RESUMEN
A series of 2-arylindole-3-acetamide farnesyl protein transferase inhibitors has been identified. The compounds inhibit the enzyme in a farnesyl pyrophosphate-competitive manner and are selective for farnesyl protein transferase over the related enzyme geranylgeranyltransferase-I. A representative member of this series of inhibitors demonstrates equal effectiveness against HDJ-2 and K-Ras farnesylation in a cell-based assay when geranylgeranylation is suppressed.
Asunto(s)
Transferasas Alquil y Aril/antagonistas & inhibidores , Ácidos Indolacéticos/metabolismo , Ácidos Indolacéticos/farmacología , Prenilación de Proteína/efectos de los fármacos , Proteínas ras/metabolismo , Transferasas Alquil y Aril/metabolismo , Proteínas Portadoras/metabolismo , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , Proteínas del Choque Térmico HSP40 , Proteínas de Choque Térmico/metabolismo , Humanos , Ácidos Indolacéticos/síntesis química , Prenilación de Proteína/fisiología , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Structure-activity studies on the oxytocin antagonist 1 (L-371,257; Ki = 9.3 nM) have led to the identification of a related series of compounds containing an ortho-trifluoroethoxyphenylacetyl core which are orally bioavailable and have significantly improved potency in vitro and in vivo, e.g., compound 8 (L-374,943; Ki = 1.4 nM).
Asunto(s)
Oxazinas/síntesis química , Oxazinas/farmacocinética , Oxitocina/antagonistas & inhibidores , Piperidinas/síntesis química , Piperidinas/farmacocinética , Animales , Benzoxazinas , Línea Celular , Humanos , Concentración 50 Inhibidora , Cinética , Ratas , Relación Estructura-ActividadRESUMEN
Structure-activity studies on the oxytocin antagonist 1 (L-371,257) have identified a new series of high affinity, receptor-selective OT antagonists in which the N-acetyl-4-piperidinyl ether terminus in 1 has been replaced with a 1-(aryl)ethoxy group.