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

详细信息    查看全文

• 作者：Folkert Reck ; Richard A. Alm ; Patrick Brassil ; Joseph V. Newman ; Paul Ciaccio ; John McNulty ; Herbert Barthlow ; Kosalaram Goteti ; John Breen ; Janelle Comita-Prevoir ; Mark Cronin ; David E. Ehmann ; Bolin Geng ; Andrew Aydon Godfrey ; Stewart L. Fisher
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：August 9, 2012
• 年：2012
• 卷：55
• 期：15
• 页码：6916-6933
• 全文大小：562K
• 年卷期：v.55,no.15(August 9, 2012)
• 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. N-Linked amino piperidines, such as 7a, generally show potent antibacterial activity, including against quinolone-resistant isolates, but suffer from hERG inhibition (IC₅₀ = 44 渭M 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 渭M 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.