A series of 5-(5,6)-dihydrouracil substituted 8-hydroxy-[1,6]naphthyridine-7-carboxylic acid 4-fluorobenzylamide inhibitors of HIV-1 integrase and viral replication in cells.
Introduction of a 5,6-dihydrouracil functionality in the 5-position of N-(4-fluorobenzyl)-8-hydroxy-[1,6]naphthyridine-7-carboxamide 1 led to a series of highly active HIV-1 integrase inhibitors. These compounds displayed low nanomolar activity in inhibiting both the strand transfer process of HIV-1 integrase and viral replication in cells. Compound 11 is a 150-fold more potent antiviral agent than 1, with a CIC(95) of 40 nM in the presence of human serum. It displays good pharmacokinetics when dosed in rats and dogs.
Embrey
Mark W
MW
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. mark_embrey@merck.com
Wai
John S
JS
Funk
Timothy W
TW
Homnick
Carl F
CF
Perlow
Debbie S
DS
Young
Steven D
SD
Vacca
Joseph P
JP
Hazuda
Daria J
DJ
Felock
Peter J
PJ
Stillmock
Kara A
KA
Witmer
Marc V
MV
Moyer
Gregory
G
Schleif
William A
WA
Gabryelski
Lori J
LJ
Jin
Lixia
L
Chen
I-Wu
IW
Ellis
Joan D
JD
Wong
Bradley K
BK
Lin
Jiunn H
JH
Leonard
Yvonne M
YM
Tsou
Nancy N
NN
Zhuang
Linghang
L
D000818:Animals; D001593:Benzyl Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D018360:Crystallography, X-Ray; D019428:HIV Integrase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D009287:Naphthyridines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D014498:Uracil / Q000031:analogs & derivatives* / Q000737:chemistry; D014779:Virus Replication / Q000187:drug effects*
C505998:8-hydroxy-(1,6)naphthyridine-7-carboxylic acid 4-fluorobenzylamide; D001593:Benzyl Compounds; D019428:HIV Integrase Inhibitors; D009287:Naphthyridines; C007419:dihydrouracil; D014498:Uracil