title: The synthesis and biological evaluation of novel series of nitrile-containing fluoroquinolones as antibacterial agents.
abstract: 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.
authors.affiliation: Pfizer Global Research and Development, La Jolla Laboratories, 10770 Science Center Drive, San Diego, CA 92121, USA. sean.murphy2@pfizer.com
authors.forename: Sean T
authors.initials: ST
authors.lastname: Murphy
authors.forename: Heather L
authors.initials: HL
authors.lastname: Case
authors.forename: Edmund
authors.initials: E
authors.lastname: Ellsworth
authors.forename: Susan
authors.initials: S
authors.lastname: Hagen
authors.forename: Michael
authors.initials: M
authors.lastname: Huband
authors.forename: Themis
authors.initials: T
authors.lastname: Joannides
authors.forename: Chris
authors.initials: C
authors.lastname: Limberakis
authors.forename: Keith R
authors.initials: KR
authors.lastname: Marotti
authors.forename: Amy M
authors.initials: AM
authors.lastname: Ottolini
authors.forename: Mark
authors.initials: M
authors.lastname: Rauckhorst
authors.forename: Jeremy
authors.initials: J
authors.lastname: Starr
authors.forename: Michael
authors.initials: M
authors.lastname: Stier
authors.forename: Clarke
authors.initials: C
authors.lastname: Taylor
authors.forename: Tong
authors.initials: T
authors.lastname: Zhu
authors.forename: Adrian
authors.initials: A
authors.lastname: Blaser
authors.forename: William A
authors.initials: WA
authors.lastname: Denny
authors.forename: Guo-Liang
authors.initials: GL
authors.lastname: Lu
authors.forename: Jeff B
authors.initials: JB
authors.lastname: Smaill
authors.forename: Freddy
authors.initials: F
authors.lastname: Rivault
mesh_terms: 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
chemical_list: D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D009570:Nitriles