10-Hydroxy-7,8-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-diones: potent, orally bioavailable HIV-1 integrase strand-transfer inhibitors with activity against integrase mutants.
A series of 10-hydroxy-7,8-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-diones was synthesized and tested for their inhibition of HIV-1 replication in cell culture. Structure-activity studies indicated that high antiviral potency against wild-type virus as well as viruses containing integrase mutations that confer resistance to three different structural classes of integrase inhibitors could be achieved by incorporation of small aliphatic groups at certain positions on the core template. An optimal compound from this study, 16, inhibits integrase strand-transfer activity with an IC(50) value of 10 nM, inhibits HIV-1 replication in cell culture with an IC(95) value of 35 nM in the presence of 50% normal human serum, and displays modest pharmacokinetic properties in rats (i.v. t(1/2)=5.3 h, F=17%).
Wiscount
Catherine M
CM
Department of Medicinal Chemistry, WP14-3, Merck Research Laboratories, West Point, PA 19486, USA. cathy_wiscount@merck.com
Williams
Peter D
PD
Tran
Lekhanh O
LO
Embrey
Mark W
MW
Fisher
Thorsten E
TE
Sherman
Vanessa
V
Homnick
Carl F
CF
Donnette Staas
D
D
Lyle
Terry A
TA
Wai
John S
JS
Vacca
Joseph P
JP
Wang
ZiQiang
Z
Felock
Peter J
PJ
Stillmock
Kara A
KA
Witmer
Marc V
MV
Miller
Michael D
MD
Hazuda
Daria J
DJ
Day
Alysha M
AM
Gabryelski
Lori J
LJ
Ecto
Linda T
LT
Schleif
William A
WA
DiStefano
Daniel J
DJ
Kochansky
Christopher J
CJ
Anari
M Reza
MR
D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D019427:HIV Integrase / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D019426:Integrases / Q000235:genetics*; D008956:Models, Chemical; D009154:Mutation; D051381:Rats; D013329:Structure-Activity Relationship; D014779:Virus Replication
D000998:Antiviral Agents; D019427:HIV Integrase; D019426:Integrases