Novel N-Linked Aminopiperidine Inhibitors of Bacterial Topoisomerase Type II: Broad-Spectrum Antibacterial Agents with Reduced hERG Activity

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• 作者：Folkert Reck ; Richard Alm ; Patrick Brassil ; Joseph Newman ; Boudewijn DeJonge ; Charles J. Eyermann ; Gloria Breault ; John Breen ; Janelle Comita-Prevoir ; Mark Cronin ; Hajnalka Davis ; David Ehmann ; Vincent Galullo ; Bolin Geng ; Tyler Grebe ; Marshall Morningstar ; Phil Walker ; Barry Hayter ; Stewart Fisher
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：November 24, 2011
• 年：2011
• 卷：54
• 期：22
• 页码：7834-7847
• 全文大小：431K
• 年卷期：v.54,no.22(November 24, 2011)
• ISSN：1520-4804

文摘

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 (IC₅₀= 3 渭M 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 (IC₅₀= 31 渭M 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.