title: Design and synthesis of 8-hydroxy-[1,6]naphthyridines as novel inhibitors of HIV-1 integrase in vitro and in infected cells.
abstract: 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 microM. It does not exhibit cytotoxicity in cell culture at < or =12.5 microM 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.
authors.affiliation: Departments of Medicinal Chemistry, Antiviral Research, and Pharmacology, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. linghang_zhuang@merck.com
authors.forename: Linghang
authors.initials: L
authors.lastname: Zhuang
authors.forename: John S
authors.initials: JS
authors.lastname: Wai
authors.forename: Mark W
authors.initials: MW
authors.lastname: Embrey
authors.forename: Thorsten E
authors.initials: TE
authors.lastname: Fisher
authors.forename: Melissa S
authors.initials: MS
authors.lastname: Egbertson
authors.forename: Linda S
authors.initials: LS
authors.lastname: Payne
authors.forename: James P
authors.initials: JP
authors.lastname: Guare
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Vacca
authors.forename: Daria J
authors.initials: DJ
authors.lastname: Hazuda
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Felock
authors.forename: Abigail L
authors.initials: AL
authors.lastname: Wolfe
authors.forename: Kara A
authors.initials: KA
authors.lastname: Stillmock
authors.forename: Marc V
authors.initials: MV
authors.lastname: Witmer
authors.forename: Gregory
authors.initials: G
authors.lastname: Moyer
authors.forename: William A
authors.initials: WA
authors.lastname: Schleif
authors.forename: Lori J
authors.initials: LJ
authors.lastname: Gabryelski
authors.forename: Yvonne M
authors.initials: YM
authors.lastname: Leonard
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Lynch
authors.forename: Stuart R
authors.initials: SR
authors.lastname: Michelson
authors.forename: Steven D
authors.initials: SD
authors.lastname: Young
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007275:Injections, Intravenous; D009287:Naphthyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D019380:Anti-HIV Agents; D019428:HIV Integrase Inhibitors; D009287:Naphthyridines