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1.
Article in English | MEDLINE | ID: mdl-27795376

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.


Subject(s)
Antiviral Agents/pharmacokinetics , Hepacivirus/drug effects , Protease Inhibitors/pharmacokinetics , Simeprevir/pharmacokinetics , Viral Nonstructural Proteins/metabolism , Animals , Antiviral Agents/therapeutic use , Binding Sites , Dogs , Haplorhini , Hepacivirus/enzymology , Hepatitis C/drug therapy , Hepatitis C/virology , Humans , Mice , Molecular Structure , Protease Inhibitors/therapeutic use , Rats , Simeprevir/therapeutic use
4.
Bioorg Med Chem Lett ; 19(15): 4480-3, 2009 Aug 01.
Article in English | MEDLINE | ID: mdl-19500983
5.
J Invest Dermatol ; 126(8): 1792-803, 2006 Aug.
Article in English | MEDLINE | ID: mdl-16628194

ABSTRACT

Atopic dermatitis (AD) is a common chronic skin inflammatory disease. Long-term use of topical corticosteroids in skin inflammation poses risks of systemic and local side effects. The NF-kappaB transcription factor family plays a central role in the progression and maintenance of AD. This study explores the possibility of using topical NF-kappaB Decoy as a novel therapeutic alternative for targeting Th1/Th2-driven skin inflammation in experimental AD. A high-affinity, topical NF-kappaB Decoy developed for human efficacy demonstrates: (i) efficient NF-kappaB Decoy penetration in pig skin, (ii) NF-kappaB Decoy nuclear localization in keratinocytes and key immune cells, and (iii) potent "steroid-like" efficacy in a chronic dust-mite antigen skin inflammation treatment model. NF-kappaB Decoy exerts its anti-inflammatory action through the effective inhibition of essential regulators of inflammation and by induction of apoptosis of key immune cells. Unlike betamethasone valerate (BMV), long-term NF-kappaB Decoy treatment does not induce skin atrophy. Moreover, topical NF-kappaB Decoy, in contrast to BMV, restores compromised stratum corneum integrity and barrier function. Steroid withdrawal causes rapid rebound of inflammation, while the NF-kappaB Decoy therapeutic benefit was maintained for weeks. Thus, topical NF-kappaB Decoy provides a novel mechanism of reducing chronic skin inflammation with improved skin homeostasis and minimal side effects.


Subject(s)
Dermatitis, Atopic/drug therapy , Immunosuppressive Agents/administration & dosage , Oligodeoxyribonucleotides/administration & dosage , Skin/drug effects , Administration, Topical , Animals , Apoptosis/drug effects , Apoptosis/immunology , Atrophy , Cell Division/drug effects , Cell Division/immunology , Dermatitis, Atopic/immunology , Dermatitis, Atopic/pathology , Ear, External , Edema/drug therapy , Edema/immunology , Male , Mice , Mice, Inbred Strains , Ointments , Permeability/drug effects , Skin/immunology , Skin/pathology
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