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Design and Synthesis of 8-Hydroxy-[1,6]Naphthyridines as Novel Inhibitors of HIV-1 Integrase in Vitro and in Infected Cells

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journal contribution
posted on 09.01.2003 by Linghang Zhuang, John S. Wai, Mark W. Embrey, Thorsten E. Fisher, Melissa S. Egbertson, Linda S. Payne, James P. Guare,, Joseph P. Vacca, Daria J. Hazuda, Peter J. Felock, Abigail L. Wolfe, Kara A. Stillmock, Marc V. Witmer, Gregory Moyer, William A. Schleif, Lori J. Gabryelski, Yvonne M. Leonard, Joseph J. Lynch,, Stuart R. Michelson, Steven D. Young
Naphthyridine 7 inhibits the strand transfer of the integration process catalyzed by integrase with an IC50 of 10 nM and inhibits 95% of the spread of HIV-1 infection in cell culture at 0.39 μM. It does not exhibit cytotoxicity in cell culture at ≤12.5 μM and shows a good pharmacokinetic profile when dosed orally to rats. The antiviral activity of 7 and its effect on integration were confirmed using viruses with specific integrase mutations.