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 useABSTRACT
2-(1,1-Dioxo-2H-[1,2,4]benzothiadiazin-3-yl)-1-hydroxynaphthalene derivatives as potential anti-HCV drugs targeting NS5B polymerase have been investigated. Their synthesis, HCV NS5B polymerase inhibition and replicon activity are discussed.
Subject(s)
Antiviral Agents/chemical synthesis , Benzothiadiazines/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Hepatitis C/drug therapy , Naphthalenes/antagonists & inhibitors , Naphthols/chemical synthesis , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Antiviral Agents/pharmacology , Benzothiadiazines/pharmacology , Chemistry, Pharmaceutical/methods , Drug Design , Enzyme Inhibitors/pharmacology , Hepacivirus/metabolism , Humans , In Vitro Techniques , Inhibitory Concentration 50 , Magnetic Resonance Spectroscopy , Models, Chemical , Molecular Structure , Naphthalenes/chemistry , Naphthols/pharmacology , Structure-Activity RelationshipABSTRACT
3-(1,1-Dioxo-2H-[1,2,4]benzothiadiazin-3-yl)-4-hydroxy-2H-quinolizin-2-one derivatives as potential anti-HCV drugs targeting NS5B polymerase have been investigated. Their synthesis, HCV NS5B polymerase inhibition, and replicon activity are discussed.
Subject(s)
Antiviral Agents/chemical synthesis , Benzothiadiazines/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Hepatitis C/drug therapy , Quinolizines/chemical synthesis , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Antiviral Agents/pharmacology , Benzothiadiazines/pharmacology , Chemistry, Pharmaceutical/methods , Drug Design , Enzyme Inhibitors/pharmacology , Hepacivirus/metabolism , In Vitro Techniques , Inhibitory Concentration 50 , Magnetic Resonance Spectroscopy , Models, Chemical , Molecular Structure , Quinolizines/pharmacology , Structure-Activity Relationship , Viral Nonstructural Proteins/chemistryABSTRACT
(1,1-Dioxo-2H-[1,2,4]benzothiadiazin-3-yl) azolo[1,5-a]pyridine and azolo[1,5-a]pyrimidine derivatives have been investigated as potential anti-HCV drugs. Their synthesis, HCV NS5B polymerase inhibition, and replicon activity are discussed.
Subject(s)
Antiviral Agents/chemical synthesis , Azoles/chemical synthesis , Benzothiadiazines/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Hepatitis C/drug therapy , Pyridines/chemical synthesis , Pyrimidines/chemical synthesis , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Antiviral Agents/pharmacology , Azoles/pharmacology , Benzothiadiazines/pharmacology , Chemistry, Pharmaceutical/methods , Drug Design , Enzyme Inhibitors/pharmacology , Hepacivirus/metabolism , In Vitro Techniques , Inhibitory Concentration 50 , Magnetic Resonance Spectroscopy , Models, Chemical , Molecular Structure , Pyridines/pharmacology , Pyrimidines/pharmacology , Structure-Activity Relationship , Viral Nonstructural Proteins/chemistryABSTRACT
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.