title: Preclinical Characterization and Human Microdose Pharmacokinetics of ITMN-8187, a Nonmacrocyclic Inhibitor of the Hepatitis C Virus NS3 Protease.
abstract: The current paradigm for the treatment of chronic hepatitis C virus (HCV) infection involves combinations of agents that act directly on steps of the HCV life cycle. Here we report the preclinical characteristics of ITMN-8187, a nonmacrocyclic 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 directly acting antiviral agents in vitro displayed additive antiviral efficacy. A 30-mg/kg of body weight 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 concentrations in plasma 16 h after dosing that exceeded the half-maximal effective concentration of ITMN-8187. Human microdose pharmacokinetics showed low intersubject 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.
authors: InterMune Incorporated, Brisbane, California, USA pt.ravi.r@gmail.com.
authors: Ravi
authors: R
authors: Rajagopalan
authors: InterMune Incorporated, Brisbane, California, USA.
authors: Lin
authors: L
authors: Pan
authors: InterMune Incorporated, Brisbane, California, USA.
authors: Caralee
authors: C
authors: Schaefer
authors: InterMune Incorporated, Brisbane, California, USA.
authors: John
authors: J
authors: Nicholas
authors: InterMune Incorporated, Brisbane, California, USA.
authors: Sharlene
authors: S
authors: Lim
authors: InterMune Incorporated, Brisbane, California, USA.
authors: Shawn
authors: S
authors: Misialek
authors: InterMune Incorporated, Brisbane, California, USA.
authors: Sarah
authors: S
authors: Stevens
authors: InterMune Incorporated, Brisbane, California, USA.
authors: Lisa
authors: L
authors: Hooi
authors: InterMune Incorporated, Brisbane, California, USA.
authors: Natalia
authors: N
authors: Aleskovski
authors: InterMune Incorporated, Brisbane, California, USA.
authors: Donald
authors: D
authors: Ruhrmund
authors: InterMune Incorporated, Brisbane, California, USA.
authors: Karl
authors: K
authors: Kossen
authors: InterMune Incorporated, Brisbane, California, USA.
authors: Lea
authors: L
authors: Huang
authors: InterMune Incorporated, Brisbane, California, USA.
authors: Sophia
authors: S
authors: Yap
authors: InterMune Incorporated, Brisbane, California, USA.
authors: Leonid
authors: L
authors: Beigelman
authors: InterMune Incorporated, Brisbane, California, USA.
authors: Vladimir
authors: V
authors: Serebryany
authors: InterMune Incorporated, Brisbane, California, USA.
authors: Jyanwei
authors: J
authors: Liu
authors: InterMune Incorporated, Brisbane, California, USA.
authors: Srikonda
authors: S
authors: Sastry
authors: InterMune Incorporated, Brisbane, California, USA.
authors: Scott
authors: S
authors: Seiwert
authors: InterMune Incorporated, Brisbane, California, USA.
authors: Brad
authors: B
authors: Buckman
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001665:Binding Sites; D004285:Dogs; D000882:Haplorhini; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology; D006526:Hepatitis C / Q000188:drug therapy / Q000821:virology; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000493:pharmacokinetics* / Q000627:therapeutic use; D051381:Rats; D000069616:Simeprevir / Q000493:pharmacokinetics* / Q000627:therapeutic use; D017361:Viral Nonstructural Proteins / Q000378:metabolism*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D011480:Protease Inhibitors; D000069616:Simeprevir; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
keywords: antiviral agents; hepatitis C virus; protease inhibitors