RESUMEN
The discovery and optimization of a series of imidazo[1,5-a]pyrazine inhibitors of mTOR is described. HTS hits were optimized for potency, selectivity and metabolic stability to provide the orally bioavailable proof of concept compound 4c that demonstrated target inhibition in vivo and concomitant inhibition of tumor growth in an MDA-MB-231 xenograft model.
Asunto(s)
Imidazoles/farmacología , Proteínas/antagonistas & inhibidores , Pirazinas/farmacología , Factores de Transcripción/antagonistas & inhibidores , Administración Oral , Línea Celular Tumoral , Humanos , Imidazoles/administración & dosificación , Diana Mecanicista del Complejo 1 de la Rapamicina , Modelos Moleculares , Complejos Multiproteicos , Pirazinas/administración & dosificación , Serina-Treonina Quinasas TOR , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A series of novel 8-amino-1,3-disubstituted-imidazo[1,5-a]pyrazines was designed and synthesized as IGF-IR inhibitors.
Asunto(s)
Imidazoles/síntesis química , Imidazoles/farmacología , Pirazinas/síntesis química , Pirazinas/farmacología , Receptor IGF Tipo 1/antagonistas & inhibidores , Adenosina Trifosfato/metabolismo , Animales , Área Bajo la Curva , Sitios de Unión , Disponibilidad Biológica , Cristalografía por Rayos X , Bases de Datos de Proteínas , Semivida , Indicadores y Reactivos , Ratones , Modelos Moleculares , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Relación Estructura-ActividadRESUMEN
A highly effective one-pot Friedländer quinoline synthesis using inexpensive reagents has been developed. o-Nitroarylcarbaldehydes were reduced to o-aminoarylcarbaldehydes with iron in the presence of catalytic HCl (aq.) and subsequently condensed in situ with aldehydes or ketones to form mono- or di-substituted quinolines in high yields (66-100%).