RESUMEN
PKCα and PKA have crucial but opposing roles in the regulation of calcium handling within myocytes. Identification of compounds that inhibit PKCα, but not PKA, are potential therapeutic targets for the treatment of heart disease. The synthesis of indolylureas are described, and a compound displaying nanomolar inhibition towards PKCα with significant selectivity over PKA has been identified.
Asunto(s)
Proteína Quinasa C-alfa/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/síntesis química , Urea/síntesis química , Urea/farmacología , Proteínas Quinasas Dependientes de AMP Cíclico , Cardiopatías/tratamiento farmacológico , Humanos , Urea/químicaRESUMEN
The discovery of a series of novel and orally efficacious type II calcimimetics, developed from the lead compound 1, is described herein. Compound 22 suppressed plasma PTH levels relative to vehicle when dosed orally in a rat pharmacodynamic model.
Asunto(s)
Bencilaminas/química , Bencilaminas/farmacología , Hormona Paratiroidea/antagonistas & inhibidores , Hormona Paratiroidea/sangre , Receptores Sensibles al Calcio/metabolismo , Administración Oral , Animales , Bencilaminas/administración & dosificación , Bencilaminas/farmacocinética , Masculino , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
(1,1-Dioxo-2H-[1,2,4]benzothiadiazin-3-yl) azolo[1,5-a]pyridine and azolo[1,5-a]pyrimidine derivatives have been investigated as potential anti-HCV drugs. Their synthesis, HCV NS5B polymerase inhibition, and replicon activity are discussed.