ABSTRACT
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.
Subject(s)
Anti-Bacterial Agents/pharmacology , Heterocyclic Compounds, 3-Ring/pharmacology , Heterocyclic Compounds, 4 or More Rings/chemistry , Heterocyclic Compounds, 4 or More Rings/pharmacology , Topoisomerase II Inhibitors/chemistry , Topoisomerase II Inhibitors/pharmacology , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacokinetics , Chemistry Techniques, Synthetic , DNA Topoisomerases, Type II/chemistry , DNA Topoisomerases, Type II/metabolism , Dogs , Drug Evaluation, Preclinical/methods , ERG1 Potassium Channel/metabolism , Gram-Negative Anaerobic Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Heterocyclic Compounds, 3-Ring/chemical synthesis , Heterocyclic Compounds, 3-Ring/chemistry , Pneumococcal Infections/drug therapy , Rats , Respiratory Tract Infections/drug therapy , Respiratory Tract Infections/microbiology , Topoisomerase II Inhibitors/pharmacokineticsABSTRACT
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.
Subject(s)
Bacteria/enzymology , Naphthyridines/chemistry , Naphthyridines/pharmacology , Topoisomerase II Inhibitors/chemistry , Topoisomerase II Inhibitors/pharmacology , Animals , Crystallography, X-Ray , Dogs , Enzyme Activation/drug effects , Haplorhini , Humans , Microbial Sensitivity Tests , Molecular Structure , RatsABSTRACT
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.
Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , DNA Topoisomerases, Type II/chemistry , Dioxanes/chemistry , Dioxanes/pharmacology , Naphthyridines/chemistry , Naphthyridines/pharmacology , Piperidines/chemistry , Topoisomerase II Inhibitors/chemistry , Animals , Anti-Bacterial Agents/therapeutic use , DNA Topoisomerases, Type II/metabolism , Dioxanes/therapeutic use , Disease Models, Animal , Dogs , Haplorhini , Humans , Lung Diseases/drug therapy , Microbial Sensitivity Tests , Naphthyridines/therapeutic use , Piperidines/pharmacology , Piperidines/therapeutic use , Rats , Structure-Activity Relationship , Topoisomerase II Inhibitors/pharmacology , Topoisomerase II Inhibitors/therapeutic useABSTRACT
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.
