RESUMO
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.
Assuntos
Aminas/síntese química , Aminas/farmacologia , Indóis/síntese química , Indóis/farmacologia , Canais de Potássio Cálcio-Ativados/efeitos dos fármacos , Bexiga Urinária/efeitos dos fármacos , Aminas/química , Animais , Compostos Aza/síntese química , Compostos Aza/química , Compostos Aza/farmacologia , Cálcio/metabolismo , Linhagem Celular , Humanos , Técnicas In Vitro , Indóis/química , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Canais de Potássio Cálcio-Ativados/metabolismo , Relação Estrutura-Atividade , Suínos , Transfecção , Bexiga Urinária/metabolismo , Doenças da Bexiga Urinária/tratamento farmacológico , Transtornos Urinários/tratamento farmacológicoRESUMO
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
