Dihydroxypyridopyrazine-1,6-dione HIV-1 integrase inhibitors.
A series of potent novel dihydroxypyridopyrazine-1,6-dione HIV-1 integrase inhibitors was identified. These compounds inhibited the strand transfer process of HIV-1 integrase and viral replication in cells. Compound 6 is active against replication of HIV with a CIC(95) of 0.31 microM and exhibits no shift in potency in the presence of 50% normal human serum. It displays a good pharmacokinetic profile when dosed in rats and no covalent binding with microsomal proteins in both in vitro and in vivo models.
Wai
John S
JS
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. john_wai@merck.com
Kim
Boyoung
B
Fisher
Thorsten E
TE
Zhuang
Linghang
L
Embrey
Mark W
MW
Williams
Peter D
PD
Staas
Donnette D
DD
Culberson
Chris
C
Lyle
Terry A
TA
Vacca
Joseph P
JP
Hazuda
Daria J
DJ
Felock
Peter J
PJ
Schleif
William A
WA
Gabryelski
Lori J
LJ
Jin
Lixia
L
Chen
I-Wu
IW
Ellis
Joan D
JD
Mallai
Rama
R
Young
Steven D
SD
D000818:Animals; D001554:Benzene / Q000737:chemistry; D002460:Cell Line; D006678:HIV / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects; D008958:Models, Molecular; D015394:Molecular Structure; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects