Novel N-Linked Aminopiperidine Inhibitors of Bacterial Topoisomerase Type II with Reduced pK a: Antibacterial Agents with an Improved Safety Profile

• Published in: Journal of medicinal chemistry 2012-08, Vol.55 (15), p.6916-6933
• Main Authors: Reck, Folkert, Alm, Richard A, Brassil, Patrick, Newman, Joseph V, Ciaccio, Paul, McNulty, John, Barthlow, Herbert, Goteti, Kosalaram, Breen, John, Comita-Prevoir, Janelle, Cronin, Mark, Ehmann, David E, Geng, Bolin, Godfrey, Andrew Aydon, Fisher, Stewart L
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - toxicity; Biological Availability; Dioxanes - chemical synthesis; Dioxanes - pharmacology; Dioxanes - toxicity; DNA Topoisomerase IV - antagonists & inhibitors; Dogs; Drug Resistance, Bacterial; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels - antagonists & inhibitors; Guinea Pigs; Methicillin-Resistant Staphylococcus aureus; Mice; Microbial Sensitivity Tests; Piperidines - chemical synthesis; Piperidines - pharmacology; Piperidines - toxicity; Quinolones - chemical synthesis; Quinolones - pharmacology; Quinolones - toxicity; Staphylococcal Infections - drug therapy; Staphylococcal Infections - microbiology; Stereoisomerism; Structure-Activity Relationship; Topoisomerase II Inhibitors - chemical synthesis; Topoisomerase II Inhibitors - pharmacology; Topoisomerase II Inhibitors - toxicity
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm300690s

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. N-Linked amino piperidines, such as 7a, generally show potent antibacterial activity, including against quinolone-resistant isolates, but suffer from hERG inhibition (IC50 = 44 μM for 7a) and QT prolongation in vivo. We now disclose the finding that new analogues of 7a with reduced pK a due to substitution with an electron-withdrawing substituent in the piperidine moiety, such as R,S-7c, retained the Gram-positive activity of 7a but showed significantly less hERG inhibition (IC50 = 233 μM for R,S-7c). This compound exhibited moderate clearance in dog, promising efficacy against a MRSA strain in a mouse infection model, and an improved in vivo QT profile as measured in a guinea pig in vivo model. As a result of its promising activity, R,S -7c was advanced into phase I clinical studies.