title: Novel N-linked aminopiperidine inhibitors of bacterial topoisomerase type II: broad-spectrum antibacterial agents with reduced hERG activity.
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.
authors: Infection Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States. folkert.reck@astrazeneca.com
authors: Folkert
authors: F
authors: Reck
authors: Richard
authors: R
authors: Alm
authors: Patrick
authors: P
authors: Brassil
authors: Joseph
authors: J
authors: Newman
authors: Boudewijn
authors: B
authors: Dejonge
authors: Charles J
authors: CJ
authors: Eyermann
authors: Gloria
authors: G
authors: Breault
authors: John
authors: J
authors: Breen
authors: Janelle
authors: J
authors: Comita-Prevoir
authors: Mark
authors: M
authors: Cronin
authors: Hajnalka
authors: H
authors: Davis
authors: David
authors: D
authors: Ehmann
authors: Vincent
authors: V
authors: Galullo
authors: Bolin
authors: B
authors: Geng
authors: Tyler
authors: T
authors: Grebe
authors: Marshall
authors: M
authors: Morningstar
authors: Phil
authors: P
authors: Walker
authors: Barry
authors: B
authors: Hayter
authors: Stewart
authors: S
authors: Fisher
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004285:Dogs; D024881:Drug Resistance, Bacterial; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors*; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D051379:Mice; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D010880:Piperidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011487:Protein Conformation; D051381:Rats; D013203:Staphylococcal Infections / Q000188:drug therapy; D013329:Structure-Activity Relationship; D059003:Topoisomerase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D010880:Piperidines; D059003:Topoisomerase Inhibitors; D004250:DNA Topoisomerases, Type II