RESUMEN
4-(1-Benzo[1,3]dioxol-5-ylmethylpiperidine-4-ylmethyl)-6-chlorochromen-2-one (7) is a potent, orally bioavailable melanin concentrating hormone receptor 1 (MCHr1) antagonist that causes dose-dependent weight loss in diet-induced obese mice. Further evaluation of 7 in an anesthetized dog model of cardiovascular safety revealed adverse hemodynamic effects at a plasma concentration comparable to the minimally effective therapeutic concentration. These results highlight the need for scrutiny of the cardiovascular safety profile of MCHr1 antagonists.
Asunto(s)
Cumarinas/síntesis química , Piperidinas/síntesis química , Receptores de la Hormona Hipofisaria/antagonistas & inhibidores , Receptores de Somatostatina/antagonistas & inhibidores , Administración Oral , Animales , Fármacos Antiobesidad/efectos adversos , Fármacos Antiobesidad/síntesis química , Fármacos Antiobesidad/farmacología , Disponibilidad Biológica , Presión Sanguínea/efectos de los fármacos , Encéfalo/metabolismo , Línea Celular Tumoral , Cumarinas/efectos adversos , Cumarinas/farmacología , Perros , Ingestión de Alimentos/efectos de los fármacos , Metabolismo Energético , Humanos , Masculino , Ratones , Ratones Obesos , Contracción Miocárdica/efectos de los fármacos , Piperidinas/efectos adversos , Piperidinas/farmacología , Ensayo de Unión Radioligante , Relación Estructura-ActividadRESUMEN
This article describes the discovery of a series of potent inhibitors of Polo-like kinase 1 (PLK1). Optimization of this benzolactam-derived chemical series produced an orally bioavailable inhibitor of PLK1 (12c, MLN0905). In vivo pharmacokinetic-pharmacodynamic experiments demonstrated prolonged mitotic arrest after oral administration of 12c to tumor bearing nude mice. A subsequent efficacy study in nude mice achieved tumor growth inhibition or regression in a human colon tumor (HT29) xenograft model.