ITMN-191 (Danoprevir, RG7227) is a potent and orally active inhibitor of hepatitis C virus (HCV) NS3/4A serine protease with an IC50 of 1.6 nM. ITMN-191 is shown to be a potent inhibitor of NS3 with a two-step binding mechanism. Progress curves are consistent with the formation of an initial collision complex (EI) that isomerizes to a highly stable complex (EI*) from which ITMN-191 dissociates very slowly. From progress curve analysis, the rate constant for dissociation of ITMN-191 from the EI* complex is 3.8 x 10(-5) s(-1) with a calculated complex half-life of approximately 5 h and a true biochemical potency (K(i)*) of approximately 62 pM. Abrogation of the tight binding and slow dissociative properties of ITMN-191 is observed with proteases that carry the R155K or D168A substitution, each of which is likely in compound resistant mutants. Slow dissociation is not observed with closely related macrocyclic inhibitors of NS3, suggesting that members of this class may display distinct binding kinetics.
| Cell Experiment | |
|---|---|
| Cell lines | Huh7 cells |
| Preparation method | The viability of Huh7 cells, human cardiac myocytes, and human cardiac fibroblasts was assessed following 72 h of exposure to ITMN-191 using a CellTiter-Glo Luminescent Cell Viability kit (Promega, Madison, WI). For these cell types, viability in the presence of ITMN-191 was fitted to a four-parameter logistic function to obtain a 50% cytotoxic concentration (CC50). Additionally, the CC50s were determined for six primary normal human cell types in stationary and proliferating (dividing) phases by Lonza, Inc. (Walkersville, MD). The cell types included normal human hepatocytes, microvascular endothelial cells, human skeletal muscle myoblasts, human articular chondrocytes, human lung fibroblasts, and renal proximal tubule epithelial cells. For the proliferating phase, ITMN-191 was added when cells reached 50% confluence. For the stationary phase, ITMN-191 was added 1 day after cells reached 100% confluence. Cell viability was quantified following 72 h of exposure to ITMN-191 using a ViaLight Plus kit on a microplate reader. CC50s were determined as described above. |
| Concentrations | 5 pM ~100 nM |
| Incubation time | 72 h |
| Animal Experiment | |
|---|---|
| Animal models | Sprague-Dawley rats and Cynomolgus monkeys |
| Formulation | water |
| Dosages | 30-mg/kg |
| Administration | oral gavage |
| Molecular Weight | 731.83 |
| Formula | C35H46FN5O9S |
| CAS Number | 850876-88-9 |
| Solubility (25°C) | DMSO ≥100 mg/mL Ethanol ≥100 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.
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