描述

Grazoprevir anhydrous is a Hepatitis C Virus NS3/4A Protease inhibitor with IC50 values of 7pM, 4pM, and 62pM for HCV genotype 1a, 1B, and 4 respectively.

IC50 & Target

体外

MK-5172 is a novel P2-P4 quinoxaline macrocyclic NS3/4a protease inhibitor currently in clinical development. The compound demonstrates subnanomolar activity against a broad enzyme panel encompassing major hepatitis C virus (HCV) genotypes as well as variants resistant to earlier protease inhibitors.

体内

In both rat and dog, MK-5172 demonstrates good plasma and liver exposures, with 24-h liver levels suggestive of once-daily dosing. When administered to HCV-infected chimpanzees harboring chronic gt1a or gt1b infections, MK-5172 suppresses viral load between 4 to 5 logs at a dose of 1 mg/kg of body weight twice daily (b.i.d.) for 7 days. MK-5172 demonstrates low to moderate clearance and a modest half-life in both rat and dog. Upon oral administration, MK-5172 demonstrates modest bioavailability of 12 to 13%, with moderate plasma exposure in both species. Significant liver concentrations are achieved in both rat and dog. The 24-h trough liver concentrations are 0.2 μM in rat and 1.4 μM in dog (1 mg per kg), yielding exposure multiples of 27- to 200-fold over the serum-adjusted replicon EC50. MK-5172 proves highly efficacious in vivo at moderate doses against chronic-HCV-infected chimpanzees, including greater viral load suppression than vaniprevir when dosed alternatively to the same animal at an otherwise identical dose and frequency.

细胞实验

• Cell lines: HB1 cells
• Concentrations: 2, 5, or 10 nM
• Incubation Time: 1, 2, 3.5 days
• Method: 30,000 HB1 cells are seeded per well of a 6-well tissue culture plate per drug concentration. The next day (day 0), the medium is replenished with fresh medium and MK-5172 at the appropriate drug concentration. Cells from a single well per drug concentration are harvested on days 0, 1, and 2, washed, and stored frozen until evaluation. The fourth well is similarly harvested on day 3.5 except that 30,000 cells are reseeded with fresh medium and MK-5172 at the appropriate drug concentration. For additional time points, cells are passaged and harvested every one-half week for 2 weeks. For the third week, cells are similarly treated except that cells received replenishing medium which contained 0.5 mg/ml G418 without protease inhibitor. 
  (Only for Reference)

动物实验

Animal Models: rats or dogs
Formulation: polyethylene glycol 200 (PEG200)
Dosages: 2 mg/kg of body weight (rat) or 0.5 mg/kg (dog)
Administration: i.v.
(Only for Reference)

1 mg

5 mg

10 mg

1 mM

1.3040 mL

6.5198 mL

13.0395 mL

5 mM

0.2608 mL

1.3040 mL

2.6079 mL

10 mM

0.1304 mL

0.6520 mL

1.3040 mL

50 mM

0.0261 mL

0.1304 mL

0.2608 mL