RESUMEN
2-Amino-4-azaindoles have been identified as a structurally novel class of BK(Ca) channel openers. Their synthesis from 2-chloro-3-nitropyridine is described together with their in vitro properties assessed by 86Rb(+) efflux and whole-cell patch-clamp assays using HEK293 cells stably transfected with the BK(Ca) alpha subunit. In vitro functional characterization of BK(Ca) channel opening activity was also assessed by measurement of relaxation of smooth muscle tissue strips obtained from Landrace pig bladders. The preliminary SAR data indicate the importance of steric bulk around the 2-amino substituent.
Asunto(s)
Aminas/síntesis química , Aminas/farmacología , Indoles/síntesis química , Indoles/farmacología , Canales de Potasio Calcio-Activados/efectos de los fármacos , Vejiga Urinaria/efectos de los fármacos , Aminas/química , Animales , Compuestos Aza/síntesis química , Compuestos Aza/química , Compuestos Aza/farmacología , Calcio/metabolismo , Línea Celular , Humanos , Técnicas In Vitro , Indoles/química , Relajación Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Músculo Liso/fisiología , Canales de Potasio Calcio-Activados/metabolismo , Relación Estructura-Actividad , Porcinos , Transfección , Vejiga Urinaria/metabolismo , Enfermedades de la Vejiga Urinaria/tratamiento farmacológico , Trastornos Urinarios/tratamiento farmacológicoRESUMEN
We have discovered a novel series of N-[2-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-naphthalen-1-yl] amides that are potent openers of K(ATP) channels and investigated structure-activity relationships (SAR) around the 1,2-disubstituted naphthyl core. A-151892, a prototype compound of this series, was found to be a potent and efficacious potassium channel opener in vitro in transfected Kir6.2/SUR2B cells and pig bladder strips. Additionally, A-151892 was found to selectively inhibit unstable bladder contractions in vivo in an obstructed rat model of myogenic bladder function
