tcsc1374 Grazoprevir

Grazoprevir (MK-5172) is a selective inhibitor of Hepatitis C virus NS3/4a protease with broad activity across genotypes and resistant variants, with K_is of 0.01 nM (gt1b), 0.01 nM (gt1a), 0.08 nM (gt2a), 0.15 nM (gt2b), 0.90 nM (gt3a), respectively.

IC50 & Target: Ki: 0.01±<0.01 nM (gt1b), 0.01±0.01 nM (gt1a), 0.08±0.02 nM (gt2a), 0.15±0.06 nM (gt2b), 0.90±0.2 nM (gt3a)^[1]

In Vitro: In biochemical assays, Grazoprevir (MK-5172) is effective against a panel of major genotypes and variants engineered with common resistant mutations, with K_i of 0.01±<0.01 nM (gt1b), 0.01±0.01 nM (gt1a), 0.08±0.02 nM (gt2a), 0.15±0.06 nM (gt2b), 0.90±0.2 nM (gt3a), 0.07±0.01 nM (gt1b^R155K), 0.14±0.03 nM (gt1b^D168V), 0.30±0.04 nM (gt1b^D168Y), 5.3±0.9 nM (gt1b^A156T), and 12±2 nM (gt1b^A156V), 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 gt1b^con1, gt1a, and gt2a, respectively. Grazoprevir is potent against a panel of HCV replication mutants NS5A (Y93H) (EC₅₀=0.7±0.3 nM), NS5B nucleosides (S282T) (EC₅₀=0.3±0.1 nM), and NS5B (C316Y) (EC₅₀=0.4±0.2)^[1]. Grazoprevir (MK-5172) 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].

In Vivo: Grazoprevir (MK-5172) demonstrates efficacy in vivo against chronic-HCV-infected chimpanzees^[1]. When dosed to dogs, Grazoprevir (MK-5172) 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 behavior 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].