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

J Med Chem. 2009 Dec 10;52(23):7446-57. doi: 10.1021/jm900729s.


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.

MeSH terms

  • 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
  • Ketolides / chemical synthesis
  • Ketolides / chemistry*
  • Ketolides / pharmacology*
  • Ketolides / therapeutic use
  • Mice
  • Microbial Sensitivity Tests
  • Respiratory Tract Infections / drug therapy*


  • Azetidines
  • Ketolides
  • azetidine
  • telithromycin