Design, synthesis, and properties of (4S)-7-(4-amino-2-substituted-pyrrolidin-1-yl)quinolone-3-carboxylic acids.
The quinolonecarboxylic acids constitute a class of extremely potent and orally active broad-spectrum antibacterial agents. These compounds have been shown to inhibit DNA gyrase, a key enzyme in bacterial DNA replication. The 7-(3-aminopyrrolidinyl)quinolone A-60969 (1) is a particularly potent member of this class and is currently undergoing clinical evaluation. We have studied a series of enantiomerically homogeneous (4S)-7-(4-amino-2-substituted-pyrrolidinyl)quinolones in an effort to utilize the 2-position of the pyrrolidine moiety to improve upon the solubility and pharmacokinetic properties of this class of compounds while still maintaining potent antibacterial activity. We have found that the absolute stereochemistry at the 2-position of the pyrrolidine ring is critical to the maintenance of such activity. In this paper, we report the full details of the asymmetric synthesis and the in vitro and in vivo structure-activity relationships of this series of compounds as well as the physiochemical properties, such as water solubility and log P, associated with the structural modifications. We also discuss the pharmacokinetic properties of several of these compounds in mice and the pharmacokinetics of 59, which has the best overall properties of agents in this study, in dog.
Rosen
T
T
Abbott Laboratories, Illinois 60064.
Chu
D T
DT
Lico
I M
IM
Fernandes
P B
PB
Marsh
K
K
Shen
L
L
Cepa
V G
VG
Pernet
A G
AG
D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001424:Bacterial Infections / Q000188:drug therapy; D055598:Chemical Phenomena; D002621:Chemistry; D004285:Dogs; D024841:Fluoroquinolones; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D051379:Mice; D009287:Naphthyridines / Q000138:chemical synthesis / Q000493:pharmacokinetics; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors
D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D009287:Naphthyridines; D011759:Pyrrolidines; D011804:Quinolines; D059005:Topoisomerase II Inhibitors; C056711:7-(4'-amino-2'-methylpyrrolidinyl)-1-(2,4-difluorophenyl)-1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acid