RESUMEN
HCV NS5A inhibitors have shown impressive in vitro potency profiles in HCV replicon assays thus making them attractive components for inclusion in an all oral fixed dose combination regimen. Herein, we describe the discovery and characterization of silyl proline-containing HCV NS5A inhibitor MK-8325 with good pan-genotype activity and acceptable pharmacokinetic properties.
Asunto(s)
Antivirales/química , Compuestos Heterocíclicos de 4 o más Anillos/química , Prolina/química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Antivirales/farmacocinética , Antivirales/farmacología , Sistema Enzimático del Citocromo P-450/metabolismo , Perros , Genotipo , Semivida , Haplorrinos , Hepacivirus/efectos de los fármacos , Hepacivirus/genética , Hepacivirus/fisiología , Compuestos Heterocíclicos de 4 o más Anillos/farmacocinética , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Humanos , Ratas , Proteínas no Estructurales Virales/metabolismo , Replicación Viral/efectos de los fármacosRESUMEN
As part of an ongoing effort in NS5A inhibition at Merck we now describe our efforts for introducing substitution around the tetracyclic indole core of MK-8742. Fluoro substitution on the core combined with the fluoro substitutions on the proline ring improved the potency against GT1a Y93H significantly. However, no improvement on GT2b potency was achieved. Limiting the fluoro substitution to C-1 of the tetracyclic indole core had a positive impact on the potency against the resistance associated variants, such as GT1a Y93H and GT2b, and the PK profile as well. Compounds, such as 62, with reduced potency shifts between wild type GT1a to GT2b, GT1a Y93H, and GT1a L31V were identified.
Asunto(s)
Antivirales/farmacología , Benzofuranos/farmacología , Imidazoles/farmacología , Indoles/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Antivirales/química , Antivirales/farmacocinética , Benzofuranos/química , Benzofuranos/farmacocinética , Imidazoles/química , Imidazoles/farmacocinética , Indoles/química , Indoles/farmacocinética , Relación Estructura-ActividadRESUMEN
A matched and mixed capping SAR study was conducted on the tetracyclic indole class of HCV NS5A inhibitors to examine the influence of modifications of this region on the overall HCV virologic resistance profiles.
Asunto(s)
Antivirales/química , Hepacivirus/metabolismo , Indoles/química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Antivirales/metabolismo , Antivirales/farmacología , Área Bajo la Curva , Genotipo , Semivida , Hepacivirus/efectos de los fármacos , Hepacivirus/genética , Indoles/metabolismo , Indoles/farmacología , Curva ROC , Ratas , Relación Estructura-Actividad , Proteínas no Estructurales Virales/metabolismoRESUMEN
HCV NS5A inhibitors have shown impressive in vitro potency profiles in HCV replicon assays thus making them attractive components for inclusion in an all oral fixed dose combination treatment regimen. Herein we describe the research efforts that led to the discovery of silyl proline containing HCV NS5A inhibitors such as 7e and 8a with pan-genotype activity profile and acceptable pharmacokinetic properties.
Asunto(s)
Antivirales/química , Antivirales/farmacología , Descubrimiento de Drogas , Hepacivirus/efectos de los fármacos , Hepacivirus/genética , Prolina/análogos & derivados , Silanos/química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Antivirales/síntesis química , Relación Dosis-Respuesta a Droga , Genotipo , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Silanos/farmacología , Relación Estructura-Actividad , Proteínas no Estructurales Virales/genética , Replicación Viral/efectos de los fármacosRESUMEN
The synthesis and hit-to-lead SAR development of a pyrazolo[1,5-a]pyrimidine hit 4 is described leading to a series of potent, selective CHK1 inhibitors such as compound 17r. In the Letter, the further utility of the pyrazolo[1,5-a]pyrimidine template for the development of potent, selective kinase inhibitors is detailed.
Asunto(s)
Inhibidores de Proteínas Quinasas/química , Proteínas Quinasas/química , Pirazoles/química , Pirimidinas/química , Sitios de Unión , Dominio Catalítico , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1) , Cristalografía por Rayos X , Quinasa 2 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 2 Dependiente de la Ciclina/metabolismo , Evaluación Preclínica de Medicamentos , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas/metabolismo , Pirazoles/síntesis química , Pirazoles/farmacología , Pirimidinas/síntesis química , Pirimidinas/farmacología , Relación Estructura-ActividadRESUMEN
Studies directed at the synthesis of (Z)-5-benzylidene-4-arylpyrrol-2(5H)-ones from (Z)-3-aryl-3-haloenoic acids are described. The successful strategy relies on the preparation of (Z)-3-aryl-3-haloenoic acids from acetophenones through the corresponding (Z)-3-aryl-3-haloenals and the conversion of the (Z)-3-aryl-3-haloenoic acids to (Z)-5-benzylidene-4-aryl-5H-furan-2-ones. The furanones were subsequently treated with primary amines and dehydrated to the corresponding (Z)-5-benzylidene-4-arylpyrrol-2(5H)-ones.
RESUMEN
Inhibition of cyclin-dependent kinases (CDKs) has emerged as an attractive strategy for the development of novel oncology therapeutics. Herein is described the utilization of an in vivo screening approach with integrated efficacy and tolerability parameters to identify candidate CDK inhibitors with a suitable balance of activity and tolerability. This approach has resulted in the identification of SCH 727965, a potent and selective CDK inhibitor that is currently undergoing clinical evaluation.
RESUMEN
Properly substituted pyrazolo[1,5-a]pyrimidines are potent and selective CDK2 inhibitors. Compound 15j is orally available and showed efficacy in a mouse A2780 xenograft model.
Asunto(s)
Quinasa 2 Dependiente de la Ciclina/antagonistas & inhibidores , Pirazoles/química , Pirazoles/farmacología , Piridinas/química , Piridinas/farmacología , Administración Oral , Animales , Cristalografía por Rayos X , Quinasa 2 Dependiente de la Ciclina/efectos de los fármacos , Perros , Ensayos de Selección de Medicamentos Antitumorales , Haplorrinos , Ratones , Modelos Animales , Modelos Moleculares , Estructura Molecular , Pirazoles/síntesis química , Piridinas/síntesis química , Ratas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A series of four bicyclic cores were prepared and evaluated as cyclin-dependent kinase-2 (CDK2) inhibitors. From the in-vitro and cell-based analysis, the pyrazolo[1,5-a]pyrimidine core (represented by 9) emerged as the superior core for further elaboration in the identification of novel CDK2 inhibitors.