RESUMO
We describe the structure-based design of a novel lead chemotype that binds to thumb pocket 2 of HCV NS5B polymerase and inhibits cell-based gt1 subgenomic reporter replicons at sub-micromolar concentrations (EC50<200nM). This new class of potent thumb pocket 2 inhibitors features a 1H-quinazolin-4-one scaffold derived from hybridization of a previously reported, low affinity thiazolone chemotype with our recently described anthranilic acid series. Guided by X-ray structural information, a key NS5B-ligand interaction involving the carboxylate group of anthranilic acid based inhibitors was replaced by a neutral two-point hydrogen bonding interaction between the quinazolinone scaffold and the protein backbone. The in vitro ADME and in vivo rat PK profile of representative analogs are also presented and provide areas for future optimization of this new class of HCV polymerase inhibitors.
Assuntos
Antivirais/química , Desenho de Fármacos , Hepacivirus/enzimologia , Quinazolinonas/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Regulação Alostérica , Animais , Antivirais/síntese química , Antivirais/farmacocinética , Sítios de Ligação , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Hepacivirus/fisiologia , Simulação de Acoplamento Molecular , Estrutura Terciária de Proteína , Quinazolinonas/síntese química , Quinazolinonas/farmacocinética , Ratos , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/metabolismo , Replicação Viral/efeitos dos fármacos , ortoaminobenzoatos/químicaRESUMO
In this report we describe the synthesis and evaluation of diverse 4-arylproline analogs as HCV NS3 protease inhibitors. Introduction of this novel P2 moiety opened up new SAR and, in combination with a synthetic approach providing a versatile handle, allowed for efficient exploitation of this novel series of NS3 protease inhibitors. Multiple structural modifications of the aryl group at the 4-proline, guided by structural analysis, led to the identification of analogs which were very potent in both enzymatic and cell based assays. The impact of this systematic SAR on different drug properties is reported.
Assuntos
Antivirais/síntese química , Hepacivirus/enzimologia , Prolina/análogos & derivados , Inibidores de Proteases/síntese química , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/química , Antivirais/farmacocinética , Sítios de Ligação , Desenho de Fármacos , Meia-Vida , Hepacivirus/fisiologia , Simulação de Acoplamento Molecular , Prolina/síntese química , Prolina/farmacocinética , Inibidores de Proteases/química , Inibidores de Proteases/farmacocinética , Estrutura Terciária de Proteína , Ratos , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/metabolismo , Replicação Viral/efeitos dos fármacosRESUMO
BACKGROUND: Imaging, in radiotherapy, has become a routine tool for repositioning of the target volume at each session. The repositioning precision, currently infracentimetric, evolves along with the irradiation techniques. This retrospective study aimed to identify practices and doses resulting from the use of high energy planar imaging (portal imaging) in daily practice. METHODS: A retrospective survey of portal images (PIs) was carried out over 10 years for 2,403 patients and for three linacs (1 Elekta SLi, 2 Varian Clinac) for postoperative mammary irradiations. Images were taken using a standardized number of monitor units (MU) for all patients. Due to the variable sensitivities of the detectors and the possibility of adjustment of the detector-patient distance, the number of MU were 3; 2 and 1 respectively, for Elekta SLi®, Clinac 600® and Clinac 2100®. Then, a representative cumulated dose was calculated in simplified reference conditions (5 cm depth, beam of 10 cm × 10 cm, 6 MV), considering the total number of images taken during the whole treatment course. The consistency between the representative doses and the actual absorbed doses received by the patients was verified by simulating a series of typical cases with the treatment plan dose calculation system. RESULTS: The delivered doses differ significantly between the three linacs. The mean representative dose values by complete treatment were 0.695; 0.241 and 0.216 Gy, respectively, for SLi, Clinac 600 and Clinac 2100. However, 15 patients were exposed to a dose >2 Gy with a maximum dose of 5.05 Gy. The simulated doses were very similar to the representative doses. CONCLUSIONS: A significant dose delivery was highlighted by this study. These representative doses are presently communicated weekly to the radiation oncologist for the radiation protection of their patients. Moreover, they should be taken into account in a possible study of long-term stochastic risks.
RESUMO
The design and synthesis of tripeptide-based inhibitors of the HCV NS3 protease containing a novel P2-triazole is described. Replacement of the P2 quinoline with a triazole moiety provided a versatile handle which could be expediently modified to generate a diverse series of inhibitors. Further refinement by the incorporation of an aryl-substituted triazole and replacement of the P1 acid with an acyl sulfonamide ultimately provided inhibitors with interesting cellular activity.
Assuntos
Prolina/análogos & derivados , Prolina/síntese química , Prolina/farmacologia , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Triazóis/síntese química , Triazóis/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Técnicas de Química Combinatória , Hepacivirus/enzimologia , Modelos Moleculares , Estrutura Molecular , Prolina/química , Inibidores de Proteases/química , Relação Estrutura-Atividade , Triazóis/químicaRESUMO
A series of novel 8-substituted dipyridodiazepinone-based inhibitors were investigated for their antiviral activity against wild type human immunodeficiency virus (HIV-1) and the clinically prevalent K103N/Y181C mutant virus. Our efforts have resulted in a series of benzoic acid analogues that are potent inhibitors of HIV-1 replication against a panel of HIV-1 strains resistant to non-nucleoside reverse transcriptase inhibitors (NNRTIs). Furthermore, the combination of good antiviral potency, a broad spectrum of activity, and an excellent pharmacokinetic profile provides strong justification for the further development of compound (7) as a potential treatment for wild type and NNRTI-resistant HIV-1 infection.
Assuntos
Fármacos Anti-HIV/síntese química , Azepinas/síntese química , Farmacorresistência Viral , HIV-1/efeitos dos fármacos , Piridinas/síntese química , Inibidores da Transcriptase Reversa/farmacologia , Animais , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Azepinas/química , Azepinas/farmacologia , Células CACO-2 , Cães , HIV-1/genética , Humanos , Técnicas In Vitro , Macaca mulatta , Masculino , Microssomos Hepáticos/metabolismo , Mutação , Permeabilidade , Piridinas/química , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacosRESUMO
C-Terminal carboxylic acid containing inhibitors of the NS3 protease are reported. A novel series of linear tripeptide inhibitors that are very potent and selective against the NS3 protease are described. A substantial contribution to the potency of these linear inhibitors arises from the introduction of a C8 substituent on the B-ring of the quinoline moiety found on the P2 of these inhibitors. The introduction of a C8 methyl group results not only in a modest increase in the cell-based potency of these inhibitors but more importantly in a much better pharmacokinetic profile in rats as well. Exploration of C8-substitutions led to the identification of the bromo derivative as the best group at this position, resulting in a significant increase in the cell-based potency of this class of inhibitors. Structure-activity studies on the C8-bromo derivatives ultimately led to the discovery of clinical candidate 29 (BI 201335), a very potent and selective inhibitor of genotype1 NS3 protease with a promising PK profile in rats.
Assuntos
Antivirais/síntese química , Hepacivirus/enzimologia , Oligopeptídeos/síntese química , Inibidores de Serina Proteinase/síntese química , Tiazóis/síntese química , Proteínas não Estruturais Virais/antagonistas & inibidores , Ácidos Aminoisobutíricos , Animais , Antivirais/farmacocinética , Antivirais/farmacologia , Hepacivirus/genética , Humanos , Leucina/análogos & derivados , Masculino , Microssomos Hepáticos/metabolismo , Oligopeptídeos/farmacocinética , Oligopeptídeos/farmacologia , Prolina/análogos & derivados , Quinolinas , Ratos , Ratos Sprague-Dawley , Replicon/efeitos dos fármacos , Inibidores de Serina Proteinase/farmacocinética , Inibidores de Serina Proteinase/farmacologia , Relação Estrutura-Atividade , Tiazóis/farmacocinética , Tiazóis/farmacologiaRESUMO
We have previously reported the discovery and initial SAR optimization of the first series of inhibitors of the human papillomavirus type-11 (HPV11) E1-E2 protein-protein interaction. These inhibitors featured an indandione system spiro-fused onto an all syn substituted tetrahydrofuran ring. In this paper, we report new SAR efforts which have led to the identification of the first low nanomolar inhibitor of the HPV11 E1-E2 protein-protein interaction. In addition, we report a combined NMR and computational chemistry approach which allowed the successful determination of the absolute stereochemistry of the active species originating from the initial racemic lead.
Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Proteínas de Ligação a DNA/antagonistas & inibidores , Papillomavirus Humano 11/efeitos dos fármacos , Proteínas Virais/antagonistas & inibidores , Química Farmacêutica , Cromatografia Líquida de Alta Pressão , Biologia Computacional , Simulação por Computador , Compostos de Epóxi/química , Papillomavirus Humano 11/metabolismo , Humanos , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Conformação Molecular , Espectrometria de Massas por Ionização por Electrospray , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
We have discovered a series of inhibitors of the assembly of the HPV11 E1-E2-origin DNA complex, which incorporate an indandione fused to a substituted tetrahydrofuran.