title: In vivo antibacterial activity of a prodrug of NM394, a thiazetoquinoline carboxylic acid derivative.
abstract: NM394 (6-fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H-[1,3]-thiazeto [3,2-a]quinoline-3-carboxylic acid) has potent, broad-spectrum antibacterial activity in vitro, but not in vivo. To increase the bioavailability of NM394, various prodrugs were synthesized and tested. One of them, NM441, an N-(5-methyl-2-oxo-1,3-dioxol-4-yl) derivative, showed potent in vivo antibacterial activity. Using thin-layer chromatography-bioautography, we confirmed that after oral administration, NM441 was readily absorbed and hydrolyzed to NM394. Other prodrugs of NM394 were only partially metabolized to NM394. In pharmacokinetic studies in mice and monkeys, we found that the blood levels of NM394 were 7.8 and 5.9 times greater, respectively, when NM441 rather than NM394 was administered. These findings suggest that NM441 is an effective prodrug of NM394.
authors.affiliation: Research Laboratories, Nippon Shinyaku Co., Ltd., Kyoto, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Ozaki
authors.forename: Y
authors.initials: Y
authors.lastname: Tomii
authors.forename: M
authors.initials: M
authors.lastname: Matsuda
authors.forename: J
authors.initials: J
authors.lastname: Segawa
authors.forename: M
authors.initials: M
authors.lastname: Kitano
authors.forename: M
authors.initials: M
authors.lastname: Kise
authors.forename: T
authors.initials: T
authors.lastname: Nishino
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D002855:Chromatography, Thin Layer; D004148:Dioxolanes / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects; D004927:Escherichia coli Infections / Q000188:drug therapy; D024841:Fluoroquinolones; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D010879:Piperazines / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011355:Prodrugs / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011552:Pseudomonas Infections / Q000188:drug therapy; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D015363:Quinolones / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*; D013203:Staphylococcal Infections / Q000188:drug therapy; D013211:Staphylococcus aureus / Q000187:drug effects
chemical_list: D000890:Anti-Infective Agents; D004148:Dioxolanes; D024841:Fluoroquinolones; D010879:Piperazines; D011355:Prodrugs; D015363:Quinolones; C074190:ulifloxacin; C074191:prulifloxacin