Dihydroxypyridopyrazine-1,6-dione HIV-1 integrase inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 17, Issue 20, 2007, Pages 5595-5599

  Wai, John S ^a   Kim, Boyoung ^a   Fisher, Thorsten E ^a   Zhuang, Linghang ^a   Embrey, Mark W ^a   Williams, Peter D ^a   Staas, Donnette D ^a   Culberson, Chris ^a   Lyle, Terry A ^a   Vacca, Joseph P ^a   Hazuda, Daria J ^a   Felock, Peter J ^a   Schleif, William A ^a   Gabryelski, Lori J ^a   Jin, Lixia ^a   Chen, I Wu ^a   Ellis, Joan D ^a   Mallai, Rama ^a   Young, Steven D ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

6 dione; Dihydroxypyridopyrazine 1; HIV; Integrase; Strand transfer inhibitors

Indexed keywords

ANTIVIRUS AGENT; DIHYDROXYPYRIDOPYRAZINE 1,6 DIONE INTEGRASE INHIBITOR; INTEGRASE INHIBITOR; UNCLASSIFIED DRUG;

ANTIVIRAL ACTIVITY; ARTICLE; COVALENT BOND; DRUG POTENCY; DRUG STRUCTURE; DRUG SYNTHESIS; HUMAN; LIVER MICROSOME; NONHUMAN; RAT; SUBSTITUTION REACTION; VIRUS REPLICATION;

ANIMALS; BENZENE; CELL LINE; HIV; HIV INTEGRASE INHIBITORS; HUMANS; MICROSOMES, LIVER; MODELS, MOLECULAR; MOLECULAR STRUCTURE; PYRAZINES; RATS; STRUCTURE-ACTIVITY RELATIONSHIP; VIRUS REPLICATION;

HUMAN IMMUNODEFICIENCY VIRUS 1; RATTUS;

EID: 34548598155     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2007.07.092     Document Type: Article

References (17)

1. For a recent review on the structure and function of HIV-1 integrase, see:. Davies D.R., and Chiu T.K. Curr. Top. Med. Chem. 4 (2004) 965
2. Pommier Y., Johnson A.A., and Marchand C. Nat. Rev. Drug Discov. 4 (2005) 236
3. For a recent review on HIV-1 integrase inhibitors, see:. Gordon C.P., Griffith R., and Keller P.A. Med. Chem. 3 (2007) 199
4. Deng J., Dayam R., Al-Mawsawi L.Q., and Neamati N. Curr. Pharm. Des. 13 (2007) 129
5. Anthony N.J. Curr. Top. Med. Chem. 4 (2004) 979
6. Wai J.S., Egbertson M.S., Payne L.S., Fisher T.E., Embrey M.W., Tran L.O., Melamed J.Y., Langford H.M., Guare Jr. J.P., Zhuang L., Grey V.E., Vacca J.P., Holloway M.K., Naylor-Olsen A.M., Hazuda D.J., Felock P.J., Wolfe A.L., Stillmock K.A., Schleif W.A., Gabryelski L.J., and Young S.D. J. Med. Chem. 43 (2000) 4923
7. For monocyclic pyrimidinone integrase inhibitors, see. Zhuang L., Wai J.S., Embrey M.W., Fisher T.E., Egbertson M.S., Payne L.S., Guare Jr. J.P., Vacca J.P., Hazuda D.J., Felock P.J., Wolfe A.L., Stillmock K.A., Witmer M.V., Moyer G., Schleif W.A., Gabryelski L.J., Leonard Y.M., Lynch Jr. J.J., Michelson S.R., and Young S.D. J. Med. Chem. 46 (2003) 453
8. Hazuda D.J., Anthony N.J., Gomez R.P., Jolly S.M., Wai J.S., Zhuang L., Fisher T.E., Embrey M.W., Guare Jr. J.P., Egbertson M.S., Vacca J.P., Huff J.R., Felock P.J., Witmer M.V., Stillmock K.A., Danovich R., Grobler J., Miller M.D., Espeseth A.S., Jin L., Chen I.-W., Lin J., Kassahun K., Ellis J.D., Wong B.K., Xu W., Pearson P.G., Schleif W.A., Cortese R., Emini E., Summa V., Holloway M.K., and Young S.D. Proc. Natl. Acad. Sci. U.S.A. 101 (2004) 11233
9. Hazuda D.J., Young S.D., Guare Jr. J.P., Anthony N.J., Gomez R.P., Wai J.S., Vacca J.P., Handt L., Motzel S.L., Klein H.J., Dornadula G., Danovich R.M., Witmer M.V., Wilson K.A.A., Tussey L., Schleif W.A., Gabryelski L.S., Lin J., Miller M.D., Casimiro D.R., Emini E.A., and Shiver J.W. Science 305 (2004) 528-532
10. Summa V., Petrocchi A., Matassa V., Gardelli C., Muraglia E., Rowley M., Paz O.G., Laufer R., Monteagudo E., and Pace P. J. Med. Chem 49 (2006) 6646
11. Petrocchi A., Koch U., Matassa V.G., Pacini B., Stillmock K.A., and Summa V. Biorg. Med. Chem. Lett. 17 (2007) 350
12. Hazuda D.J., Felock P., Hastings J.C., Pramanik B., and Wolfe A. J. Virol. 71 (1997) 7005 Assays were performed with recombinant HIV-1 integrase (0.1 μM) preassembled on immobilized oligonucleotides. Inhibitors were either added during assembly without washing or subsequent to assembly and washings. Inhibition was determined in relation to the integrase control reaction (without inhibitor) performed in quadruplicate and averaged. All samples were background subtracted
13. Spartan '04 Windows ES 2.0.0. 2003.
14. 95) are defined as those which inhibited by ≥95% the spread of HIV-1 infection in susceptible cell culture. MT-4 human T-lymphoid cells were maintained in RPMI 1640 medium containing 10% heat inactivated fetal bovine serum. Cells were infected en masse at low multiplicity (0.01) using HIV-1 strain IIIb and were incubated for 24 h. At this time, cells were washed and distributed into 96-well microtiter dishes. Serial 2-fold dilutions of inhibitor were added to the wells and the cultures were maintained for three additional days. Virus spread was assessed by HIV-1 p24 core antigen ELISA. Control cultures in the absence of inhibitor were fully infected at 4 days
15. 14C-labeled diethyl oxalate.
16. Evans D.C., Watt A.P., Nicoll-Griffith D.A., and Baillie T.A. Chem. Res. Toxicol. 17 (2004) 3-16
17. Kim J.H., Lee Y.S., and Kim S.S. Heterocycles 48 (1998) 2279-2286