Dolutegravir (GSK1349572) is a novel potent integrase inhibitor with an IC50 of 2.7 nM in vitro. Dolutegravir (GSK1349572) is a compound for the treatment of HIV infection. Dolutegravir (GSK1349572) exhibited in vitro activity against most clinical isolates obtained from patients failing RAL-based therapy. In PBMC cell assay, Dolutegravir (GSK1349572) inhibited HIV integrase with the antiviral IC50=0.51 and IC90=2.0 nM. In MT-4 antiviral assays, potency shift extrapolated to 100% human serum was 75-fold providing PA-IC90=152 nM in PBMCs. Dolutegravir (GSK1349572) had a markedly different resistance profile as evidenced by limited cross-resistance to RAL-resistant molecular clones, by its in vitro activity against clinical isolates obtained from patients failing RAL-based therapy, and in selecting different mutations with low level FC during serial passage. In vitro experiments support the potential for Dolutegravir (GSK1349572) to have a higher genetic barrier to resistance when compared to 1st generation integrase inhibitors.
| Cell Experiment | |
|---|---|
| Cell lines | MT-4 |
| Preparation method | Growing MT-4 cells exponentially at a density of 500000 or 600000 /mL are infected with HIV-1 strain IIIB at a viral multiplicity of infection of 0.001 or a 50% tissue culture infective dose of 4 to 10. Then aliquoting the cells to 96-well plates in the presence of varying concentrations of S/GSK1349572. After incubation for 4 or 5 days, using the yellow tetrazolium MTT reagent [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide] to determine antiviral activity by a cell viability assay that either measured bioluminescence with a CellTiter-Glo luminescent reagent or measured absorbance at 560 and 690 nm . |
| Concentrations | 0 to 10 μM |
| Incubation time | 4 days or 5 days |
| Animal Experiment | |
|---|---|
| Animal models | |
| Formulation | |
| Dosages | |
| Administration | |
| Molecular Weight | 419.38 |
| Formula | C20H19F2N3O5 |
| CAS Number | 1051375-16-6 |
| Solubility (25°C) | DMSO 60 mg/mL |
| 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.
| Related Integrase Products |
|---|
| Bictegravir Sodium
Bictegravir (GS-9883) Sodium is a novel and potent inhibitor of HIV-1 integrase, specifically targets IN strand transfer activity with an IC50 of 7.5 nM. |
| Lavendustin B
Lavendustin B inhibits HIV-1 integrase (IN) interaction with its cognate cellular cofactor lens epithelium-derived growth factor (LEDGF/p75). Lavendustin B is an inhibitor of Tyrosine Kinase and also a competitive inhibitor of glucose transporter 1 (Glut1). |
| Bictegravir
Bictegravir (GS-9883) is a novel, potent inhibitor of HIV-1 integrase with an IC50 of 7.5 nM. |
| Raltegravir potassium
Raltegravir potassium (MK0518 potassium) is a potent integrase (IN) inhibitor, used to treat HIV infection. |
| Dolutegravir sodium
Dolutegravir sodium is a potent, second generation HIV integrase inhibitor (IC₅₀ = 2.7 nM) that displays potent antiviral activity. |
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