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. N-Linked amino piperidines, such as 7a, generally show potent antibacterial activity, including against quinolone-resistant isolates, but suffer from hERG inhibition (IC(50) = 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 (IC(50) = 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.
MeSH terms
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Administration, Oral
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Animals
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Anti-Bacterial Agents / chemical synthesis*
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Anti-Bacterial Agents / pharmacology
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Anti-Bacterial Agents / toxicity
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Biological Availability
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DNA Topoisomerase IV / antagonists & inhibitors
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Dioxanes / chemical synthesis*
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Dioxanes / pharmacology
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Dioxanes / toxicity
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Dogs
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Drug Resistance, Bacterial
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ERG1 Potassium Channel
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Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
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Guinea Pigs
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Methicillin-Resistant Staphylococcus aureus
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Mice
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Microbial Sensitivity Tests
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Piperidines / chemical synthesis*
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Piperidines / pharmacology
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Piperidines / toxicity
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Quinolones / chemical synthesis*
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Quinolones / pharmacology
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Quinolones / toxicity
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Staphylococcal Infections / drug therapy
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Staphylococcal Infections / microbiology
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Stereoisomerism
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Structure-Activity Relationship
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Topoisomerase II Inhibitors / chemical synthesis*
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Topoisomerase II Inhibitors / pharmacology
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Topoisomerase II Inhibitors / toxicity
Substances
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1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)-3-fluoropiperidin-1-yl)ethyl)-2-oxo-1,2-dihydroquinoline-7-carbonitrile
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Anti-Bacterial Agents
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Dioxanes
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ERG1 Potassium Channel
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Ether-A-Go-Go Potassium Channels
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Piperidines
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Quinolones
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Topoisomerase II Inhibitors
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DNA Topoisomerase IV