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Volumn 13, Issue 20, 2003, Pages 3483-3486

Pyrimido[1,2-b]-1,2,4,5-tetrazin-6-ones as HCMV protease inhibitors: A new class of heterocycles with flavin-like redox properties

Author keywords

[No Author keywords available]

Indexed keywords

CYSTEINE; PROTEINASE INHIBITOR; TETRAZINE DERIVATIVE;

EID: 0141517088     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(03)00789-3     Document Type: Article
Times cited : (19)

References (25)
  • 1
    • 0010665337 scopus 로고    scopus 로고
    • Fields, B. N., Knipe, D. M., Howley, P. M., Eds; Lippincott-Raven: Philadelphia, PA
    • Mocarski, E. S. In Virology; Fields, B. N., Knipe, D. M., Howley, P. M., Eds; Lippincott-Raven: Philadelphia, PA, 1996; p 2447. Britt, W. J.; Alford, C. A. In Virology; Fields, B. N., Knipe, D. M., Howley, P. M., Eds, Lippincott-Raven: Philadelphia, PA, 1996; p 2493.
    • (1996) Virology , pp. 2447
    • Mocarski, E.S.1
  • 2
    • 0001450002 scopus 로고    scopus 로고
    • Fields, B. N., Knipe, D. M., Howley, P. M., Eds, Lippincott-Raven: Philadelphia, PA
    • Mocarski, E. S. In Virology; Fields, B. N., Knipe, D. M., Howley, P. M., Eds; Lippincott-Raven: Philadelphia, PA, 1996; p 2447. Britt, W. J.; Alford, C. A. In Virology; Fields, B. N., Knipe, D. M., Howley, P. M., Eds, Lippincott-Raven: Philadelphia, PA, 1996; p 2493.
    • (1996) Virology , pp. 2493
    • Britt, W.J.1    Alford, C.A.2
  • 3
    • 0037061903 scopus 로고    scopus 로고
    • More recently, valganciclovir, a valine ester prodrug of ganciclovir has been demonstrated to have improved bioavailability and is at least as efficacious as intravenous ganciclovir, see:
    • More recently, valganciclovir, a valine ester prodrug of ganciclovir has been demonstrated to have improved bioavailability and is at least as efficacious as intravenous ganciclovir, see: Martin D.F., Sierra-Madero J., Walmsey S., Wolitz R.A., Macey K., Georgiou P., Robinson C.A., Stempien M.J. New Engl. J. Med. 346:2002;1119.
    • (2002) New Engl. J. Med. , vol.346 , pp. 1119
    • Martin, D.F.1    Sierra-Madero, J.2    Walmsey, S.3    Wolitz, R.A.4    Macey, K.5    Georgiou, P.6    Robinson, C.A.7    Stempien, M.J.8
  • 4
    • 0020678189 scopus 로고
    • HCMV protease is presumed to be required on the basis that the analogous HSV protease is known to be essential; see: Preston V.G., Coates J.A., Rixon F.J. J. Virol. 45:1983;1056 Gao M., Matusick-Kumar L., Hurlburt W., Ditusa S., Newcomb W., Brown J.R., McCann P.J., Devkman I., Colonno R.J. J. Virol. 68:1994;3702.
    • (1983) J. Virol. , vol.45 , pp. 1056
    • Preston, V.G.1    Coates, J.A.2    Rixon, F.J.3
  • 5
    • 0028308504 scopus 로고
    • HCMV protease is presumed to be required on the basis that the analogous HSV protease is known to be essential; see:
    • HCMV protease is presumed to be required on the basis that the analogous HSV protease is known to be essential; see: Preston V.G., Coates J.A., Rixon F.J. J. Virol. 45:1983;1056 Gao M., Matusick-Kumar L., Hurlburt W., Ditusa S., Newcomb W., Brown J.R., McCann P.J., Devkman I., Colonno R.J. J. Virol. 68:1994;3702.
    • (1994) J. Virol. , vol.68 , pp. 3702
    • Gao, M.1    Matusick-Kumar, L.2    Hurlburt, W.3    Ditusa, S.4    Newcomb, W.5    Brown, J.R.6    McCann, P.J.7    Devkman, I.8    Colonno, R.J.9
  • 6
    • 0141822535 scopus 로고    scopus 로고
    • For a recent review, see: Olgilvie W.W. Curr. Med. Chem. Anti-Infective Agents. 1:2002;177. Also see: Borthwick A.D., Exall A.M., Haley T.M., Jackson D.L., Mason A.M., Weingarten G.G. Bioorg. Med. Chem. Lett. 12:2002;1719 Borthwick A.D., Crame A.J., Ertl P.F., Exall A.M., Haley T.M., Hart G.G., Mason A.M., Pennell A.M.K., Singh O.M.P., Weingarten G.G., Woolven J.M. J. Med. Chem. 45:2002;1 Borthwick A.D., Angier S.J., Crame A.J., Exall A.M., Haley T.M., Hart G.H., Mason A.M., Pennell A.M.K., Weingarten G.G. J. Med. Chem. 43:2000;4452 Borthwick A.D., Weingarten G., Haley T.M., Tomaszewski M., Wang W., Hu Z., Bedard J., Jin J., Yuen L., Mansour T. Bioorg. Med. Chem. Lett. 8:1998;365 Yoakim C., Ogilivie W.W., Cameron D.R., Chabot C., Grand-Maitre C., Guse I., Hache B., Kawai S., Nuad J., O'Meara J.A., Plante R., Deziel R. Antiviral Chem. Chemother. 9:1998;379 Deziel R., Malenfant E. Bioorg. Med. Chem. Lett. 8:1998;1437 Yoakim C., Ogilivie W.W., Cameron D.R., Chabot C., Guse I., Hache B., Naud J., O'Meara J.A., Plante R., Deziel R. J. Med. Chem. 41:1998;2882. and references cited therein.
    • (2002) Curr. Med. Chem. Anti-Infective Agents , vol.1 , pp. 177
    • Olgilvie, W.W.1
  • 7
    • 0037042763 scopus 로고    scopus 로고
    • For a recent review, see: Olgilvie W.W. Curr. Med. Chem. Anti-Infective Agents. 1:2002;177. Also see: Borthwick A.D., Exall A.M., Haley T.M., Jackson D.L., Mason A.M., Weingarten G.G. Bioorg. Med. Chem. Lett. 12:2002;1719 Borthwick A.D., Crame A.J., Ertl P.F., Exall A.M., Haley T.M., Hart G.G., Mason A.M., Pennell A.M.K., Singh O.M.P., Weingarten G.G., Woolven J.M. J. Med. Chem. 45:2002;1 Borthwick A.D., Angier S.J., Crame A.J., Exall A.M., Haley T.M., Hart G.H., Mason A.M., Pennell A.M.K., Weingarten G.G. J. Med. Chem. 43:2000;4452 Borthwick A.D., Weingarten G., Haley T.M., Tomaszewski M., Wang W., Hu Z., Bedard J., Jin J., Yuen L., Mansour T. Bioorg. Med. Chem. Lett. 8:1998;365 Yoakim C., Ogilivie W.W., Cameron D.R., Chabot C., Grand-Maitre C., Guse I., Hache B., Kawai S., Nuad J., O'Meara J.A., Plante R., Deziel R. Antiviral Chem. Chemother. 9:1998;379 Deziel R., Malenfant E. Bioorg. Med. Chem. Lett. 8:1998;1437 Yoakim C., Ogilivie W.W., Cameron D.R., Chabot C., Guse I., Hache B., Naud J., O'Meara J.A., Plante R., Deziel R. J. Med. Chem. 41:1998;2882. and references cited therein.
    • (2002) Bioorg. Med. Chem. Lett. , vol.12 , pp. 1719
    • Borthwick, A.D.1    Exall, A.M.2    Haley, T.M.3    Jackson, D.L.4    Mason, A.M.5    Weingarten, G.G.6
  • 8
    • 0037011893 scopus 로고    scopus 로고
    • For a recent review, see: Olgilvie W.W. Curr. Med. Chem. Anti-Infective Agents. 1:2002;177. Also see: Borthwick A.D., Exall A.M., Haley T.M., Jackson D.L., Mason A.M., Weingarten G.G. Bioorg. Med. Chem. Lett. 12:2002;1719 Borthwick A.D., Crame A.J., Ertl P.F., Exall A.M., Haley T.M., Hart G.G., Mason A.M., Pennell A.M.K., Singh O.M.P., Weingarten G.G., Woolven J.M. J. Med. Chem. 45:2002;1 Borthwick A.D., Angier S.J., Crame A.J., Exall A.M., Haley T.M., Hart G.H., Mason A.M., Pennell A.M.K., Weingarten G.G. J. Med. Chem. 43:2000;4452 Borthwick A.D., Weingarten G., Haley T.M., Tomaszewski M., Wang W., Hu Z., Bedard J., Jin J., Yuen L., Mansour T. Bioorg. Med. Chem. Lett. 8:1998;365 Yoakim C., Ogilivie W.W., Cameron D.R., Chabot C., Grand-Maitre C., Guse I., Hache B., Kawai S., Nuad J., O'Meara J.A., Plante R., Deziel R. Antiviral Chem. Chemother. 9:1998;379 Deziel R., Malenfant E. Bioorg. Med. Chem. Lett. 8:1998;1437 Yoakim C., Ogilivie W.W., Cameron D.R., Chabot C., Guse I., Hache B., Naud J., O'Meara J.A., Plante R., Deziel R. J. Med. Chem. 41:1998;2882. and references cited therein.
    • (2002) J. Med. Chem. , vol.45 , pp. 1
    • Borthwick, A.D.1    Crame, A.J.2    Ertl, P.F.3    Exall, A.M.4    Haley, T.M.5    Hart, G.G.6    Mason, A.M.7    Pennell, A.M.K.8    Singh, O.M.P.9    Weingarten, G.G.10    Woolven, J.M.11
  • 9
    • 0034676308 scopus 로고    scopus 로고
    • For a recent review, see: Olgilvie W.W. Curr. Med. Chem. Anti-Infective Agents. 1:2002;177. Also see: Borthwick A.D., Exall A.M., Haley T.M., Jackson D.L., Mason A.M., Weingarten G.G. Bioorg. Med. Chem. Lett. 12:2002;1719 Borthwick A.D., Crame A.J., Ertl P.F., Exall A.M., Haley T.M., Hart G.G., Mason A.M., Pennell A.M.K., Singh O.M.P., Weingarten G.G., Woolven J.M. J. Med. Chem. 45:2002;1 Borthwick A.D., Angier S.J., Crame A.J., Exall A.M., Haley T.M., Hart G.H., Mason A.M., Pennell A.M.K., Weingarten G.G. J. Med. Chem. 43:2000;4452 Borthwick A.D., Weingarten G., Haley T.M., Tomaszewski M., Wang W., Hu Z., Bedard J., Jin J., Yuen L., Mansour T. Bioorg. Med. Chem. Lett. 8:1998;365 Yoakim C., Ogilivie W.W., Cameron D.R., Chabot C., Grand-Maitre C., Guse I., Hache B., Kawai S., Nuad J., O'Meara J.A., Plante R., Deziel R. Antiviral Chem. Chemother. 9:1998;379 Deziel R., Malenfant E. Bioorg. Med. Chem. Lett. 8:1998;1437 Yoakim C., Ogilivie W.W., Cameron D.R., Chabot C., Guse I., Hache B., Naud J., O'Meara J.A., Plante R., Deziel R. J. Med. Chem. 41:1998;2882. and references cited therein.
    • (2000) J. Med. Chem. , vol.43 , pp. 4452
    • Borthwick, A.D.1    Angier, S.J.2    Crame, A.J.3    Exall, A.M.4    Haley, T.M.5    Hart, G.H.6    Mason, A.M.7    Pennell, A.M.K.8    Weingarten, G.G.9
  • 10
    • 0032539506 scopus 로고    scopus 로고
    • For a recent review, see: Olgilvie W.W. Curr. Med. Chem. Anti-Infective Agents. 1:2002;177. Also see: Borthwick A.D., Exall A.M., Haley T.M., Jackson D.L., Mason A.M., Weingarten G.G. Bioorg. Med. Chem. Lett. 12:2002;1719 Borthwick A.D., Crame A.J., Ertl P.F., Exall A.M., Haley T.M., Hart G.G., Mason A.M., Pennell A.M.K., Singh O.M.P., Weingarten G.G., Woolven J.M. J. Med. Chem. 45:2002;1 Borthwick A.D., Angier S.J., Crame A.J., Exall A.M., Haley T.M., Hart G.H., Mason A.M., Pennell A.M.K., Weingarten G.G. J. Med. Chem. 43:2000;4452 Borthwick A.D., Weingarten G., Haley T.M., Tomaszewski M., Wang W., Hu Z., Bedard J., Jin J., Yuen L., Mansour T. Bioorg. Med. Chem. Lett. 8:1998;365 Yoakim C., Ogilivie W.W., Cameron D.R., Chabot C., Grand-Maitre C., Guse I., Hache B., Kawai S., Nuad J., O'Meara J.A., Plante R., Deziel R. Antiviral Chem. Chemother. 9:1998;379 Deziel R., Malenfant E. Bioorg. Med. Chem. Lett. 8:1998;1437 Yoakim C., Ogilivie W.W., Cameron D.R., Chabot C., Guse I., Hache B., Naud J., O'Meara J.A., Plante R., Deziel R. J. Med. Chem. 41:1998;2882. and references cited therein.
    • (1998) Bioorg. Med. Chem. Lett. , vol.8 , pp. 365
    • Borthwick, A.D.1    Weingarten, G.2    Haley, T.M.3    Tomaszewski, M.4    Wang, W.5    Hu, Z.6    Bedard, J.7    Jin, J.8    Yuen, L.9    Mansour, T.10
  • 11
    • 17344377814 scopus 로고    scopus 로고
    • For a recent review, see: Olgilvie W.W. Curr. Med. Chem. Anti-Infective Agents. 1:2002;177. Also see: Borthwick A.D., Exall A.M., Haley T.M., Jackson D.L., Mason A.M., Weingarten G.G. Bioorg. Med. Chem. Lett. 12:2002;1719 Borthwick A.D., Crame A.J., Ertl P.F., Exall A.M., Haley T.M., Hart G.G., Mason A.M., Pennell A.M.K., Singh O.M.P., Weingarten G.G., Woolven J.M. J. Med. Chem. 45:2002;1 Borthwick A.D., Angier S.J., Crame A.J., Exall A.M., Haley T.M., Hart G.H., Mason A.M., Pennell A.M.K., Weingarten G.G. J. Med. Chem. 43:2000;4452 Borthwick A.D., Weingarten G., Haley T.M., Tomaszewski M., Wang W., Hu Z., Bedard J., Jin J., Yuen L., Mansour T. Bioorg. Med. Chem. Lett. 8:1998;365 Yoakim C., Ogilivie W.W., Cameron D.R., Chabot C., Grand-Maitre C., Guse I., Hache B., Kawai S., Nuad J., O'Meara J.A., Plante R., Deziel R. Antiviral Chem. Chemother. 9:1998;379 Deziel R., Malenfant E. Bioorg. Med. Chem. Lett. 8:1998;1437 Yoakim C., Ogilivie W.W., Cameron D.R., Chabot C., Guse I., Hache B., Naud J., O'Meara J.A., Plante R., Deziel R. J. Med. Chem. 41:1998;2882. and references cited therein.
    • (1998) Antiviral Chem. Chemother. , vol.9 , pp. 379
    • Yoakim, C.1    Ogilivie, W.W.2    Cameron, D.R.3    Chabot, C.4    Grand-Maitre, C.5    Guse, I.6    Hache, B.7    Kawai, S.8    Nuad, J.9    O'Meara, J.A.10    Plante, R.11    Deziel, R.12
  • 12
    • 0032474569 scopus 로고    scopus 로고
    • For a recent review, see: Olgilvie W.W. Curr. Med. Chem. Anti-Infective Agents. 1:2002;177. Also see: Borthwick A.D., Exall A.M., Haley T.M., Jackson D.L., Mason A.M., Weingarten G.G. Bioorg. Med. Chem. Lett. 12:2002;1719 Borthwick A.D., Crame A.J., Ertl P.F., Exall A.M., Haley T.M., Hart G.G., Mason A.M., Pennell A.M.K., Singh O.M.P., Weingarten G.G., Woolven J.M. J. Med. Chem. 45:2002;1 Borthwick A.D., Angier S.J., Crame A.J., Exall A.M., Haley T.M., Hart G.H., Mason A.M., Pennell A.M.K., Weingarten G.G. J. Med. Chem. 43:2000;4452 Borthwick A.D., Weingarten G., Haley T.M., Tomaszewski M., Wang W., Hu Z., Bedard J., Jin J., Yuen L., Mansour T. Bioorg. Med. Chem. Lett. 8:1998;365 Yoakim C., Ogilivie W.W., Cameron D.R., Chabot C., Grand-Maitre C., Guse I., Hache B., Kawai S., Nuad J., O'Meara J.A., Plante R., Deziel R. Antiviral Chem. Chemother. 9:1998;379 Deziel R., Malenfant E. Bioorg. Med. Chem. Lett. 8:1998;1437 Yoakim C., Ogilivie W.W., Cameron D.R., Chabot C., Guse I., Hache B., Naud J., O'Meara J.A., Plante R., Deziel R. J. Med. Chem. 41:1998;2882. and references cited therein.
    • (1998) Bioorg. Med. Chem. Lett. , vol.8 , pp. 1437
    • Deziel, R.1    Malenfant, E.2
  • 13
    • 15644380718 scopus 로고    scopus 로고
    • For a recent review, see: Also see: and references cited therein
    • For a recent review, see: Olgilvie W.W. Curr. Med. Chem. Anti-Infective Agents. 1:2002;177. Also see: Borthwick A.D., Exall A.M., Haley T.M., Jackson D.L., Mason A.M., Weingarten G.G. Bioorg. Med. Chem. Lett. 12:2002;1719 Borthwick A.D., Crame A.J., Ertl P.F., Exall A.M., Haley T.M., Hart G.G., Mason A.M., Pennell A.M.K., Singh O.M.P., Weingarten G.G., Woolven J.M. J. Med. Chem. 45:2002;1 Borthwick A.D., Angier S.J., Crame A.J., Exall A.M., Haley T.M., Hart G.H., Mason A.M., Pennell A.M.K., Weingarten G.G. J. Med. Chem. 43:2000;4452 Borthwick A.D., Weingarten G., Haley T.M., Tomaszewski M., Wang W., Hu Z., Bedard J., Jin J., Yuen L., Mansour T. Bioorg. Med. Chem. Lett. 8:1998;365 Yoakim C., Ogilivie W.W., Cameron D.R., Chabot C., Grand-Maitre C., Guse I., Hache B., Kawai S., Nuad J., O'Meara J.A., Plante R., Deziel R. Antiviral Chem. Chemother. 9:1998;379 Deziel R., Malenfant E. Bioorg. Med. Chem. Lett. 8:1998;1437 Yoakim C., Ogilivie W.W., Cameron D.R., Chabot C., Guse I., Hache B., Naud J., O'Meara J.A., Plante R., Deziel R. J. Med. Chem. 41:1998;2882. and references cited therein.
    • (1998) J. Med. Chem. , vol.41 , pp. 2882
    • Yoakim, C.1    Ogilivie, W.W.2    Cameron, D.R.3    Chabot, C.4    Guse, I.5    Hache, B.6    Naud, J.7    O'Meara, J.A.8    Plante, R.9    Deziel, R.10
  • 15
    • 85031083933 scopus 로고    scopus 로고
    • These compounds demonstrated selectivity for HCMV protease over other known serine proteases - data not shown
    • These compounds demonstrated selectivity for HCMV protease over other known serine proteases - data not shown.
  • 16
    • 0021740311 scopus 로고
    • Prepared by condensing 1,3-diaminoguanidine with ethyl 2-methylacetoacetate; see:
    • Prepared by condensing 1,3-diaminoguanidine with ethyl 2-methylacetoacetate; see: Hlavka J.J., Bitha P., Lin Y., Strohmeyer T. J. Heterocyclic Chem. 21:1984;1537.
    • (1984) J. Heterocyclic Chem. , vol.21 , pp. 1537
    • Hlavka, J.J.1    Bitha, P.2    Lin, Y.3    Strohmeyer, T.4
  • 18
    • 0002151740 scopus 로고
    • For a review of orthoester syntheses, see:
    • For a review of orthoester syntheses, see: DeWolfe R.H. Synthesis. 1974;153.
    • (1974) Synthesis , pp. 153
    • DeWolfe, R.H.1
  • 19
    • 85031081270 scopus 로고    scopus 로고
    • That acetylation occurs at this position is presumed based on previously reported results with other electrophilic reagents; see ref 8.
  • 20
    • 85031074111 scopus 로고    scopus 로고
    • 2-, Ac-3a and the dimethyl amide precursor 5 were the only observable products under these conditions.
  • 21
    • 85031079776 scopus 로고    scopus 로고
    • 2O with a trace of AcOH to give analytically pure 1d (1.5 g; 49%).
  • 22
    • 85031068302 scopus 로고    scopus 로고
    • -1, Rigaku AFC5R diffractometer, 3704 reflections (unique), R=0.084.
  • 23
    • 85031079001 scopus 로고    scopus 로고
    • 2O was the reagent of choice, offering higher yields, easier workups and cleaner reactions.
  • 24
    • 85031080500 scopus 로고    scopus 로고
    • HCMV protease (2 μM) was preincubated with potential inhibitors for 2 h at 25 °C in 10 mM Tris-Cl, pH 7.5, 50 mM NaCl. Substrate was added and incubation continued for 2 h. The reaction was terminated with pH 5.5 stop buffer containing streptavidin-coated SPA beads followed by scintillation counting. For more details, see ref 5.
  • 25
    • 85031074708 scopus 로고    scopus 로고
    • This is easy to monitor visually - the tetrazines 2 are orange to red and are soluble whereas the dihydro analogues 1 are yellow and insoluble in chloroform.


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