RESUMO
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.
Assuntos
Antivirais/farmacocinética , Hepacivirus/efeitos dos fármacos , Inibidores de Proteases/farmacocinética , Simeprevir/farmacocinética , Proteínas não Estruturais Virais/metabolismo , Animais , Antivirais/uso terapêutico , Sítios de Ligação , Cães , Haplorrinos , Hepacivirus/enzimologia , Hepatite C/tratamento farmacológico , Hepatite C/virologia , Humanos , Camundongos , Estrutura Molecular , Inibidores de Proteases/uso terapêutico , Ratos , Simeprevir/uso terapêuticoRESUMO
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.
Assuntos
Antivirais/síntese química , Benzotiadiazinas/síntese química , Inibidores Enzimáticos/síntese química , Hepatite C/tratamento farmacológico , Quinolizinas/síntese química , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/farmacologia , Benzotiadiazinas/farmacologia , Química Farmacêutica/métodos , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Hepacivirus/metabolismo , Técnicas In Vitro , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Modelos Químicos , Estrutura Molecular , Quinolizinas/farmacologia , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/químicaRESUMO
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.
Assuntos
Antivirais/síntese química , Benzotiadiazinas/síntese química , Inibidores Enzimáticos/síntese química , Hepatite C/tratamento farmacológico , Naftalenos/antagonistas & inibidores , Naftóis/síntese química , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/farmacologia , Benzotiadiazinas/farmacologia , Química Farmacêutica/métodos , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Hepacivirus/metabolismo , Humanos , Técnicas In Vitro , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Modelos Químicos , Estrutura Molecular , Naftalenos/química , Naftóis/farmacologia , Relação Estrutura-AtividadeRESUMO
(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.
Assuntos
Antivirais/síntese química , Azóis/síntese química , Benzotiadiazinas/síntese química , Inibidores Enzimáticos/síntese química , Hepatite C/tratamento farmacológico , Piridinas/síntese química , Pirimidinas/síntese química , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/farmacologia , Azóis/farmacologia , Benzotiadiazinas/farmacologia , Química Farmacêutica/métodos , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Hepacivirus/metabolismo , Técnicas In Vitro , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Modelos Químicos , Estrutura Molecular , Piridinas/farmacologia , Pirimidinas/farmacologia , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/químicaRESUMO
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.
