Discovery of Azetidinyl Ketolides for the Treatment of Susceptible and Multidrug Resistant Community-Acquired Respiratory Tract Infections
Journal of Medicinal Chemistry2009Vol. 52(23), pp. 7446–7457
Citations Over TimeTop 10% of 2009 papers
Thomas V. Magee, Sharon L. Ripp, Bryan Li, Richard A. Buzon, Lou Chupak, Thomas J. Dougherty, Steven M. Finegan, D 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 Penzien, Usa Reilly, John 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
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.
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