Design and synthesis of monocyclic β-lactams as mechanism-based inhibitors of human cytomegalovirus protease

Bioorganic and Medicinal Chemistry Letters

Volumn 8, Issue 4, 1998, Pages 365-370

  Borthwick, Alan D ^a   Weingarten, Gordon ^a   Haley, Terry M ^a   Tomaszewski, Mirek ^b   Wang, Wei ^b   Hu, Zhouhan ^b   Bedard, Jean ^b   Jin, Haloun ^b   Yuen, Leonard ^b   Mansour, Tarek S ^b  

^a GLAXOSMITHKLINE   (United Kingdom)

^b BioChem Therapeutic ^*  (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

BETA LACTAM DERIVATIVE; ENZYME INHIBITOR; MONOCYCLIC BETA LACTAM; PROTEINASE; SERINE PROTEINASE; SUICIDE SUBSTRATE; UNCLASSIFIED DRUG;

ARTICLE; CONTROLLED STUDY; DRUG DESIGN; DRUG SYNTHESIS; HUMAN CYTOMEGALOVIRUS; NONHUMAN;

BETA-LACTAMS; DRUG STABILITY; HUMANS; ISOMERISM; PROTEASE INHIBITORS; SERINE ENDOPEPTIDASES; STRUCTURE-ACTIVITY RELATIONSHIP; SUBSTRATE SPECIFICITY;

EID: 0032539506     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(98)00032-8     Document Type: Article

References (16)

1. 1. Gibson, W.; Welch, A. R.; Hall, M. R. T. Perspect. Drug Discov. Design 1994 2, 413-426.
2. 2. Holwerda, B. C. Antiviral Res. 1997, 35, 1-21.
3. 3. Chen, P.; Tsuge, H.; Almassy, R. J.; Gribskov, C. L.; Katoh, S.; Vanderpool, D. L.; Marbosiak, S. A.; Pinko, C.; Matthews, D. A.; Kan, C.C. Cell. 1996, 86, 835-843.
4. 4. Tong, L.; Qian C. G.; Massariol, M. J.; Bonneau, P. R.; Cordingley, M. G.; LaGace, L. A. Nature 1996, 383(N6597), 272-275.
5. 5. Qiu, X. Y.; Culp, J. S.; Dilella, A. G.; Hellmig, B.; Hoog, S. S.; Janson, C. A.; Smith, W. W.; Abdelmeguid, S.S. Nature 1996, 383(N6597), 275-279.
6. 6. Shieh, H. S.; Kurumbail, R. G.; Stevens, A. M.; Stegeman, R. A.; Sturman, E.J.; Pak, J. Y.; Wittwer, A. J.; Palmier, M. O.; Wiegand, R. C.; Holwerda, B. C.; Stallings, W. C. Nature 1996, JS3(N6597), 279-282.
7. 7. Shah, K. S.; Dorn, C. P.; Finke, P. E.; Hale, J. J.; Hagmann, W. K.; Brause, K. A.; Chandler, G. O.; Kissenger, A. L.; Ashe, B. M.; Weston, H.; Knight, W. B.; Maycock, A. L.; Dellea, P. S.; Flechter, D. S.; Hand, K. M.; Mumford, R.A.; Underwood, D. J.; Doherty, J.B. J. Med. Chem. 1992, 35, 3745-3754.
8. 8. Han, T. W.; Trehan, A. K.; Wright, J.J.K.; Federici, M. E.; Seiler, S. M.; Meanwell, N. A. Bioorganic Med. Chem. 1995, 3, 1123-1143.
9. 9. Clauss, K.; Grimm, D.; Prossel, G. Liebigs Ann. Chem. 1974, 539-560.
10. 10. Firestone, R.A.; Barker, P.L.; Pisano, J.M.; Ashe, B.M.; Dahlgren, M.E. Tetrahedron 1990, 46, 2255 2262.
11. 11. δAla HCMV is a mutant prepared by deleting residues Ala 143 and Ala 144 to decrease the self cleavage seen in the wild-type HCMV protease.
12. 12. van der Steen, F.H.; Kleijn, H.; Britovesek, G.J.P.; Jastrzebski, J.T.B.H.; van Koten, G. J. Org. Chem. 1992, 57, 3906-3916. Yamashita, H.; Minami, N.; Sakakibara, K.; Kobayashi, S.; Ohno, M. Chem. Pharm. Bull. 1988, 36, 469-480.
13. 12. van der Steen, F.H.; Kleijn, H.; Britovesek, G.J.P.; Jastrzebski, J.T.B.H.; van Koten, G. J. Org. Chem. 1992, 57, 3906-3916. Yamashita, H.; Minami, N.; Sakakibara, K.; Kobayashi, S.; Ohno, M. Chem. Pharm. Bull. 1988, 36, 469-480.
14. 13. Compounds are dissolved in DMSO and added at a concentration of 500μM (2% DMSO carry over) to a reaction mixture containing 6.65μM HCMV δAla protease with a final buffer composition of 85mM HEPES pH7.5, 170mM EDTA, 8.5mM NaCl, 1.7mM DTT and 25.5% glycerol. The reaction mixture is then pre-incubated at 37 °C for 15min, prior to addition of 1 mM substrate (RESYVKASVSPEAA), and then incubated for a further 15 minutes. The reaction is stopped by the addition of 1% TFA and the extent of inhibition of peptide substrate cleavage is analysed by reverse phase HPLC. The results obtained provide a % inhibition for each compound.
15. 50 results determined.
16. 15. Full mass spectral and sequencing analysis will be presented elsewhere.