MK-5172钾盐（MK-5172钾盐）是丙型肝炎病毒NS3/4a蛋白酶的选择性抑制剂，具有跨基因型和耐药变体的广泛活性，Kis为0.01 nM（gt1b），0.01 nM（gt1a），0.08 nM (gt2a)、0.15 nM (gt2b)、0.90 nM (gt3a)。
Animal experiment: | Rats and Dogs[1] Studies are performed in both rats and dogs. For studies in which Grazoprevir is dosed intravenously to rats or dogs, the compound is formulated in polyethylene glycol 200 (PEG200) and administered as a bolus at either 2 mg/kg of body weight (Rats) or 0.5 mg/kg (dog). For oral studies, the crystalline potassium salt of the compound is dosed as a solution in PEG400 at 5 mg/kg (Rats) or 1 mg/kg (dog). For all studies, blood samples are collected in EDTA-containing tubes at appropriate times and plasma is separated by centrifugation and stored at –70℃ until analysis. Quantitation of Grazoprevir levels is conducted by high-performance liquid chromatography/mass spectroscopy (LC/MS/MS) following protein precipitation. Liver samples are obtained from rat studies at the termination of the experiment. For dog, liver biopsy samples (20 μL) are collected following sedation. Tissue samples are homogenized in four volumes of deionized water, and drug concentrations are determined by LC/MS/MS after protein precipitation. |
| 产品描述 | IC50 Value: 7.4nM and 7nM for genotype1b and 1a respectively, in replicon system [1]
MK-5172 is a novel P2-P4 quinoxaline macrocyclic HCV NS3/4a protease inhibitor currently in clinical development.
in vitro: In biochemical assays, MK-5172 was effective against a panel of major genotypes and variants engineered with common resistant mutations observed in clinical studies with other NS3/4a protease inhibitors. In the replicon assay, MK-5172 demonstrated subnanomolar to low-nanomolar EC50s against genotypes 1a, 1b, and 2a [2].
in vivo: In rats, MK-5172 showed a plasma clearance of 28 ml/min/kg and plasma half-life of 1.4 hr. When dosed p.o. at 5 mg/kg, the plasma exposure of MK-5172 was good with an AUC of 0.7 uM.hr. The liver exposure of the compound was quite good (23 uM at 4 hr), and MK-5172 remained in liver 24 hr after a single p.o. 5 mg/kg dose. At 24 hr, the liver concentration of MK-5172 was 0.2 uM, which was over 25-fold higher than the IC50 in the replicon assay with 50% NHS. When dosed to dogs, MK-5172 showed low clearance of 5 ml/min/kg and a 3 hr half-life after i.v. 2 mg/kg dosing and had good plasma exposure (AUC=0.4 uM.hr) after a p.o. 1 mg/kg dose [1].
Clinical trial: Evaluation of Hepatic Pharmacokinetics for MK-5172 in Participants With Chronic Hepatitis C . Phase1 |
