The synthesis and biological evaluation of novel series of nitrile-containing fluoroquinolones as antibacterial agents.
Several novel series of nitrile-containing fluoroquinolones with weakly basic amines are reported which have reduced potential for hERG (human ether-a-go-go gene) channel inhibition as measured by the dofetilide assay. The new fluoroquinolones are potent against both Gram-positive and fastidious Gram-negative strains, including Methicillin resistant Staphylococcus aureus and fluoroquinolone-resistant Streptococcus pneumoniae. Several analogs also showed low potential for human genotoxicity as measured by the clonogenicity test. Compounds 22 and 37 (designated PF-00951966 and PF-02298732, respectively), which had good in vitro activity and in vitro safety profiles, also showed good pharmacokinetic properties in rats.
Murphy
Sean T
ST
Pfizer Global Research and Development, La Jolla Laboratories, 10770 Science Center Drive, San Diego, CA 92121, USA. sean.murphy2@pfizer.com
Case
Heather L
HL
Ellsworth
Edmund
E
Hagen
Susan
S
Huband
Michael
M
Joannides
Themis
T
Limberakis
Chris
C
Marotti
Keith R
KR
Ottolini
Amy M
AM
Rauckhorst
Mark
M
Starr
Jeremy
J
Stier
Michael
M
Taylor
Clarke
C
Zhu
Tong
T
Blaser
Adrian
A
Denny
William A
WA
Lu
Guo-Liang
GL
Smaill
Jeff B
JB
Rivault
Freddy
F
D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D024881:Drug Resistance, Bacterial / Q000187:drug effects; D024841:Fluoroquinolones / Q000138:chemical synthesis* / Q000494:pharmacology; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D006801:Humans; D015394:Molecular Structure; D009152:Mutagenicity Tests; D009570:Nitriles / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D009570:Nitriles