrrolidinylmethyl)phenyl]methyl]-
UNII:O8M467C50G
GS 9620
CS-1352
4-amino-2-butoxy-8-(3-(pyrrolidin-1-ylmethyl)benzyl)-7,8-dihydropteridin-6(5H)-one
UNII-O8M467C50G
4-amino-2-n-butoxy-8-[3'-(pyrrolidin-1"-ylmethyl)-benzyl]-5,6,7,8-tetrahydropteridin-6-one
GS-9620
vesatolimod
8-(3-(pyrrolidin-1-ylmethyl)benzyl)-4-amino-2-butoxy-7,8-dihydropteridin-6(5H)-one
4-Amino-2-butoxy-8-[3-(1-pyrrolidinylmethyl)benzyl]-7,8-dihydro-6(5H)-pteridinone

Biological Activity

[Description]:

Vesatolimod (GS-9620) is a potent, selective and orally active agonist of Toll-Like Receptor (TLR7) with an EC50 of 291 nM.

[Related Catalog]:

Signaling Pathways >> Immunology/Inflammation >> Toll-like Receptor (TLR)

Research Areas >> Inflammation/Immunology

[Target]

EC50: 291 nM (TLR7), 9 μM (TLR8)[3]

[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[1].

[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 interferon-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 interferon 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[2].

[Cell Assay]

Daudi cells are incubated for indicated times with varying concentrations [3H]Vesatolimod (GS-9620) (0.7μCi/mL). Cell associated radioactivity is extracted with ice cold 80% ethanol and measured using liquid scintillation counting. The total amount of Vesatolimod in cells is calculated from a calibration curve for Vesatolimod (GS-9620) mass versus radioactivity. Cell volume is measured[1].

[Animal admin]

Chimpanzee[2] Chimpanzees are used. The trial design includes 4 weeks of pre-study evaluation (Day-28, -13 and just prior to first dose) and two cycles of oral Vesatolimod (GS-9620) treatment every other day three times per week for 4 weeks with one cycle at 1 mg/kg, and, after a one week rest, a second cycle at 2 mg/kg. Animals are also intensely monitored for 14 weeks after treatment to assess tolerability and durability of response.

[References]

[1]. Rebbapragada I, et al. Molecular Determinants of GS-9620-Dependent TLR7 Activation. PLoS One. 2016 Jan 19;11(1):e0146835.

[2]. Lanford RE, et al. GS-9620, an Oral Agonist of Toll-Like Receptor-7, Induces Prolonged Suppression of Hepatitis B Virus in Chronically Infected Chimpanzees. Gastroenterology. 2013 Feb 13. pii: S0016-5085(13)00169-8.

[3]. D Tumas, et al. Preclinical Characterization of GS-9620, A Potent and Selective Oral TLR7 Agonist.

[Related Small Molecules]

Chemical & Physical Properties

[ Density]:
1.2±0.1 g/cm3

[ Molecular Formula ]:
C₂₂H₃₀N₆O₂

[ Molecular Weight ]:
410.513

[ Exact Mass ]:
410.243011

[ PSA ]:
100.10000

[ LogP ]:
3.10

[ Index of Refraction ]:
1.622

[ Storage condition ]:
-20℃

GS-9620

Names

Biological Activity

Chemical & Physical Properties

Synthetic Route

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Precursor & DownStream

Precursor

DownStream

Related Compounds