Danoprevir

Danoprevir (ITMN-191) is an orally active NS3/4A protease inhibitor for hepatitis C virus (HCV) with an IC₅₀ of 0.29 nM and is selective for NS3/4A over a panel of 53 proteases (IC₅₀ higher than 10 μM). Danoprevir (ITMN-191) inhibits HCV genotypes 1a, 1b, 4, 5, and 6 (IC₅₀s=0.2-0.4 nM) as well as 2b and 3a (IC₅₀s=1.6, 3.5 nM)^[1][2]. Danoprevir is also a SARS-CoV 3CL^pro inhibitor with an IC₅₀ of 0.05 μM^[3]. IC50 & Target: IC50: 0.29 nM (NS3/4A protease), 0.2-3.5 nM (HCV genotypes 1a, 1b, 2b, 3a, 4, 5, 6)^[2] In Vitro: In Huh7.5 cells transfected with chimeric recombinant virus, Danoprevir (ITMN-191) shows antiviral inhibition effects against HCV genotypes 1, 4 and 6 with IC₅₀ of 2-3 nM, which are >100-fold lower than genotypes 2/3/5 (280-750 nM)^[1].
Danoprevir (ITMN-191) inhibits the reference genotype 1 NS3/4A protease half-maximally, but a high dose of Danoprevir (ITMN-191) (10 μM) shows no appreciably inhibition in a panel of 79 proteases, ion channels, transporters, and cell surface receptors. Danoprevir (ITMN-191) remains bound to and inhibits NS3/4A for more than 5 hours after its initial association. Danoprevir (ITMN-191) (45 nM) eliminates a patient-derived HCV genotype 1b replicon from hepatocyte-derived Huh7 cells with an EC₅₀ of 1.8 nM^[2].
In HCV subgenomic replicon cell lines containing the individual mutations, V36M, R109K, and V170A substitutions confer little or no resistance to Danoprevir (ITMN-191), but the R155K substitution confers a high level (62-fold increase) of resistance to Danoprevir^[3]. In Vivo: Danoprevir (ITMN-191) (30 mg/kg, p.o.) administered to rats or monkeys shows that its concentrations in liver 12 hours after dosing exceed the Danoprevir concentration required to eliminate replicon RNA from cells^[2].