RESUMEN
Efforts to improve the genotype 1a potency and pharmacokinetics of earlier naphthyridine-based HCV NS5A inhibitors resulted in the discovery of a novel series of pyrido[2,3-d]pyrimidine compounds, which displayed potent inhibition of HCV genotypes 1a and 1b in the replicon assay. SAR in this system revealed that the introduction of amides bearing an additional 'E' ring provided compounds with improved potency and pharmacokinetics. Introduction of a chiral center on the amide portion resulted in the observation of a stereochemical dependence for replicon potency and provided a site for the attachment of functional groups useful for improving the solubility of the series. Compound 21 was selected for administration in an HCV-infected chimpanzee. Observation of a robust viral load decline provided positive proof of concept for inhibition of HCV replication in vivo for the compound series.
Asunto(s)
Pirimidinas/química , Pirimidinas/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Descubrimiento de Drogas , Humanos , Relación Estructura-Actividad , Proteínas no Estructurales Virales/química , Proteínas no Estructurales Virales/metabolismoRESUMEN
Isatins are valuable intermediates for heterocyclic chemistry. Most of the common methods for their production are less than adequate when the number and lipophilicity of substituents on the targeted isatin are increased. Our group desired such molecules and identified an alternative method for their production.
RESUMEN
The synthesis of several pyrido[2,3-d]pyrimidine and pyrimido[4,5-d]pyrimidine analogs is described with one such analog possessing subnanomolar potency in both genotype 1a and 1b cell culture HCV replicon assays.
Asunto(s)
Antivirales/síntesis química , Hepacivirus/efectos de los fármacos , Pirimidinas/síntesis química , ARN Viral/antagonistas & inhibidores , Antivirales/farmacología , Línea Celular Tumoral , Genotipo , Hepacivirus/fisiología , Humanos , Pirimidinas/farmacología , ARN Viral/biosíntesis , Replicón/efectos de los fármacos , Relación Estructura-Actividad , Replicación Viral/efectos de los fármacosRESUMEN
ABT-072 is a non-nucleoside HCV NS5B polymerase inhibitor that was discovered as part of a program to identify new direct-acting antivirals (DAAs) for the treatment of HCV infection. This compound was identified during a medicinal chemistry effort to improve on an original lead, inhibitor 1, which we described in a previous publication. Replacement of the amide linkage in 1 with a trans-olefin resulted in improved compound permeability and solubility and provided much better pharmacokinetic properties in preclinical species. Replacement of the dihydrouracil in 1 with an N-linked uracil provided better potency in the genotype 1 replicon assay. Results from phase 1 clinical studies supported once-daily oral dosing with ABT-072 in HCV infected patients. A phase 2 clinical study that combined ABT-072 with the HCV protease inhibitor ABT-450 provided a sustained virologic response at 24 weeks after dosing (SVR24) in 10 of 11 patients who received treatment.
Asunto(s)
Citosina/análogos & derivados , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Hepacivirus/enzimología , Estilbenos/química , Sulfonamidas/síntesis química , Sulfonamidas/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Administración Oral , Disponibilidad Biológica , Técnicas de Química Sintética , Citosina/síntesis química , Citosina/química , Citosina/farmacocinética , Citosina/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Humanos , Permeabilidad , Estereoisomerismo , Sulfonamidas/química , Sulfonamidas/farmacocinética , Distribución Tisular , Proteínas no Estructurales Virales/químicaRESUMEN
We describe here N-phenylpyrrolidine-based inhibitors of HCV NS5A with excellent potency, metabolic stability, and pharmacokinetics. Compounds with 2S,5S stereochemistry at the pyrrolidine ring provided improved genotype 1 (GT1) potency compared to the 2R,5R analogues. Furthermore, the attachment of substituents at the 4-position of the central N-phenyl group resulted in compounds with improved potency. Substitution with tert-butyl, as in compound 38 (ABT-267), provided compounds with low-picomolar EC50 values and superior pharmacokinetics. It was discovered that compound 38 was a pan-genotypic HCV inhibitor, with an EC50 range of 1.7-19.3 pM against GT1a, -1b, -2a, -2b, -3a, -4a, and -5a and 366 pM against GT6a. Compound 38 decreased HCV RNA up to 3.10 log10 IU/mL during 3-day monotherapy in treatment-naive HCV GT1-infected subjects and is currently in phase 3 clinical trials in combination with an NS3 protease inhibitor with ritonavir (r) (ABT-450/r) and an NS5B non-nucleoside polymerase inhibitor (ABT-333), with and without ribavirin.
Asunto(s)
Anilidas/farmacología , Antivirales/farmacología , Carbamatos/farmacología , Genotipo , Hepacivirus/efectos de los fármacos , Sulfonamidas/farmacología , Uracilo/análogos & derivados , Proteínas no Estructurales Virales/antagonistas & inhibidores , 2-Naftilamina , Anilidas/química , Anilidas/farmacocinética , Animales , Antivirales/química , Antivirales/farmacocinética , Disponibilidad Biológica , Carbamatos/química , Carbamatos/farmacocinética , Línea Celular , Descubrimiento de Drogas , Hepacivirus/enzimología , Humanos , Prolina , Ratas , Sulfonamidas/química , Sulfonamidas/farmacocinética , Uracilo/química , Uracilo/farmacocinética , Uracilo/farmacología , ValinaRESUMEN
Structure-activity relationships for a recently discovered novel ribosome inhibitor (NRI) class of antibacterials were investigated. Preliminary efforts to optimize protein synthesis inhibitory activity of the series through modification of positions 3 and 4 of the naphthyridone lead template resulted in the identification of several biochemically potent analogues. A lack of corresponding whole cell antibacterial activity is thought to be a consequence of poor cellular penetration as evidenced by the enhancement of activity observed for a lead analogue tested in the presence of a cell permeabilizing agent.