RESUMO
Families of 2-arylbenzotriazoles and 2-arylindazoles that show positive effects in screens predictive of endogenous utrophin upregulation have been identified. Synthesis and structure-activity relationships are described leading to compounds with attractive in vitro profiles.
Assuntos
Descoberta de Drogas , Indazóis/síntese química , Microssomos Hepáticos/efeitos dos fármacos , Triazóis/síntese química , Relação Dose-Resposta a Droga , Humanos , Indazóis/química , Indazóis/uso terapêutico , Estrutura Molecular , Distrofia Muscular de Duchenne/tratamento farmacológico , Solubilidade , Estereoisomerismo , Relação Estrutura-Atividade , Triazóis/química , Triazóis/uso terapêuticoRESUMO
A series of novel 2-arylbenzoxazoles that upregulate the production of utrophin in murine H2K cells, as assessed using a luciferase reporter linked assay, have been identified. This compound class appears to hold considerable promise as a potential treatment for Duchenne muscular dystrophy. Following the delineation of structure-activity relationships in the series, a number of potent upregulators were identified, and preliminary ADME evaluation is described. These studies have resulted in the identification of 1, a compound that has been progressed to clinical trials.