title: Synthesis and antibacterial activity of novel C12 vinyl ketolides.
abstract: A novel series of C12 vinyl erythromycin derivatives have been discovered which exhibit in vitro and in vivo potency against key respiratory pathogens. The C12 modification involves replacing the natural C12 methyl group in the erythromycin core with a vinyl group via chemical synthesis. From the C12 vinyl macrolide core, a series of C12 vinyl ketolides was prepared. Several compounds were found to be potent against macrolide-sensitive and -resistant bacteria. The C12 vinyl ketolides 6j and 6k showed a similar antimicrobial spectrum and comparable activity to the commercial ketolide telithromycin. However, the pharmacokinetic profiles of C12 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.
authors.affiliation: Chiron Corporation, Biopharma Research, 4560 Horton Street, Emeryille, California 94608-2916, USA. matthew_burger@chiron.com
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Burger
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Lin
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Chu
authors.forename: Christy
authors.initials: C
authors.lastname: Hiebert
authors.forename: Alice C
authors.initials: AC
authors.lastname: Rico
authors.forename: Mehran
authors.initials: M
authors.lastname: Seid
authors.forename: Georgia L
authors.initials: GL
authors.lastname: Carroll
authors.forename: Lynn
authors.initials: L
authors.lastname: Barker
authors.forename: Kay
authors.initials: K
authors.lastname: Huh
authors.forename: Mike
authors.initials: M
authors.lastname: Langhorne
authors.forename: Ribhi
authors.initials: R
authors.lastname: Shawar
authors.forename: Jolene
authors.initials: J
authors.lastname: Kidney
authors.forename: Kelly
authors.initials: K
authors.lastname: Young
authors.forename: Scott
authors.initials: S
authors.lastname: Anderson
authors.forename: Manoj C
authors.initials: MC
authors.lastname: Desai
authors.forename: Jacob J
authors.initials: JJ
authors.lastname: Plattner
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D024881:Drug Resistance, Bacterial; D013293:Enterococcus faecalis / Q000187:drug effects; D006192:Haemophilus Infections / Q000188:drug therapy; D006193:Haemophilus influenzae / Q000187:drug effects; D006207:Half-Life; D048628:Ketolides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008171:Lung Diseases / Q000188:drug therapy / Q000382:microbiology; D008297:Male; D008826:Microbial Sensitivity Tests; D011008:Pneumococcal Infections / Q000188:drug therapy; D051381:Rats; D017207:Rats, Sprague-Dawley; D013211:Staphylococcus aureus / Q000187:drug effects; D013296:Streptococcus pneumoniae / Q000187:drug effects; D013297:Streptococcus pyogenes / Q000187:drug effects; D013329:Structure-Activity Relationship; D014753:Vinyl Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D048628:Ketolides; D014753:Vinyl Compounds