Novel N-linked aminopiperidine inhibitors of bacterial topoisomerase type II with reduced pK(a): antibacterial agents with an improved safety profile.
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 (IC(50) = 44 μM 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 (IC(50) = 233 μM 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.
Infection Innovative Medicines Unit, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States. folkert.reck@novartis.com
Folkert
F
Reck
Richard A
RA
Alm
Patrick
P
Brassil
Joseph V
JV
Newman
Paul
P
Ciaccio
John
J
McNulty
Herbert
H
Barthlow
Kosalaram
K
Goteti
John
J
Breen
Janelle
J
Comita-Prevoir
Mark
M
Cronin
David E
DE
Ehmann
Bolin
B
Geng
Andrew Aydon
AA
Godfrey
Stewart L
SL
Fisher
D000284:Administration, Oral; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D001682:Biological Availability; D027101:DNA Topoisomerase IV / Q000037:antagonists & inhibitors; D004146:Dioxanes / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D004285:Dogs; D024881:Drug Resistance, Bacterial; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D006168:Guinea Pigs; D055624:Methicillin-Resistant Staphylococcus aureus; D051379:Mice; D008826:Microbial Sensitivity Tests; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D015363:Quinolones / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000382:microbiology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity
C576048:1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)-3-fluoropiperidin-1-yl)ethyl)-2-oxo-1,2-dihydroquinoline-7-carbonitrile; D000900:Anti-Bacterial Agents; D004146:Dioxanes; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D010880:Piperidines; D015363:Quinolones; D059005:Topoisomerase II Inhibitors; D027101:DNA Topoisomerase IV