RESUMO
During the course of our research on the lead optimisation of the NBTI (Novel Bacterial Type II Topoisomerase Inhibitors) class of antibacterials, we discovered a series of tricyclic compounds that showed good Gram-positive and Gram-negative potency. Herein we will discuss the various subunits that were investigated in this series and report advanced studies on compound 1 (GSK945237) which demonstrates good PK and in vivo efficacy properties.
Assuntos
Antibacterianos/farmacologia , Compostos Heterocíclicos com 3 Anéis/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/química , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Inibidores da Topoisomerase II/química , Inibidores da Topoisomerase II/farmacologia , Animais , Antibacterianos/química , Antibacterianos/farmacocinética , Técnicas de Química Sintética , DNA Topoisomerases Tipo II/química , DNA Topoisomerases Tipo II/metabolismo , Cães , Avaliação Pré-Clínica de Medicamentos/métodos , Canal de Potássio ERG1/metabolismo , Bactérias Anaeróbias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/síntese química , Compostos Heterocíclicos com 3 Anéis/química , Infecções Pneumocócicas/tratamento farmacológico , Ratos , Infecções Respiratórias/tratamento farmacológico , Infecções Respiratórias/microbiologia , Inibidores da Topoisomerase II/farmacocinéticaRESUMO
During the course of our research to find novel mode of action antibacterials, we discovered a series of hydroxyl tricyclic compounds that showed good potency against Gram-positive and Gram-negative pathogens. These compounds inhibit bacterial type IIA topoisomerases. Herein we will discuss structure-activity relationships in this series and report advanced studies on compound 1 (GSK966587) which demonstrates good PK and in vivo efficacy properties. X-ray crystallographic studies were used to provide insight into the structural basis for the difference in antibacterial potency between enantiomers.
Assuntos
Bactérias/enzimologia , Naftiridinas/química , Naftiridinas/farmacologia , Inibidores da Topoisomerase II/química , Inibidores da Topoisomerase II/farmacologia , Animais , Cristalografia por Raios X , Cães , Ativação Enzimática/efeitos dos fármacos , Haplorrinos , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , RatosRESUMO
We have identified a series of amino-piperidine antibacterials with a good broad spectrum potency. We report the investigation of various subunits in this series and advanced studies on compound 8. Compound 8 possesses good pharmacokinetics, broad spectrum antibacterial activity and demonstrates oral efficacy in a rat lung infection model.
Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , DNA Topoisomerases Tipo II/química , Dioxanos/química , Dioxanos/farmacologia , Naftiridinas/química , Naftiridinas/farmacologia , Piperidinas/química , Inibidores da Topoisomerase II/química , Animais , Antibacterianos/uso terapêutico , DNA Topoisomerases Tipo II/metabolismo , Dioxanos/uso terapêutico , Modelos Animais de Doenças , Cães , Haplorrinos , Humanos , Pneumopatias/tratamento farmacológico , Testes de Sensibilidade Microbiana , Naftiridinas/uso terapêutico , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Ratos , Relação Estrutura-Atividade , Inibidores da Topoisomerase II/farmacologia , Inibidores da Topoisomerase II/uso terapêuticoRESUMO
As part of our wider efforts to exploit novel mode of action antibacterials, we have discovered a series of cyclohexyl-amide compounds that has good Gram positive and Gram negative potency. The mechanism of action is via inhibition of bacterial topoisomerases II and IV. We have investigated various subunits in this series and report advanced studies on compound 7 which demonstrates good PK and in vivo efficacy properties.
