RESUMEN
(2'R)-Ethynyl uridine 3, and its (2'S)-diastereomer 10, are synthesised in a divergent fashion from the inexpensive parent nucleoside. Both nucleoside analogues are obtained from a total of 5 simple synthetic steps and 3 trivial column chromatography purifications. To evaluate their effectiveness against HCV NS5B polymerase, the nucleosides were converted to their respective 5'-O-triphosphates. Subsequently, this lead to the discovery of the 2'-ß-ethynyl 18 and -propynyl 20 nucleotides having significantly improved potency over Sofosbuvir triphosphate 24.
Asunto(s)
Antivirales/farmacología , Hepacivirus/efectos de los fármacos , Nucleósidos/farmacología , Uridina/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Antivirales/síntesis química , Antivirales/química , Relación Dosis-Respuesta a Droga , Pruebas de Sensibilidad Microbiana , Conformación Molecular , Nucleósidos/síntesis química , Nucleósidos/química , Relación Estructura-Actividad , Uridina/análogos & derivados , Uridina/químicaRESUMEN
Novel 2'-modified guanosine nucleosides were synthesized from inexpensive starting materials in 7-10 steps via hydroazidation or hydrocyanation reactions of the corresponding 2'-olefin. The antiviral effectiveness of the guanosine nucleosides was evaluated by converting them to the corresponding 5'-O-triphosphates (compounds 38-44) and testing their biochemical inhibitory activity against the wild-type NS5B polymerase.
Asunto(s)
Antivirales/síntesis química , Nucleótidos de Guanina/síntesis química , Inhibidores de la Síntesis del Ácido Nucleico/síntesis química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Alquenos/síntesis química , Azidas/síntesis química , Hepacivirus/enzimología , Proteínas no Estructurales Virales/químicaRESUMEN
The discovery of lead compound 2e was described. Its covalent binding to HCV NS5B polymerase enzyme was investigated by X-ray analysis. The results of distribution, metabolism and pharmacokinetics were reported. Compound 2e was demonstrated to be potent (replicon GT-1b EC50 = 0.003 µM), highly selective, and safe in in vitro and in vivo assays.
Asunto(s)
Inhibidores Enzimáticos/química , Hepacivirus/enzimología , Indoles/química , Quinolinas/química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Cristalografía por Rayos X , Perros , Evaluación Preclínica de Medicamentos , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Haplorrinos , Humanos , Indoles/síntesis química , Indoles/farmacocinética , Indoles/farmacología , Masculino , Simulación de Dinámica Molecular , Unión Proteica , Estructura Terciaria de Proteína , Quinolinas/síntesis química , Quinolinas/farmacocinética , Quinolinas/farmacología , Ratas , Ratas Sprague-Dawley , Proteínas no Estructurales Virales/metabolismoRESUMEN
Starting from indole-based C-3 pyridone HCV NS5B polymerase inhibitor 2, structure-activity relationship (SAR) investigations of the indole N-1 benzyl moiety were performed. This study led to the discovery of irreversible inhibitors with p-fluoro-sulfone- or p-fluoro-nitro-substituted N-1 benzyl groups which achieved breakthrough replicon assay potency (EC(50) = 1 nM). The formation of a covalent bond with adjacent cysteine-366 thiol was was proved by mass spectroscopy and X-ray crystal structure studies. The C-5 ethyl C-2 carboxylic acid derivative 47 had an excellent oral area-under-the-curve (AUC) of 18 µM·h (10 mg/kg). Its oral exposure in monkeys and dogs was also very good. The NMR ALARM assay, mass spectroscopy experiments, in vitro counter screening, and toxicology assays demonstrated that the covalent bond formation between compound 47 and the protein was highly selective and specific. The overall excellent profile of 47 made it an interesting candidate for further investigation.
Asunto(s)
Antivirales/síntesis química , Hepacivirus/efectos de los fármacos , Indoles/síntesis química , Nitrocompuestos/síntesis química , Sulfonas/síntesis química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Antivirales/farmacocinética , Antivirales/farmacología , Cristalografía por Rayos X , Perros , Haplorrinos , Hepacivirus/enzimología , Indoles/farmacocinética , Indoles/farmacología , Modelos Moleculares , Estructura Molecular , Pruebas de Mutagenicidad , Nitrocompuestos/farmacocinética , Nitrocompuestos/farmacología , Piridonas/síntesis química , Piridonas/farmacocinética , Piridonas/farmacología , Ratas , Relación Estructura-Actividad , Sulfonas/farmacocinética , Sulfonas/farmacologíaRESUMEN
Development of SAR at the C2 position of indole lead 1, a palm site inhibitor of HCV NS5B polymerase (NS5B IC(50)=0.053µM, replicon EC(50)=4.8µM), is described. Initial screening identified an acyl sulfonamide moiety as an isostere for the C2 carboxylic acid group. Further SAR investigation resulted in identification of acyl sufonamide analog 7q (NS5B IC(50)=0.039µM, replicon EC(50)=0.011µM) with >100-fold improved replicon activity.
Asunto(s)
Antivirales/farmacología , Indoles/química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Química Farmacéutica/métodos , Cristalografía por Rayos X/métodos , Diseño de Fármacos , Humanos , Enlace de Hidrógeno , Concentración 50 Inhibidora , Modelos Químicos , Modelos Moleculares , Conformación Molecular , Relación Estructura-Actividad , Sulfonamidas/químicaRESUMEN
SAR development of indole-based palm site inhibitors of HCV NS5B polymerase exemplified by initial indole lead 1 (NS5B IC(50)=0.9 µM, replicon EC(50)>100 µM) is described. Structure-based drug design led to the incorporation of novel heterocyclic moieties at the indole C3-position which formed a bidentate interaction with the protein backbone. SAR development resulted in leads 7q (NS5B IC(50)=0.032 µM, replicon EC(50)=1.4 µM) and 7r (NS5B IC(50)=0.017 µM, replicon EC(50)=0.3 µM) with improved enzyme and replicon activity.
Asunto(s)
Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Compuestos Heterocíclicos/farmacología , Indoles/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Ácidos Carboxílicos , Dominio Catalítico/efectos de los fármacos , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/química , Indoles/síntesis química , Indoles/química , Modelos Moleculares , Estructura Molecular , Estereoisomerismo , Relación Estructura-Actividad , Proteínas no Estructurales Virales/metabolismoRESUMEN
Several analogs of aristolochic acids were isolated and derivatized into their lactam derivatives to study their inhibition in CDK2 assay. The study helped to derive some conclusions about the structure-activity relation around the phenanthrin moiety. Semi-synthetic aristolactam 21 showed good activity with inhibition IC50 of 35 nM in CDK2 assay. The activity of this compound was comparable to some of the most potent synthetic compounds reported in the literature.
Asunto(s)
Ácidos Aristolóquicos/síntesis química , Proteína Quinasa CDC2/antagonistas & inhibidores , Pirazoles/síntesis química , Quinolinas/síntesis química , Ácidos Aristolóquicos/química , Ácidos Aristolóquicos/farmacología , Línea Celular Tumoral , Simulación por Computador , Cristalografía por Rayos X , Humanos , Concentración 50 Inhibidora , Modelos Moleculares , Estructura Molecular , Pirazoles/química , Pirazoles/farmacología , Quinolinas/química , Quinolinas/farmacología , Relación Estructura-ActividadRESUMEN
Investigation of unexpected levels of impurities in Intron product has revealed the presence of low levels of impurities leached from the silicone tubing (Rehau RAU-SIK) on the Bosch filling line. In order to investigate the effect of these compounds (1a, 1b and 2) on humans, they were isolated identified and synthesized. They were extracted from the tubing by stirring in Intron placebo at room temperature for 72 h and were enriched on a reverse phase CHP-20P column, eluting with gradient aqueous ACN and were separated by HPLC. Structural elucidation of 1a, 1b and 2 by MS and NMR studies demonstrated them to be halogenated biphenyl carboxylic acids. The structures were confirmed by independent synthesis. Levels of extractable impurities in first filled vials of actual production are estimated to be in the range of 0.01-0.55 microg/vial for each leached impurity. Potential toxicity of these extractables does not represent a risk for patients under the conditions of clinical use.
Asunto(s)
Contaminación de Medicamentos , Interferón-alfa/química , Interferón-alfa/aislamiento & purificación , Compuestos Orgánicos/química , Siliconas/química , Tampones (Química) , Química Farmacéutica , Cromatografía Líquida de Alta Presión/métodos , Liofilización , Humanos , Concentración de Iones de Hidrógeno , Interferón alfa-2 , Espectroscopía de Resonancia Magnética/métodos , Espectrometría de Masas/métodos , Estructura Molecular , Polvos , Control de Calidad , Proteínas Recombinantes , Temperatura , Factores de TiempoRESUMEN
The 70% aqueous methanolic extract of the Peruvian plant Oryctanthus sp. was found to contain a novel saccharide of a diene alpha,omega-diacid. Compound 1 was identified as an inhibitor of the VEGF receptor. The structure of this compound was established based on NMR studies. Compound 1 inhibited ligand binding to the VEGF receptor with an IC50 of 5.0 microM.
Asunto(s)
Antineoplásicos/aislamiento & purificación , Antineoplásicos/farmacología , Magnolia/química , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Antineoplásicos/química , Concentración 50 Inhibidora , Espectroscopía de Resonancia Magnética , Estructura Molecular , Receptores de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
The 70% aqueous methanol extract of the Peruvian plant Lippia alva (Verbenaceae) was found to contain three novel compounds, 1, 2, and 3, which were identified as inhibitors of the chemokine receptor CCR5. The structures of 1-3 were established based on extensive NMR studies. Compounds 1-3 inhibited CCR5 receptor signaling as measured by a calcium mobilization assay with IC(50) values of 5.5, 6.0, and 7.2 microg/mL, respectively.
Asunto(s)
Fármacos Anti-VIH/aislamiento & purificación , Antagonistas de los Receptores CCR5 , Ciclopropanos/aislamiento & purificación , Lactonas/aislamiento & purificación , Lippia/química , Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacología , Señalización del Calcio , Línea Celular Tumoral , Ciclopropanos/química , Ciclopropanos/farmacología , Humanos , Lactonas/química , Lactonas/farmacología , Espectroscopía de Resonancia Magnética , Extractos Vegetales/química , Relación Estructura-ActividadRESUMEN
The 70% aqueous methanolic extract of the Peruvian plant Polygonum cuspidatum sp. was found to contain two novel phenolic saccharides 1 and 2, which were identified as inhibitors of the bacterial DNA primase enzyme. Structures of these two compounds were established based on high resolution NMR studies. Compound 1 and 2 inhibited the primase enzyme with an IC(50) of 4 and 5 microM, respectively.
Asunto(s)
Bacterias/enzimología , ADN Primasa/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Fallopia japonica/química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/aislamiento & purificación , Análisis EspectralRESUMEN
The 70% aq methanolic extract of the Peruvian plant Stylogne cauliflora was found to contain two novel oligophenolic compounds SCH 644343 (1) and SCH 644342 (2), which were identified as inhibitors of HCV NS3 protease. The structure of 1 and 2 was established based on high-resolution NMR studies. Compound 1 inhibited HCV NS3 protease with an IC(50) of 0.3 microM, while compound 2 showed an IC(50) of 0.8 microM.
Asunto(s)
Antivirales/aislamiento & purificación , Antivirales/farmacología , Fenoles/farmacología , Plantas Medicinales/química , Inhibidores de Proteasas/aislamiento & purificación , Inhibidores de Proteasas/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Antivirales/química , Concentración 50 Inhibidora , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Fenoles/química , Fenoles/aislamiento & purificación , Inhibidores de Proteasas/química , Proteínas Recombinantes/antagonistas & inhibidores , Serina Endopeptidasas/metabolismoRESUMEN
The aqueous methanolic extract of a sea cucumber was found to contain two triterpene glycosides 1 and 2. The structures of 1 and 2 were established based on high-resolution NMR studies. Compounds 1 and 2 exhibited inhibitory activity (K(i)) of 30 and 5microM, respectively, in a chemokine receptor subtype 5 (CCR5) assay. Both compounds did not show any significant inhibition in a CXCR2 assay at 50microM, suggesting their selectivity for the CCR5 receptor.