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

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 whe...

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Veröffentlicht in:	Journal of medicinal chemistry 2003-02, Vol.46 (4), p.453-456
Hauptverfasser:	Zhuang, Linghang, Wai, John S, Embrey, Mark W, Fisher, Thorsten E, Egbertson, Melissa S, Payne, Linda S, Guare, James P, Vacca, Joseph P, Hazuda, Daria J, Felock, Peter J, Wolfe, Abigail L, Stillmock, Kara A, Witmer, Marc V, Moyer, Gregory, Schleif, William A, Gabryelski, Lori J, Leonard, Yvonne M, Lynch, Joseph J, Michelson, Stuart R, Young, Steven D
Format:	Artikel
Sprache:	eng
Schlagworte:	8-hydroxy-[1,6]naphthyridine 8-hydroxy-[1,6]naphthyridines Administration, Oral Animals Anti-HIV Agents - chemical synthesis Anti-HIV Agents - chemistry Anti-HIV Agents - pharmacology Antibiotics. Antiinfectious agents. Antiparasitic agents Antiviral agents Biological and medical sciences Cell Line HIV Integrase Inhibitors - chemical synthesis HIV Integrase Inhibitors - chemistry HIV Integrase Inhibitors - pharmacology HIV-1 - drug effects Human immunodeficiency virus 1 Humans Injections, Intravenous Medical sciences Naphthyridines - chemical synthesis Naphthyridines - chemistry Naphthyridines - pharmacology Pharmacology. Drug treatments Rats Structure-Activity Relationship
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Beschreibung
Zusammenfassung:	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.
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm025553u