RESUMEN
The synthesis, structure-activity relationships, and biological properties of a novel series of imidazole-containing inhibitors of farnesyltransferase are described. Starting from a 3-aminopyrrolidinone core, a systematic series of modifications provided 5h, a non-thiol, non-peptide farnesyltransferase inhibitor with excellent bioavailability in dogs. Compound 5h was found to have an unusually favorable ratio of cell potency to intrinsic potency, compared with other known FTIs. It exhibited excellent potency against a range of tumor cell lines in vitro and showed full efficacy in the K-rasB transgenic mouse model.
Asunto(s)
Transferasas Alquil y Aril/antagonistas & inhibidores , Antineoplásicos/síntesis química , Inhibidores Enzimáticos/síntesis química , Imidazoles/síntesis química , Lactamas/síntesis química , Nitrilos/síntesis química , Pirrolidinonas/síntesis química , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Sitios de Unión , Unión Competitiva , Disponibilidad Biológica , Línea Celular Transformada , Perros , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Farnesiltransferasa , Genes ras , Imidazoles/química , Imidazoles/farmacología , Lactamas/química , Lactamas/farmacología , Ratones , Ratones Transgénicos , Modelos Moleculares , Neoplasias Experimentales/patología , Nitrilos/química , Nitrilos/farmacología , Pirrolidinonas/química , Pirrolidinonas/farmacología , Ensayo de Unión Radioligante , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A series of amino acid-based linkers was used to investigate the effects of various substituents upon the potency, pharmacokinetic properties, and conformation of macrocyclic farnesyl-protein transferase inhibitors (FTIs). As a result of the studies described herein, highly potent FTIs with improved pharmacokinetic profiles have been identified.