Grazoprevir (MK-5172) is a nitrogenous macrocyclic compound used as an inhibitor of the hepatitis C virus NS3/4A protease. Grazoprevir is commonly combined with elbasvir for treating chronic HCV genotype 1 or 4 infections in adults.

GT3a:0.90 nM (Ki), GT2b:0.15 nM (Ki), GT1b:0.01 nM (Ki), GT2a:0.08 nM (Ki), GT1a:0.01 nM (Ki)

In biochemical assays, Grazoprevir is effective against a panel of major genotypes and variants engineered with common resistant mutations, with Ki of 0.01 nM (gt1b), 0.01 nM (gt1a), 0.08 nM (gt2a), 0.15 nM (gt2b), 0.90 nM (gt3a), 0.07 nM (gt1bR155K), 0.14 nM (gt1bD168V), 0.30 nM (gt1bD168Y), 5.3 nM (gt1bA156T), and 12 nM (gt1bA156V), respectively. In the replicon assay, Grazoprevir demonstrates subnanomolar to low-nanomolar EC50s against genotypes 1a, 1b, and 2a, with EC50s of 0.5±0.1 nM, 2±1 nM, and 2±1 nM for gt1bcon1, gt1a, and gt2a, respectively. Grazoprevir is potent against a panel of HCV replication mutants NS5A (Y93H) (EC50: 0.7 nM), NS5B nucleosides (S282T) (EC50: 0.3 nM), and NS5B (C316Y) (EC50: 0.4 nM)[1]. Grazoprevir maintains the excellent potency against the gt 3a enzyme as well as a broad panel of mutant enzymes, has excellent potency in the replicon system [gt1b IC50(50% NHS): 7.4 nM; gt1a IC50(40% NHS): 7 nM], and shows excellent rat liver exposure[2].

When dosed to dogs, Grazoprevir shows low clearance of 5 mL/min/kg and a 3 h half-life after iv dosing and has good plasma exposure (AUC: 0.4 μM/h) after a 1 mg/kg oral dose. Dog liver biopsy studies showed that the liver concentration of Grazoprevir after the 1 mg/kg oral dose is 1.4 μM at the 24 h time point. Similar to its behaviour in rats, Grazoprevir demonstrates effective partitioning into liver tissue and maintains high liver concentration, relative to potency, 24 h after oral dosing in dogs [2].