RESUMO
5,6-Dihydro-1H-pyridin-2-one analogs were discovered as a novel class of inhibitors of genotype 1 HCV NS5B polymerase. Among these, compound 4ad displayed potent inhibitory activities in biochemical and replicon assays (IC(50) (1b)<10nM; IC(50) (1a)<25nM, EC(50) (1b)=16nM), good in vitro DMPK properties, as well as moderate oral bioavailability in monkeys (F=24%).
Assuntos
RNA Polimerases Dirigidas por DNA/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Piridonas/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Haplorrinos , Piridonas/administração & dosagem , Piridonas/química , Piridonas/farmacocinética , Relação Estrutura-AtividadeRESUMO
The discovery of 5,5'- and 6,6'-dialkyl-5,6-dihydro-1H-pyridin-2-ones as potent inhibitors of the HCV RNA-dependent RNA polymerase (NS5B) is described. Several of these agents also display potent antiviral activity in cell culture experiments (EC50 <0.10 microM). In vitro DMPK data for selected compounds as well as crystal structures of representative inhibitors complexed with the NS5B protein are also disclosed.
Assuntos
Antivirais/química , Inibidores Enzimáticos/química , Hepacivirus/enzimologia , Piridonas/química , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Proteínas não Estruturais Virais/metabolismo , Animais , Antivirais/síntese química , Antivirais/farmacologia , Sítios de Ligação , Cristalografia por Raios X , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Humanos , Macaca fascicularis , Microssomos Hepáticos/metabolismo , Piridonas/síntese química , Piridonas/farmacologia , RNA Polimerase Dependente de RNA/metabolismo , Relação Estrutura-AtividadeRESUMO
A novel series of non-nucleoside small molecules containing a tricyclic dihydropyridinone structural motif was identified as potent HCV NS5B polymerase inhibitors. Driven by structure-based design and building on our previous efforts in related series of molecules, we undertook extensive SAR studies, in which we identified a number of metabolically stable and very potent compounds in genotype 1a and 1b replicon assays. This work culminated in the discovery of several inhibitors, which combined potent in vitro antiviral activity against both 1a and 1b genotypes, metabolic stability, good oral bioavailability, and high C(12) (PO)/EC(50) ratios.
Assuntos
Disponibilidade Biológica , Desenho de Fármacos , Relação Estrutura-Atividade , Antivirais/farmacocinética , Química Farmacêutica , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Genótipo , Hepacivirus/efeitos dos fármacos , Hepatite C , Estrutura Molecular , RNA Polimerase Dependente de RNA , Proteínas não Estruturais Virais/antagonistas & inibidoresRESUMO
The synthesis of 4-(1',1'-dioxo-1',4'-dihydro-1'lambda(6)-benzo[1',2',4']thiadiazin-3'-yl)-5-hydroxy-2H-pyridazin-3-ones bearing 6-amino substituents as potent inhibitors of the HCV RNA-dependent RNA polymerase (NS5B) is described. Several of these agents also display potent antiviral activity in cell culture experiments (EC(50)<0.10 microM). In vitro DMPK data (microsome t(1/2), Caco-2 P(app)) for many of the compounds are also disclosed, and a crystal structure of a representative inhibitor complexed with the NS5B protein is discussed.
Assuntos
Antivirais/síntese química , Química Farmacêutica/métodos , Óxidos S-Cíclicos/síntese química , Piridazinas/química , Piridazinas/síntese química , Tiadiazinas/síntese química , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/química , Antivirais/farmacologia , Células CACO-2 , Cristalografia por Raios X/métodos , Óxidos S-Cíclicos/farmacologia , RNA Polimerases Dirigidas por DNA/química , Desenho de Fármacos , Genótipo , Humanos , Concentração Inibidora 50 , Microssomos/metabolismo , Modelos Químicos , Conformação Molecular , Piridazinas/farmacologia , Relação Estrutura-Atividade , Tiadiazinas/farmacologiaRESUMO
BACKGROUND: The effect of smoking on soft tissues after periodontal treatment has been extensively studied. However, little focus has been placed on the impact of smoking on bone regeneration after treatment. The aim of this review is to systematically assess the effect of smoking on bone regeneration after periodontal treatment. METHODS: A protocol was established and studies were sourced from five electronic databases. Screening, data abstraction, and quality assessment was conducted by two review authors. Prospective and retrospective clinical studies assessing bone regeneration in smokers and non-smokers after periodontal therapy were selected. In addition, arms of clinical trials comparing different interventions that reported results separately for smokers and non-smokers were also included. Primary outcome measures were based on clinical and/or radiographic indicators of bone regeneration after periodontal therapy. The review and meta-analysis followed many of the recommendations outlined in the preferred reporting items for systematic reviews and meta-analyses statement. RESULTS: Six of 10 studies included in this review concluded that smoking negatively influenced bone regeneration. A meta-analysis of a subgroup of three studies demonstrated that smoking resulted in significantly less bone gain (P = 0.03) as measured by a change in the probing bone level after the treatment of intrabony defects with guided tissue regeneration. The meta-analysis showed a standardized mean difference of -2.05 (95% confidence interval: -2.64 to -1.47) using the random-effects model. CONCLUSIONS: Smoking has a negative effect on bone regeneration after periodontal treatment. Patients should be advised that their smoking habit may result in poorer bone regeneration after periodontal treatment.