ABSTRACT
Novel non-fluoroquinolone inhibitors of bacterial type II topoisomerases (DNA gyrase and topoisomerase IV) are of interest for the development of new antibacterial agents that are not impacted by target-mediated cross-resistance with fluoroquinolones. Aminopiperidines that have a bicyclic aromatic moiety linked through a carbon to an ethyl bridge, such as 1, generally show potent broad-spectrum antibacterial activity, including quinolone-resistant isolates, but suffer from potent hERG inhibition (IC(50)= 3 µM for 1). We now disclose the finding that new analogues of 1 with an N-linked cyclic amide moiety attached to the ethyl bridge, such as 24m, retain the broad-spectrum antibacterial activity of 1 but show significantly less hERG inhibition (IC(50)= 31 µM for 24m) and higher free fraction than 1. One optimized analogue, compound 24l, showed moderate clearance in the dog and promising efficacy against Staphylococcus aureus in a mouse thigh infection model.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Bacterial Proteins/antagonists & inhibitors , DNA Topoisomerases, Type II/metabolism , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Piperidines/chemical synthesis , Topoisomerase Inhibitors/chemical synthesis , Animals , Anti-Bacterial Agents/pharmacokinetics , Anti-Bacterial Agents/pharmacology , Dogs , Drug Resistance, Bacterial , ERG1 Potassium Channel , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Mice , Microbial Sensitivity Tests , Models, Molecular , Piperidines/pharmacokinetics , Piperidines/pharmacology , Protein Conformation , Rats , Staphylococcal Infections/drug therapy , Structure-Activity Relationship , Topoisomerase Inhibitors/pharmacokinetics , Topoisomerase Inhibitors/pharmacologyABSTRACT
In this paper, a range of issues influencing and affecting NHS information governance policy and practice will be considered. The expansion of electronic information services within the NHS and with its other information partners has reinforced the need for effective security and confidentiality arrangements to apply at multiple levels and in a variety of different business contexts. Added to these, the need to consistently address issues of data protection, records management and data quality, has resulted in a NHS information governance initiative. This initiative is intended to provide approved tools, methods and guidance that may be applied consistently throughout the NHS and that will be underpinned through appropriate support and helpdesk services. This paper emphasises the need to consider a range of applicable topics when determining a responsible and extensible approach to the governance of information collected, used and shared by healthcare organisations.
