Structure-based design of irreversible, tripeptidyl human rhinovirus 3C protease inhibitors containing N-methyl amino acids

Bioorganic and Medicinal Chemistry Letters

Volumn 9, Issue 15, 1999, Pages 2189-2194

  Dragovich, Peter S ^a   Webber, Stephen E ^a   Prins, Thomas J ^a   Zhou, Ru ^a   Marakovits, Joseph T ^a   Tikhe, Jayashree G ^a   Fuhrman, Shella A ^a   Patick, Amy K ^a   Matthews, David A ^a   Ford, Clifford E ^a   Brown, Edward L ^a   Binford, Susan L ^a   Meador III, James W ^a   Ferre, Rose Ann ^a   Worland, Stephen T ^a  

^a AGOURON PHARMACEUTICALS INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMINO ACID; CYSTEINE; PROTEINASE; PROTEINASE INHIBITOR;

ANTIVIRAL ACTIVITY; ARTICLE; DRUG DESIGN; DRUG STRUCTURE; ENZYME INHIBITION; HUMAN RHINOVIRUS; NONHUMAN; STRUCTURE ACTIVITY RELATION;

CYSTEINE ENDOPEPTIDASES; DRUG DESIGN; HUMANS; PEPTIDES; PROTEASE INHIBITORS; RHINOVIRUS; STRUCTURE-ACTIVITY RELATIONSHIP; VIRAL PROTEINS;

HUMAN RHINOVIRUS 3; HUMAN RHINOVIRUS SP.; RNA VIRUSES;

EID: 0033516899     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(99)00368-6     Document Type: Article

References (38)

1. Couch, R. B. In Fields Virology, 3rd Ed.; Fields, B. N., Knipe, D. M., Howley, P. M., et al. Eds.; Lippincott-Raven Publishers: Philadelphia, 1996; Vol. 1, Chapter 23, pp 713-734 and references therein.
2. Rueckert, R. R. In Fields Virology, 3rd Ed.; Fields, B. N., Knipe, D. M., Howley, P. M., et al. Eds.; Lippincott-Raven Publishers: Philadelphia, 1996; Vol. 1, Chapter 21, pp 609-654 and references therein.
3. (a) Orr, D. C.; Long, A. C.; Kay, J.; Dunn, B. M.; Cameron, J. M. J. Gen. Virol. 1989, 70, 2931.
4. (b) Cordingley, M. G.; Register, R. B.; Callahan, P. L.; Garsky, V. M.; Colonno, R. J. J. Virol. 1989, 63, 5037.
5. Matthews, D. A.; Smith, W. W.; Ferre, R. A.; Condon, B.; Budahazi, G.; Sisson, W.; Villafranca, J. E.; Janson, C. A.; McElroy, H. E.; Gribskov, C. L.; Worland, S. Cell 1994, 77, 761.
6. (a) Webber, S. E.; Okano, K.; Little, T. L.; Reich, S. H.; Xin, Y.; Fuhrman, S. A.; Matthews, D. A.; Hendrickson, T. F.; Love, R. A.; Patick, A. K.; Meador, J. W., III; Ferre, R. A.; Brown, E. L.; Ford, C. E.; Binford, S. L.; Worland, S. T. J. Med. Chem. 1998, 41, 2786.
7. (b) Shepherd, T. A.; Cox, G. A.; McKinney, E.; Tang, J.; Wakulchik, M.; Zimmerman, R. E.; Villarreal, E. C. Bioorg. Med. Chem. Lett. 1996, 6, 2893.
8. (c) Kaldor, S. W.; Hammond, M.; Dressman, B. A.; Labus, J. M.; Chadwell, F. W.; Kline, A. D.; Heinz, B. A. Bioorg. Med. Chem. Lett. 1995, 5, 2021.
9. Webber, S. E.; Tikhe J.; Worland, S. T.; Fuhrman, S. A.; Hendrickson, T. F.; Matthews, D. A.; Love, R. A.; Patick, A. K.; Meador, J. W.; Ferre, R. A.; Brown, E. L.; DeLisle, D. M.; Ford, C. E.; Binford, S. L. J. Med. Chem. 1996, 39, 5072.
10. Jungheim, L. N.; Cohen, J. D.; Johnson, R. B.; Villarreal, E. C.; Wakulchik; M.; Loncharich, R. J.; Wang, Q. M. Bioorg. Med. Chem. Lett. 1997, 7, 1589.
11. (a) Brill, G. M.; Kati, W. M.; Montgomery, D.; Karwowski, J. P.; Humphrey, P. E.; Jackson, M.; Clement, J. J.; Kadam, S.; Chen, R. H.; McAlpine, J. B. J. Antibiotics 1996, 49, 541.
12. (b) Sham, H. L.; Rosenbrook, W.; Kati, W.; Betebenner, D. A.; Wideburg, N. E.; Saldivar, A.; Plattner, J. J.; Norbeck, D. W. J. Chem. Soc., Perkin Trans. 1 1995, 1081.
13. (c) Kadam, S.; Poddig, J.; Humphrey, P.; Karwowski, J.; Jackson, M.; Tennent, S.; Fung, L.; Hochlowski, J.; Rasmussen, R.; McAlpine, J. J. Antibiotics 1994, 47, 836.
14. (d) Singh, S. B.; Cordingley, M. G.; Ball, R. G.; Smith, J. L.; Dombrowski, A. W.; Goetz, M. A. Tetrahedron Lett. 1991, 32, 5279.
15. (e) Skiles, J. W.; McNeil, D. Tetrahedron Lett. 1990, 31, 7277.
16. Dragovich, P. S.; Webber, S. E.; Babine, R. E.; Fuhrman, S. A.; Patick, A. K.; Matthews, D. A.; Lee, C. A.; Reich, S. R.; Prins, T. J.; Marakovits, J. T.; Littlefield, E. S.; Zhou, R.; Tikhe, J.; Ford, C. E.; Wallace, M. B.; Meador, J. W., III; Ferre, R. A.; Brown, E. L.; Binford, S. L.; Harr, J. E. V.; DeLisle, D. M.; Worland, S. T. J. Med. Chem. 1998, 41, 2806.
17. Dragovich, P. S.; Webber, S. E.; Babine, R. E.; Fuhrman, S. A.; Patick, A. K.; Matthews, D. A.; Reich, S. H.; Marakovits, J. T.; Prins, T. J.; Zhou, R.; Tikhe, J.; Littlefield, E. S.; Bleckman, T. M.; Wallace, M. B.; Little, T. L.; Ford, C. E.; Meador, J. W., III; Ferre, R. A.; Brown, E. L.; Binford, S. L.; DeLisle, D. M.; Worland, S. T. J. Med. Chem. 1998, 41, 2819.
18. A similar series of HRV 3CP inhibitors has also recently been described. See: Kong, J.-S.; Venkatraman, S.; Furness, K.; Nimkar, S.; Shepherd, T. A.; Wang, Q. M.; Aubé, J.; Hanzlik, R. P. J. Med. Chem. 1998, 41, 2579.
19. For other examples of Michael acceptor-containing cysteine protease inhibitors, see: (a) Roush, W. R.; Gwaltney, S. L., II; Cheng, J.; Scheidt, K. A.; McKerrow, J. H.; Hansell, E. J. Am. Chem. Soc. 1998, 120, 10994.
20. (b) McGrath, M. E.; Klaus, J. L.; Barnes, M. G.; Brömme, D. Nature Struct. Biol. 1997, 4, 105.
21. (c) Brömme, D.; Klaus, J. L.; Okamoto, K.; Rasnick, D.; Palmer, J. T. Biochem. J. 1996, 315, 85.
22. (d) Palmer, J. T.; Rasnick, D.; Klaus, J. L.; Brömme, D. J. Med. Chem. 1995, 38, 3193.
23. (e) Liu, S.; Hanzlik, R. P. J. Med. Chem. 1992, 35, 1067.
24. (f) Hanzlik, R. P.; Thompson, S. A. J. Med. Chem. 1984, 27, 711.
25. 2′, etc.) is described in: Schechter, I.; Berger, A. Biochem. Biophys. Res. Commun. 1967, 27, 157.
26. Enzyme assays were performed as described in ref. 9.
27. All amino acids described in this work are L isomers.
28. Antiviral assays were performed using H1 HeLa cells as described in ref. 9. The antirhinoviral properties of certain 3CP inhibitors were determined against several additional HRV serotypes in cell culture. In general, compounds which displayed activity against HRV serotype 14 exhibited related, albeit less potent (2 to 10-fold), antirhinoviral properties when tested against serotypes 1A, 2, and 10.
29. The toxicities of the molecules described in this work were determined using H1 HeLa cells as described in ref. 9. All compounds were non-toxic when tested to the 10 μM level.
30. Dragovich, P. S.; Prins, T. J.; Zhou, R.; Fuhrman, S. A.; Patick, A. K.; Matthews, D. A.; Ford, C. E.; Meador, J. W., III; Ferre, R. A.; Worland, S. T. J. Med. Chem. 1999, 42, 1203.
31. 2 N-methylamide moiety. Otherwise, the N-methylamide-containing inhibitor 3 bound to 3CP in a manner that was nearly identical to that noted for the non-methylated compound 1 (D. Matthews, unpublished results).
32. 3 Val for Leu substitution resulted in a 2.5-fold improvement in anti-3CP activity (HRV-14) when applied to non-methylated tripeptidyl inhibitors. See ref. 10.
33. Dragovich, P. S.; Zhou, R.; Skalitzky, D. J.; Fuhrman, S. A.; Patick, A. K.; Ford, C. E.; Meador, J. W., III; Worland, S. T. Bioorg. Med. Chem. 1999, 7, 589.
34. In Vitro Stability was Evaluated Using Human Liver Microsomes (C. A. Lee, unpublished results).
35. Dragovich, P. S.; Prins, T. J.; Zhou, R.; Webber, S. E.; Marakovits, J. T.; Fuhrman, S. A.; Patick, A. K.; Matthews, D. A.; Lee, C. A.; Ford, C. E.; Burke, B. J.; Rejto, P. A.; Hendrickson, T. F.; Tuntland, T.; Brown, E. L.; Meador, J. W., III; Ferre, R. A.; Harr, J. E. V.; Kosa, M. B.; Worland, S. T. J. Med. Chem. 1999, 42, 1213.
36. HATU [O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate] was also utilized as a coupling reagent in the course of several syntheses. See: Carpino, L. A.; El-Faham, A. J. Org. Chem. 1995, 60, 3561.
37. 2O.
38. The Boc-protected, lactam-containing intermediate required for the preparation of compound 13 was synthesized according to the published procedure (ref. 23).