Referenced in: none

Automatically associated channels: Kv11.1

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

Authors: 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

Journal, date & volume: J. Med. Chem., 2011 Nov 24 , 54, 7834-47

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/21999508

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.