A prodrug approach toward the development of water soluble fluoroquinolones and structure--activity relationships of quinoline-3-carboxylic acids.
A fluoroquinolone prodrug, PA2808, was prepared and shown to convert to the highly active parent drug PA2789. In vitro and in vivo activation of PA2808 by alkaline phosphatase was demonstrated using disk diffusion and rat lung infection models. The water solubility of PA2808 showed a marked increase compared to PA2789 over a pH range suitable for aerosol drug delivery. A total of 48 analogues based on PA2789 were prepared and screened against a panel of Gram-positive and Gram-negative pathogens. Incorporating a cyclopropane-fused pyrrolidine (amine) at C-7 resulted in some of the most active analogues.
Baker
William R
WR
Chiron Corporation, 201 Elliott Avenue West, Seattle, Washington 98119, USA.
Cai
Shaopei
S
Dimitroff
Martin
M
Fang
Liming
L
Huh
Kay K
KK
Ryckman
David R
DR
Shang
Xiao
X
Shawar
Ribhi M
RM
Therrien
Joseph H
JH
D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects; D002264:Carboxylic Acids / Q000737:chemistry*; D024841:Fluoroquinolones / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D008168:Lung / Q000378:metabolism; D015394:Molecular Structure; D009268:Nalidixic Acid / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D010755:Organophosphates / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D010879:Piperazines / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship; D014867:Water / Q000737:chemistry*
D000900:Anti-Bacterial Agents; D002264:Carboxylic Acids; D024841:Fluoroquinolones; D010755:Organophosphates; C491849:PA 2789; C491848:PA 2808; D010879:Piperazines; D011355:Prodrugs; D014867:Water; D009268:Nalidixic Acid