RESUMEN
Anaplastic lymphoma kinase (ALK) is a highly attractive therapeutic target for the treatment of some non-small cell lung cancer patients. This Letter describes the further SAR exploration on the novel 3-sulfonylpyrazol-4-amino pyrimidine scaffold. This work identified a compound 53 with very good in vitro/in vivo efficacies, good DMPK properties together with better hERG tolerability and it is currently being profiled for the evaluation as a potential pre-clinical candidate.
Asunto(s)
Antineoplásicos/farmacología , Diseño de Fármacos , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/síntesis química , Pirazoles/farmacología , Pirimidinas/síntesis química , Pirimidinas/farmacología , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Quinasa de Linfoma Anaplásico , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Perros , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Modelos Moleculares , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/patología , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirazoles/química , Pirimidinas/química , Ratas , Proteínas Tirosina Quinasas Receptoras/metabolismo , Relación Estructura-ActividadRESUMEN
A new series of 2,4-diamino pyrimidine derivatives with a sulfone-substituted pyrazole right side-chain were discovered as potent anaplastic lymphoma kinase inhibitors. Structure-activity relationship of the left side-chain on phenyl substitutions were explored which delivered many potent ALK inhibitors. Among them, 29a showed favorable pharmacokinetic profiles in rats and dogs together with significant antitumor efficacy in EML4-ALK fusion xenograft model.