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 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.
Zhuang
Linghang
L
Departments of Medicinal Chemistry, Antiviral Research, and Pharmacology, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. linghang_zhuang@merck.com
Wai
John S
JS
Embrey
Mark W
MW
Fisher
Thorsten E
TE
Egbertson
Melissa S
MS
Payne
Linda S
LS
Guare
James P
JP
Vacca
Joseph P
JP
Hazuda
Daria J
DJ
Felock
Peter J
PJ
Wolfe
Abigail L
AL
Stillmock
Kara A
KA
Witmer
Marc V
MV
Moyer
Gregory
G
Schleif
William A
WA
Gabryelski
Lori J
LJ
Leonard
Yvonne M
YM
Lynch
Joseph J
JJ
Michelson
Stuart R
SR
Young
Steven D
SD
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
D019380:Anti-HIV Agents; D019428:HIV Integrase Inhibitors; D009287:Naphthyridines