RESUMEN
We recently described a novel series of aminopyridopyrazinones as PDE5 inhibitors. Efforts toward optimization of this series culminated in the identification of 3-[4-(2-hydroxyethyl)piperazin-1-yl]-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one, which possessed an excellent potency and selectivity profile and demonstrated robust in vivo blood pressure lowering in a spontaneously hypertensive rat (SHR) model. Furthermore, this compound is brain penetrant and will be a useful agent for evaluating the therapeutic potential of central inhibition of PDE5. This compound has recently entered clinical trials.
Asunto(s)
Encéfalo/metabolismo , Inhibidores de Fosfodiesterasa 5 , Inhibidores de Fosfodiesterasa/síntesis química , Inhibidores de Fosfodiesterasa/farmacología , Pirazinas/síntesis química , Pirazinas/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Administración Oral , Animales , Disponibilidad Biológica , Presión Sanguínea/efectos de los fármacos , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/metabolismo , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Humanos , Masculino , Modelos Químicos , Estructura Molecular , Inhibidores de Fosfodiesterasa/farmacocinética , Pirazinas/farmacocinética , Piridinas/farmacocinética , Ratas , Ratas Endogámicas SHR , Ratas Sprague-DawleyRESUMEN
We describe efforts to improve the pharmacokinetic profile of the aminopyridopyrazinone class of PDE5 inhibitors. These efforts led to the discovery of 3-[(trans-4-hydroxycyclohexyl)amino]-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one, a potent and selective inhibitor of PDE5 with an excellent PK profile.
Asunto(s)
Inhibidores de Fosfodiesterasa 5 , Inhibidores de Fosfodiesterasa/química , Pirazinas/química , Piridinas/química , Animales , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 6/antagonistas & inhibidores , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 6/metabolismo , Perros , Descubrimiento de Drogas , Humanos , Inhibidores de Fosfodiesterasa/síntesis química , Inhibidores de Fosfodiesterasa/farmacocinética , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/metabolismo , Pirazinas/síntesis química , Pirazinas/farmacocinética , Piridinas/síntesis química , Piridinas/farmacocinética , Ratas , Ratas Endogámicas SHR , Relación Estructura-ActividadRESUMEN
Efforts to improve the potency and physical properties of the aminopyridiopyrazinone class of PDE5 inhibitors through modification of the core ring system are described. Five new ring systems are evaluated and features that impart improved potency and improved solubility are delineated.