期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 49, 期 5, 页码 1730-1743出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm051157a
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A novel series Of C-12 vinyl erythromycin derivatives have been discovered which exhibit in vitro and in vivo potency against key respiratory pathogens. The C-12 modification involves replacing the natural C-12 methyl group in the erythromycin core with a vinyl group via chemical synthesis. From the C-12 vinyl macrolide core, a series Of C-12 vinyl ketolides was prepared. Several compounds were found to be potent against macrolide-sensitive and -resistant bacteria. The C-12 vinyl ketolides 6j and 6k showed a similar antimicrobial spectrum and comparable activity to the commercial ketolide telithromycin. However, the pharmacokinetic profiles Of C-12 vinyl ketolides 6j and 6k in rats differ from that of telithromycin by having higher lung-to-plasma ratios, larger volumes of distribution, and longer half-lives. These pharmacokinetic differences have a pharmacodynamic effect as both 6j and 6k exhibited better in vivo efficacy than telithromycin in rat lung infection models against Streptococcus pneumoniae and Haemophilus influenzae.
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