2. Academic Validation
  3. Novel N-linked aminopiperidine inhibitors of bacterial topoisomerase type II: broad-spectrum antibacterial agents with reduced hERG activity

Novel N-linked aminopiperidine inhibitors of bacterial topoisomerase type II: broad-spectrum antibacterial agents with reduced hERG activity

  • J Med Chem. 2011 Nov 24;54(22):7834-47. doi: 10.1021/jm2008826.
Folkert Reck 1,  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
Affiliations

Affiliation

  • 1 Infection Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States. folkert.reck@astrazeneca.com
PMID: 21999508 DOI: 10.1021/jm2008826
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.

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