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
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
The previously reported oxytocin antagonist L-371,257 (2) has been modified at its acetylpiperidine terminus to incorporate various pyridine N-oxide groups. This modification has led to the identification of compounds with improved pharmacokinetics and excellent oral bioavailability. The pyridine N-oxide series is exemplified by L-372,662 (30), which possessed good potency in vitro (Ki = 4.1 nM, cloned human oxytocin receptor) and in vivo (intravenous AD50 = 0.71 mg/kg in the rat), excellent oral bioavailability (90% in the rat, 96% in the dog), good aqueous solubility (>8.5 mg/mL at pH 5.2) which should facilitate formulation for iv administration, and excellent selectivity against the human arginine vasopressin receptors. Incorporation of a 5-fluoro substituent on the central benzoyl ring of this class of oxytocin antagonists enhanced in vitro and in vivo potency but was detrimental to the pharmacokinetic profiles of these compounds. Although lipophilic substitution around the pyridine ring of compound 30 gave higher affinity in vitro, such substituents were a metabolic liability and caused shortfalls in vivo. Two approaches to prevent this metabolism, addition of a cyclic constraint and incorporation of trifluoromethyl groups, were examined. The former approach was ineffective because of metabolic hydroxylation on the constrained ring system, whereas the latter showed improvement in plasma pharmacokinetics in some cases.