Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Resultados 1 - 1 de 1
Filtrar
Más filtros

Banco de datos
Tipo del documento
Publication year range
1.
Bioorg Med Chem Lett ; 43: 128058, 2021 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-33895276

RESUMEN

The protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is one of the three endoplasmic reticulum (ER) transmembrane sensors of the unfolded protein response (UPR) that regulates protein synthesis, alleviates cellular ER stress and has been implicated in tumorigenesis and prolonged cancer cell survival. In this study, we report a series of 2-amino-3-amido-5-aryl-pyridines that we have identified as potent, selective, and orally bioavailable PERK inhibitors. Amongst the series studied herein, compound (28) a (R)-2-Amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-ethylphenyl)-N-isopropylnicotinamide has demonstrated potent biochemical and cellular activity, robust pharmacokinetics and 70% oral bioavailability in mice. Given these data, this compound (28) was studied in the 786-O renal cell carcinoma xenograft model. We observed dose-dependent, statistically significant tumor growth inhibition, supporting the use of this tool compound in additional mechanistic studies.


Asunto(s)
Descubrimiento de Drogas , Piridinas/farmacología , eIF-2 Quinasa/antagonistas & inhibidores , Administración Oral , Disponibilidad Biológica , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Piridinas/administración & dosificación , Piridinas/química , Relación Estructura-Actividad , eIF-2 Quinasa/metabolismo
SELECCIÓN DE REFERENCIAS
Detalles de la búsqueda