In vitro: TLR7-agonist-1 is a potent and selective Toll-like Receptor 7 (TLR7) agonist with a lowest effective concentration (LEC) of 0.4 μM in HEK293 cell. TLR7-agonist-1 is found to be selective for TLR7 over TLR8 with LEC of >100 μM for human TLR8. TLR7-agonist-1 demonstrates low inhibition across five CYP450 isozymes (IC50 >10 μM) and is also not a time dependent inhibitor of CYP450 3A4. TLR7-agonist-1 has limited inhibition of the hERG potassium ion channel 3H-dofetilide binding in vitro (IC50 >50 μM).
In vivo: TLR7-agonist-1 is found to be rapidly cleared in conjunction with our target profile. Both Cmax and AUC increase less than dose proportionally between 0.3 and 3 mg/kg and more than dose-proportionally between 3 and 10 mg/kg. TLR7-agonist-1 can induce an antiviral interferon stimulated gene (ISG) response without inducing an IFNα response at a low dose. TLR7-agonist-1 also induces a 2.7 log decrease in serum HBV viral load from 0.3 mg/kg, and a maximum 3.1 log decrease is observed for doses between 1 and 5 mg/kg.
| Cell Experiment | |
|---|---|
| Cell lines | HEK293 cells |
| Preparation method | HEK293 cells are grown in culture medium (DMEM supplemented with 10% FCS and 2 mM Glutamine). Transfected cells are then detached with Trypsin-EDTA, washed in PBS and resuspended in medium to a density of 1.67×105 cells/mL. Thirty microliters of cells are then dispensed into each well in 384-well plates, where 10 μL of TLR7-agonist-1 in 4% DMSO is already present. |
| Concentrations | 10 μL of TLR7-agonist-1 in 4% DMSO |
| Incubation time | 6 h |
| Animal Experiment | |
|---|---|
| Animal models | C57Bl/6 mice |
| Formulation | |
| Dosages | 0.3, 1, 3, and 10 mg/kg |
| Administration | oral administration |
| Molecular Weight | 336.35 |
| Formula | C17H16N6O2 |
| CAS Number | 1642857-69-9 |
| Form | Solid |
| Solubility (25°C) | 160 mg/mL in DMSO |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
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