Design and synthesis of 8-hydroxy-[1,6]naphthyridines as novel inhibitors of HIV-1 integrase in vitro and in infected cells

Journal of Medicinal Chemistry

Volumn 46, Issue 4, 2003, Pages 453-456

  Zhuang, Linghang ^a   Wai, John S ^a   Embrey, Mark W ^a   Fisher, Thorsten E ^a   Egbertson, Melissa S ^a   Payne, Linda S ^a   Guare Jr , James P ^a   Vacca, Joseph P ^a   Hazuda, Daria J ^a   Felock, Peter J ^a   Wolfe, Abigail L ^a   Stillmock, Kara A ^a   Witmer, Marc V ^a   Moyer, Gregory ^a   Schleif, William A ^a   Gabryelski, Lori J ^a   Leonard, Yvonne M ^a   Lynch Jr , Joseph J ^a   Michelson, Stuart R ^a   Young, Steven D ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

8 HYDROXY [1,6]NAPHTHYRIDINE; INTEGRASE; INTEGRASE INHIBITOR; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANTIVIRAL ACTIVITY; ARTICLE; CATALYSIS; CELL CULTURE; CYTOTOXICITY; DRUG DESIGN; DRUG EFFECT; DRUG HALF LIFE; DRUG MECHANISM; DRUG POTENCY; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME INHIBITION; HUMAN IMMUNODEFICIENCY VIRUS 1; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; IC 50; IN VITRO STUDY; NONHUMAN; RAT; STRUCTURE ACTIVITY RELATION;

ADMINISTRATION, ORAL; ANIMALS; ANTI-HIV AGENTS; CELL LINE; HIV INTEGRASE INHIBITORS; HIV-1; HUMANS; INJECTIONS, INTRAVENOUS; NAPHTHYRIDINES; RATS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 0037434509     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm025553u     Document Type: Article

References (25)

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5. Recent reviews on biology of HIV-1 integrase: (a) Esposito, D.; Craigie, R. HIV integrase structure and function. Adv. Virus Res. 1999, 52, 319-333. (b) Asante-Appiah, E.; Skalka, A. M. HIV-1 integrase: structural organization, conformational changes, and catalysis. Adv. Virus Res. 1999, 52, 351-369. For a recent review on HIV-1 integrase inhibitors, see the following. Young, S. D. Inhibition of HIV-1 integrase by small molecules: the potential for a new class of AIDS chemotherapeutics. Curr. Opin. Drug Discovery Dev. 2001, 4, 402-410.
6. Recent reviews on biology of HIV-1 integrase: (a) Esposito, D.; Craigie, R. HIV integrase structure and function. Adv. Virus Res. 1999, 52, 319-333. (b) Asante-Appiah, E.; Skalka, A. M. HIV-1 integrase: structural organization, conformational changes, and catalysis. Adv. Virus Res. 1999, 52, 351-369. For a recent review on HIV-1 integrase inhibitors, see the following. Young, S. D. Inhibition of HIV-1 integrase by small molecules: the potential for a new class of AIDS chemotherapeutics. Curr. Opin. Drug Discovery Dev. 2001, 4, 402-410.
7. Recent reviews on biology of HIV-1 integrase: (a) Esposito, D.; Craigie, R. HIV integrase structure and function. Adv. Virus Res. 1999, 52, 319-333. (b) Asante-Appiah, E.; Skalka, A. M. HIV-1 integrase: structural organization, conformational changes, and catalysis. Adv. Virus Res. 1999, 52, 351-369. For a recent review on HIV-1 integrase inhibitors, see the following. Young, S. D. Inhibition of HIV-1 integrase by small molecules: the potential for a new class of AIDS chemotherapeutics. Curr. Opin. Drug Discovery Dev. 2001, 4, 402-410.
8. (a) 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, J. P., Jr.; 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.; Young, S. D. 4-Aryl-2,4-dioxobutanoic acid inhibitors of HIV-1 integrase and viral replication in cells. J. Med. Chem. 2000, 43, 4923-4926. (b) Grobler, J. A.; Stillmock, K.; Hu, B.; Witmer, M.; Felock, P.; Espeseth, A.; Wolfe, A.; Egbertson, M. S.; Bourgeois, M.; Melamed, J. Y.; Wai, J. S.; Young, S. D.; Vacca, J. P.; Hazuda, D. J. Diketo acid inhibitor mechanism and HIV-1 integrase: Implications for metal binding in the active site of phosphotransferase enzymes. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 6661-6666. (c) Hazuda, D. J.; Felock, P.; Witmar, M.; Wolfe, A.; Stillmock, K.; Grobler, J. A.; Espeseth, A.; Gabryelski, L.; Schleif, W.; Blau, C.; Miller, M. D. Inhibitors of strand transfer that prevent integration and inhibit HIV-1 replication in cells. Science 2000, 287, 646-650.
9. (a) 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, J. P., Jr.; 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.; Young, S. D. 4-Aryl-2,4-dioxobutanoic acid inhibitors of HIV-1 integrase and viral replication in cells. J. Med. Chem. 2000, 43, 4923-4926. (b) Grobler, J. A.; Stillmock, K.; Hu, B.; Witmer, M.; Felock, P.; Espeseth, A.; Wolfe, A.; Egbertson, M. S.; Bourgeois, M.; Melamed, J. Y.; Wai, J. S.; Young, S. D.; Vacca, J. P.; Hazuda, D. J. Diketo acid inhibitor mechanism and HIV-1 integrase: Implications for metal binding in the active site of phosphotransferase enzymes. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 6661-6666. (c) Hazuda, D. J.; Felock, P.; Witmar, M.; Wolfe, A.; Stillmock, K.; Grobler, J. A.; Espeseth, A.; Gabryelski, L.; Schleif, W.; Blau, C.; Miller, M. D. Inhibitors of strand transfer that prevent integration and inhibit HIV-1 replication in cells. Science 2000, 287, 646-650.
10. (a) 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, J. P., Jr.; 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.; Young, S. D. 4-Aryl-2,4-dioxobutanoic acid inhibitors of HIV-1 integrase and viral replication in cells. J. Med. Chem. 2000, 43, 4923-4926. (b) Grobler, J. A.; Stillmock, K.; Hu, B.; Witmer, M.; Felock, P.; Espeseth, A.; Wolfe, A.; Egbertson, M. S.; Bourgeois, M.; Melamed, J. Y.; Wai, J. S.; Young, S. D.; Vacca, J. P.; Hazuda, D. J. Diketo acid inhibitor mechanism and HIV-1 integrase: Implications for metal binding in the active site of phosphotransferase enzymes. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 6661-6666. (c) Hazuda, D. J.; Felock, P.; Witmar, M.; Wolfe, A.; Stillmock, K.; Grobler, J. A.; Espeseth, A.; Gabryelski, L.; Schleif, W.; Blau, C.; Miller, M. D. Inhibitors of strand transfer that prevent integration and inhibit HIV-1 replication in cells. Science 2000, 287, 646-650.
11. Preparations of compounds 2-7 are in Supporting Information.
12. 2 using 0.5 nM target substrate as indicated. After strand transfer, the FITC-labeled products were detected using an anti-FITC antibody conjugated with alkaline phosphatase (Boehringer Mannheim) and a chemiluminescence substrate (Sapphire II, Tropix). The assay was performed in a final concentration of 10% DMSO. To specifically evaluate inhibition of strand transfer, compounds were added after assembly, just prior to the addition of the target DNA.
13. 2 using 0.5 nM target substrate as indicated. After strand transfer, the FITC-labeled products were detected using an anti-FITC antibody conjugated with alkaline phosphatase (Boehringer Mannheim) and a chemiluminescence substrate (Sapphire II, Tropix). The assay was performed in a final concentration of 10% DMSO. To specifically evaluate inhibition of strand transfer, compounds were added after assembly, just prior to the addition of the target DNA.
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16. (a) Payne, L. S.; Tran, L. O.; Zhuang, L.; Young, S. D.; Egbertson, M. S.; Wai, J. S.; Embrey, M. W.; Fisher, T. E.; Guare, J. P.; Langford, H., M.; Melamed, J. Y.; Clark, D. L. Preparation of 1,3-diaryl-1,3-propanediones as HIV integrase inhibitors. Patent WO0100578 A1 (Merck & Co., Inc. and Tularik, Inc.). (b) Fujishita, T.; Yoshinaga, T.; Sato, A. Preparation of aromatic heterocycle compounds having HIV integrase inhibiting activities. Patent WO0039086 A1 (Shionogi and Co., Ltd., Japan; in Japanese).
17. 95) are defined as those that 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.
18. Cytotoxicity is evaluated by visual inspection of the culture for cytopathic effects distinguished as gross morphological changes, growth pattern change, and metabolic change as indicated by lack of change in the medium pH indicator. With inhibitor 7, all cells remain viable after 4 days. During the 4-day incubation period, MT-4 cells will typically double at least 4 times. No effect on cell numbers was observed with 7 at up to 12.5 μM.
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