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Discovery of azetidinyl ketolides for the treatment of susceptible and multidrug resistant community-acquired respiratory tract infections.

Abstract
Respiratory tract bacterial strains are becoming increasingly resistant to currently marketed macrolide antibiotics. The current alternative telithromycin (1) from the newer ketolide class of macrolides addresses resistance but is hampered by serious safety concerns, hepatotoxicity in particular. We have discovered a novel series of azetidinyl ketolides that focus on mitigation of hepatotoxicity by minimizing hepatic turnover and time-dependent inactivation of CYP3A isoforms in the liver without compromising the potency and efficacy of 1.
AuthorsThomas V Magee, Sharon L Ripp, Bryan Li, Richard A Buzon, Lou Chupak, Thomas J Dougherty, Steven M Finegan, Dennis Girard, Anne E Hagen, Michael J Falcone, Kathleen A Farley, Karl Granskog, Joel R Hardink, Michael D Huband, Barbara J Kamicker, Takushi Kaneko, Michael J Knickerbocker, Jennifer L Liras, Andrea Marra, Ivy Medina, Thuy-Trinh Nguyen, Mark C Noe, R Scott Obach, John P O'Donnell, Joseph B Penzien, Usa Datta Reilly, John R Schafer, Yue Shen, Gregory G Stone, Timothy J Strelevitz, Jianmin Sun, Amelia Tait-Kamradt, Alfin D N Vaz, David A Whipple, Daniel W Widlicka, Donn G Wishka, Joanna P Wolkowski, Mark E Flanagan
JournalJournal of medicinal chemistry (J Med Chem) Vol. 52 Issue 23 Pg. 7446-57 (Dec 10 2009) ISSN: 1520-4804 [Electronic] United States
PMID19775168 (Publication Type: Journal Article)
Chemical References
  • Azetidines
  • Ketolides
  • azetidine
  • telithromycin
Topics
  • Animals
  • Azetidines (chemistry)
  • Bacteria (drug effects)
  • Community-Acquired Infections (drug therapy)
  • Disease Susceptibility
  • Drug Discovery
  • Drug Resistance, Multiple (drug effects)
  • Drug-Related Side Effects and Adverse Reactions
  • Humans
  • Ketolides (adverse effects, chemical synthesis, chemistry, pharmacology, therapeutic use)
  • Mice
  • Microbial Sensitivity Tests
  • Respiratory Tract Infections (drug therapy)

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