HCV-796 is a specific inhibitor of hepatitis C virus (HCV) replication that targets protein 5B (NS5B) polymerase with IC50 of 0.01-0.14 μM for genotype 1, with EC50 of 5 nM and 9 nM against genotype 1a and 1b replicons.HCV-796 is a nonnucleoside inhibitor which binds to a site in the palm domain of the HCV polymerase. In vitro replicon resistance studies indentifies substitutions at NS5B residues C316Y/F/S, S365T/A/L, and M414I, which are located near the inhibitor binding site and confer a loss of sensitivity to HCV-796. HCV-796 shows slow binding kinetics to NS5B. The binding affinity of HCV-796 to NS5B increased 27-fold over a 3-h incubation period with an equilibrium Kd of 71 nM. Slow binding kinetics of HCV-796 is driven by slow dissociation from NS5B with a Koff of 4.9 × 10-4/s .HCV-796 at 50 mg/kg three times daily for 5 days resulted in a 2.02 log10 decrease in HCV titer with one mouse below the level of detection, whereas levels in the control mice are relatively stable (0.26 log10 decline). Seven days after stopping treatments, control mouse HCV titers are unchanged, whereas the titers in the HCV-796 group rebounded to within 1.16 log of baseline. In the chimeric mouse model, a 2.02 log10 reduction in HCV titer is seen with monotherapy, whereas a suboptimal dose of 30 mg/kg three times per day in combination with interferon demonstrated a 2.44 log10 reduction. Clinical outcomes in combination with pegylated interferon and ribavirin have revealed additive efficacy in treatment naive patients. Abnormal liver function test results are observed in 8%of HCV-796 patients treated for over 8 weeks, resulting in suspension of further trial activity .
| Molecular Weight | 446.49 |
| Formula | C22H23FN2O5S |
| CAS Number | 691852-58-1 |
| Form | Solid |
| Solubility (25°C) | 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.
[5] Gustine Liu-Young, et al. Hepatitis C protease and polymerase inhibitors in development
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