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

被引：17

作者：

Wiscount, Catherine M. ^{[1
]}

Williams, Peter D. ^{[1
]}

Tran, Lekhanh O. ^{[1
]}

Embrey, Mark W. ^{[1
]}

Fisher, Thorsten E. ^{[1
]}

Sherman, Vanessa ^{[1
]}

Homnick, Carl F. ^{[1
]}

Staas, D. Donnette ^{[1
]}

Lyle, Terry A. ^{[1
]}

Wai, John S. ^{[1
]}

Vacca, Joseph P. ^{[1
]}

Wang, ZiQiang ^{[1
]}

Felock, Peter J. ^{[2
]}

Stillmock, Kara A. ^{[2
]}

Witmer, Marc V. ^{[2
]}

Miller, Michael D. ^{[2
]}

Hazuda, Daria J. ^{[2
]}

Day, Alysha M. ^{[2
]}

Gabryelski, Lori J. ^{[3
]}

Ecto, Linda T. ^{[3
]}

Schleif, William A. ^{[3
]}

DiStefano, Daniel J. ^{[3
]}

Kochansky, Christopher J. ^{[4
]}

Anari, M. Reza ^{[4
]}

机构：

[1] Merck Res Labs, Dept Med Chem, West Point, PA 19486 USA

[2] Merck Res Labs, Dept Antiviral Res, West Point, PA 19486 USA

[3] Merck Res Labs, Dept Vaccine & Biol Res, West Point, PA 19486 USA

[4] Merck Res Labs, Dept Drug Metab, West Point, PA 19486 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2008年 / 18卷 / 16期

关键词：

HIV integrase; antiviral;

D O I：

10.1016/j.bmcl.2008.07.037

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 IC50 value of <= 10 nM, inhibits HIV-1 replication in cell culture with an IC95 value of 35 nM in the presence of 50% normal human serum, and displays modest pharmacokinetic properties in rats (iv t(1/2) = 5.3 h, F = 17%). (C) 2008 Elsevier Ltd. All rights reserved.

引用

页码：4581 / 4583

页数：3

共 10 条

[1] HIV-1 integrase: A target for new AIDS chemotherapeutics
Anthony, NJ
[J]. CURRENT TOPICS IN MEDICINAL CHEMISTRY, 2004, 4 (09) : 979 - 990
[2] ABSOLUTE-CONFIGURATION OF 6-METHYL-5,6,7,8-TETRAHYDROPTERIN PRODUCED BY ENZYMIC REDUCTION (DIHYDROFOLATE-REDUCTASE AND NADPH) OF 6-METHYL-7,8-DIHYDROPTERIN
ARMAREGO, WLF
WARING, P
WILLIAMS, JW
[J]. JOURNAL OF THE CHEMICAL SOCIETY-CHEMICAL COMMUNICATIONS, 1980, (08) : 334 - 336
[3] FEHRENTZ JA, 1983, SYNTHESIS-STUTTGART, P676
[4] 8-Hydroxy-3,4-dihydropyrrolo[1,2-a]pyrazine-1(2H)-one HIV-1 integrase inhibitors
Fisher, Thorsten E.
Kim, Boyoung
Staas, Donnette D.
Lyle, Terry A.
Young, Steven D.
Vacca, Joseph P.
Zrada, Matthew M.
Hazuda, Daria J.
Felock, Peter J.
Schleif, William A.
Gabryelski, Lori J.
Anari, M. Reza
Kochansky, Christopher J.
Wai, John S.
[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2007, 17 (23) : 6511 - 6515
[5] Diketo acid inhibitor mechanism and HIV-1 integrase: Implications for metal binding in the active site of phosphotransferase enzymes
Grobler, JA
Stillmock, K
Hu, BH
Witmer, M
Felock, P
Espeseth, AS
Wolfe, A
Egbertson, M
Bourgeois, M
Melamed, J
Wai, JS
Young, S
Vacca, J
Hazuda, DJ
[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2002, 99 (10) : 6661 - 6666
[6] Differential divalent cation requirements uncouple the assembly and catalytic reactions of human immunodeficiency virus type 1 integrase
Hazuda, DJ
Felock, PJ
Hastings, JC
Pramanik, B
Wolfe, AL
[J]. JOURNAL OF VIROLOGY, 1997, 71 (09) : 7005 - 7011
[7] A naphthyridine carboxamide provides evidence for discordant resistance between mechanistically identical inhibitors of HIV-1 integrase
Hazuda, DJ
Anthony, NJ
Gomez, RP
Jolly, SM
Wai, JS
Zhuang, LH
Fisher, TE
Embrey, M
Guare, JP
Egbertson, MS
Vacca, JP
Huff, JR
Felock, PJ
Witmer, MV
Stillmock, KA
Danovich, R
Grobler, J
Miller, MD
Espeseth, AS
Jin, LX
Chen, IW
Lin, JH
Kassahun, K
Ellis, JD
Wong, BK
Xu, W
Pearson, PG
Schleif, WA
Cortese, R
Emini, E
Summa, V
Holloway, MK
Young, SD
[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (31) : 11233 - 11238
[8] KE Y, 2007, 14 C RETR OPP INF FE
[9] L-735,524 - AN ORALLY BIOAVAILABLE HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 PROTEASE INHIBITOR
VACCA, JP
DORSEY, BD
SCHLEIF, WA
LEVIN, RB
MCDANIEL, SL
DARKE, PL
ZUGAY, J
QUINTERO, JC
BLAHY, OM
ROTH, E
SARDANA, VV
SCHLABACH, AJ
GRAHAM, PI
CONDRA, JH
GOTLIB, L
HOLLOWAY, MK
LIN, J
CHEN, IW
VASTAG, K
OSTOVIC, D
ANDERSON, PS
EMINI, EA
HUFF, JR
[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1994, 91 (09) : 4096 - 4100
[10] N-arylpiperazinone inhibitors of farnesyltransferase:: Discovery and biological activity
Williams, TM
Bergman, JM
Brashear, K
Breslin, MJ
Dinsmore, CJ
Hutchinson, JH
MacTough, SC
Stump, CA
Wei, DD
Zartman, CB
Bogusky, MJ
Culberson, JC
Buser-Doepner, C
Davide, J
Greenberg, IB
Hamilton, KA
Koblan, KS
Kohl, NE
Liu, DM
Lobell, RB
Mosser, SD
O'Neill, TJ
Rands, E
Schaber, MD
Wilson, F
Senderak, E
Motzel, SL
Gibbs, JB
Graham, SL
Heimbrook, DC
Hartman, GD
Oliff, AI
Huff, JR
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 1999, 42 (19) : 3779 - 3784

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