RESUMEN
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.
Asunto(s)
Antivirales/química , Inhibidores Enzimáticos/química , Hepacivirus/enzimología , Piridonas/química , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , Proteínas no Estructurales Virales/metabolismo , Animales , Antivirales/síntesis química , Antivirales/farmacología , Sitios de Unión , Cristalografía por Rayos X , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Humanos , Macaca fascicularis , Microsomas Hepáticos/metabolismo , Piridonas/síntesis química , Piridonas/farmacología , ARN Polimerasa Dependiente del ARN/metabolismo , Relación Estructura-ActividadRESUMEN
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%).
Asunto(s)
ARN Polimerasas Dirigidas por ADN/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Piridonas/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Administración Oral , Animales , Disponibilidad Biológica , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Haplorrinos , Piridonas/administración & dosificación , Piridonas/química , Piridonas/farmacocinética , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Disponibilidad Biológica , Diseño de Fármacos , Relación Estructura-Actividad , Antivirales/farmacocinética , Química Farmacéutica , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Genotipo , Hepacivirus/efectos de los fármacos , Hepatitis C , Estructura Molecular , ARN Polimerasa Dependiente del ARN , Proteínas no Estructurales Virales/antagonistas & inhibidoresRESUMEN
5-Hydroxy-3(2H)-pyridazinone derivatives were investigated as potent inhibitors of genotype 1 HCV NS5B polymerase focusing on the optimization of their drug metabolism and pharmacokinetics (DMPK) profiles. This investigation led to the discovery of potent inhibitors with improved DMPK properties.
Asunto(s)
Antivirales/síntesis química , Antivirales/farmacocinética , Hepacivirus/enzimología , Piridazinas/síntesis química , Piridazinas/farmacocinética , Proteínas no Estructurales Virales/antagonistas & inhibidores , Administración Oral , Animales , Antivirales/química , Técnicas Químicas Combinatorias , Diseño de Fármacos , Haplorrinos , Concentración 50 Inhibidora , Modelos Moleculares , Estructura Molecular , Piridazinas/química , Relación Estructura-ActividadRESUMEN
Hexahydro-pyrrolo- and hexahydro-1H-pyrido[1,2-b]pyridazin-2-one analogs were discovered as a novel class of inhibitors of genotype 1 HCV NS5B polymerase. Among these, compound 4c displayed potent inhibitory activities in biochemical and replicon assays (IC(50) (1b) <10 nM; EC(50) (1b)=34 nM) as well as good stability towards human liver microsomes (HLM t(1/2) =59 min).
Asunto(s)
Antivirales/síntesis química , Antivirales/farmacología , Hepacivirus/efectos de los fármacos , Microsomas Hepáticos/efectos de los fármacos , Piridazinas/síntesis química , Piridazinas/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Antivirales/química , Técnicas Químicas Combinatorias , Cristalografía por Rayos X , Diseño de Fármacos , Humanos , Estructura Molecular , Piridazinas/química , Relación Estructura-ActividadRESUMEN
5-Hydroxy-3(2H)-pyridazinone derivatives were investigated as inhibitors of genotype 1 HCV NS5B polymerase. Lead optimization led to the discovery of compound 3a, which displayed potent inhibitory activities in biochemical and replicon assays [IC(50) (1b)<10nM; IC(50) (1a)=22 nM; EC(50) (1b)=5nM], good stability toward human liver microsomes (HLM t(1/2)>60 min), and high ratios of liver to plasma concentrations 12h after a single oral administration to rats.
Asunto(s)
Antivirales/síntesis química , Antivirales/farmacocinética , Hepacivirus/efectos de los fármacos , Piridazinas/síntesis química , Piridazinas/farmacocinética , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , Proteínas no Estructurales Virales/antagonistas & inhibidores , Administración Oral , Animales , Antivirales/sangre , Antivirales/química , Técnicas Químicas Combinatorias , Diseño de Fármacos , Humanos , Microsomas Hepáticos/efectos de los fármacos , Estructura Molecular , Piridazinas/sangre , Piridazinas/química , Ratas , Relación Estructura-ActividadRESUMEN
A novel series of HCV NS5B polymerase inhibitors comprising 1,1-dioxoisothiazoles and benzo[b]thiophene-1,1-dioxides were designed, synthesized, and evaluated. SAR studies guided by structure-based design led to the identification of a number of potent NS5B inhibitors with nanomolar IC(50) values. The most potent compound exhibited IC(50) less than 10nM against the genotype 1b HCV polymerase and EC(50) of 70 nM against a genotype 1b replicon in cell culture. The DMPK properties of selected compounds were also evaluated.
Asunto(s)
Antivirales/síntesis química , Antivirales/farmacocinética , Inhibidores Enzimáticos/farmacocinética , Tiazoles/síntesis química , Tiofenos/síntesis química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Química Farmacéutica/métodos , Cristalografía por Rayos X/métodos , Diseño de Fármacos , Genotipo , Humanos , Concentración 50 Inhibidora , Modelos Químicos , Conformación Molecular , ARN Viral/metabolismo , Relación Estructura-Actividad , Tiazoles/farmacocinética , Tiofenos/farmacocinéticaRESUMEN
Pyrrolo[1,2-b]pyridazin-2-one analogs were discovered as a novel class of inhibitors of genotype 1 HCV NS5B polymerase. Structure-based design led to the discovery of compound 3 k, which displayed potent inhibitory activities in biochemical and replicon assays (IC(50) (1b)<10nM; EC(50) (1b)=12 nM) as well as good stability towards human liver microsomes (HLM t(1/2)>60 min).
Asunto(s)
Antivirales/farmacología , Piridazinas/farmacología , Pirroles/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Antivirales/síntesis química , Antivirales/química , Sitios de Unión/efectos de los fármacos , Línea Celular , Cristalografía por Rayos X , Humanos , Enlace de Hidrógeno , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Piridazinas/síntesis química , Piridazinas/química , Pirroles/síntesis química , Pirroles/química , Relación Estructura-Actividad , Proteínas no Estructurales Virales/químicaRESUMEN
4-(1,1-Dioxo-1,4-dihydro-1lambda(6)-benzo[1,4]thiazin-3-yl)-5-hydroxy-2H-pyridazin-3-one analogs were discovered as a novel class of inhibitors of HCV NS5B polymerase. Structure-based design led to the identification of compound 3a that displayed potent inhibitory activities in biochemical and replicon assays (1b IC(50)<10 nM; 1b EC(50)=1.1 nM) as well as good stability toward human liver microsomes (HLM t(1/2)>60 min).
Asunto(s)
Química Farmacéutica/métodos , Hepacivirus/enzimología , Microsomas Hepáticos/enzimología , Piridazinas/síntesis química , Piridazinas/farmacología , Tiazinas/síntesis química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Proteínas no Estructurales Virales/química , Células CACO-2 , Cristalografía por Rayos X/métodos , Diseño de Fármacos , Hepacivirus/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Modelos Químicos , Conformación Molecular , Piridazinas/química , Relación Estructura-Actividad , Tiazinas/química , Tiazinas/farmacología , Factores de TiempoRESUMEN
ANA975, a 5-amino-3-beta -D-ribofuranosyl-3H-thiazolo[4,5-d]pyrimidin-2-one derivative, was synthesized in the search of an oral prodrug of isatoribine, a small molecule toll-like receptor 7 (TLR-7) agonist. Several strategies were studied to enable the kilogram-scale synthesis of ANA975. Three general total syntheses are described. In the phase I clinical study of ANA975 against hepatitis C virus (HCV), conversion to isatoribine in plasma was rapid and effective, delivering levels of isatoribine that have been shown to be clinically relevant.