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

Bioorganic and Medicinal Chemistry Letters

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

  Di Grandi, Martin J ^a   Curran, Kevin J ^a   Baum, Ellen Z ^a,c   Bebernitz, Geraldine ^a   Ellestad, George A ^a   Ding, Wei Dong ^a   Lang, Stanley A ^a,d   Rossi, Miriam ^b   Bloom, Jonathan D ^a  

^a WYETH RESEARCH   (United States)

^b VASSAR COLLEGE   (United States)

^c JOHNSON AND JOHNSON PHARMACEUTICAL RESEARCH AND DEVELOPMENT   (United States)

^d Ribapharm Inc   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CYSTEINE; PROTEINASE INHIBITOR; TETRAZINE DERIVATIVE;

ARTICLE; CROSS LINKING; CRYSTAL STRUCTURE; DRUG ACTIVITY; DRUG MECHANISM; DRUG SYNTHESIS; HUMAN CYTOMEGALOVIRUS; OXIDATION; OXIDATION REDUCTION REACTION; STRUCTURE ACTIVITY RELATION; X RAY ANALYSIS;

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

References (25)

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
12. 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.
13. 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.
14. Baum E.Z., Ding W.-D., Siegel M.M., Hulmes J., Bebernitz G.A., Sridharan L., Tabei K., Krishnamurthy G., Carofigli T., Groves J.T., Bloom J., Di Grandi M.J., Bradley M., Ellestad G., Seddon A.P., Gluzman Y. Biochemistry. 35:1996;5847.
15. These compounds demonstrated selectivity for HCMV protease over other known serine proteases - data not shown.
16. 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.
17. Bitha P., Hlavka J.J., Lin Y.-i. J. Org. Chem. 52:1987;2220.
18. For a review of orthoester syntheses, see: DeWolfe R.H. Synthesis. 1974;153.
19. That acetylation occurs at this position is presumed based on previously reported results with other electrophilic reagents; see ref 8.
20. 2-, Ac-3a and the dimethyl amide precursor 5 were the only observable products under these conditions.
21. 2O with a trace of AcOH to give analytically pure 1d (1.5 g; 49%).
22. -1, Rigaku AFC5R diffractometer, 3704 reflections (unique), R=0.084.
23. 2O was the reagent of choice, offering higher yields, easier workups and cleaner reactions.
24. 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. 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.