Preclinical Characterization and Human Microdose Pharmacokinetics of ITMN-8187, a Non-Macrocyclic Inhibitor of the Hepatitis C Virus NS3 Protease [PublishAheadOfPrint]

The current paradigm for the treatment of chronic hepatitis C virus (HCV) infection involves combinations of agents which act directly on steps of the HCV lifecycle. Here we report the preclinical characteristics of ITMN-8187, a non-macrocyclic inhibitor of the NS3/4A HCV protease. X-ray crystallographic studies of ITMN-8187 and simeprevir binding to NS3/4A protease demonstrated good agreement between structures. Low nanomolar biochemical potency was maintained against NS3/4A derived from HCV genotypes 1, 2b, 4, 5, and 6. In cell-based potency assays, half-maximal reduction of genotype 1a and 1b HCV replicon RNA was afforded by 11 and 4 nM doses of ITMN-8187, respectively. Combinations of ITMN-8187 with other direct-acting antiviral agents in vitro displayed additive antiviral efficacy. A 30 mg/kg dose of ITMN-8187 administered for 4 days yielded significant viral load reductions through Day 5 in a chimeric mouse model of HCV. A 3 mg/kg oral dose administered to rats, dogs, or monkeys yielded plasma concentrations 16 hours after dosing that exceeded the half-maximal effective concentration of ITMN-8187. Human microdose pharmacokinetics showed low inter-subject variability and prolonged oral absorption with first-order elimination kinetics compatible with once-daily dosing. These preclinical characteristics compare favorably with those of other NS3/4A inhibitors approved for the treatment of chronic HCV infection.

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