RESUMEN
The discovery, proposed binding mode, and optimization of a novel class of Rho-kinase inhibitors are presented. Appropriate substitution on the 6-position of the azabenzimidazole core provided subnanomolar enzyme potency in vitro while dramatically improving selectivity over a panel of other kinases. Pharmacokinetic data was obtained for the most potent and selective examples and one (6n) has been shown to lower blood pressure in a rat model of hypertension.
Asunto(s)
Antihipertensivos/síntesis química , Bencimidazoles/síntesis química , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Oxadiazoles/síntesis química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Animales , Antihipertensivos/farmacocinética , Antihipertensivos/farmacología , Aorta/efectos de los fármacos , Aorta/fisiología , Bencimidazoles/farmacocinética , Bencimidazoles/farmacología , Presión Sanguínea/efectos de los fármacos , Técnicas In Vitro , Modelos Moleculares , Contracción Muscular/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/fisiología , Oxadiazoles/farmacocinética , Oxadiazoles/farmacología , Ratas , Ratas Endogámicas SHR , Relación Estructura-Actividad , Quinasas Asociadas a rhoRESUMEN
Rho kinase (ROCK1) mediates vascular smooth muscle contraction and is a potential target for the treatment of hypertension and related disorders. Indazole amide 3 was identified as a potent and selective ROCK1 inhibitor but possessed poor oral bioavailability. Optimization of this lead resulted in the discovery of a series of dihydropyridones, exemplified by 13, with improved pharmacokinetic parameters relative to the initial lead. Indazole substitution played a critical role in decreasing clearance and improving oral bioavailability.