From 1-acyl-β-lactam human cytomegalovirus protease inhibitors to 1-benzyloxycarbonylazetidines with improved antiviral activity. A straightforward approach to convert covalent to noncovalent inhibitors

Journal of Medicinal Chemistry

Volumn 48, Issue 7, 2005, Pages 2612-2621

  Gerona Navarro, Guillermo ^a   Pérez De Vega, M Jesús ^a   García López, M Teresa ^a   Andrei, Graciela ^b   Snoeck, Robert ^b   De Clercq, Erik ^b   Balzarini, Jan ^b   González Muñiz, Rosario ^a  

^a INSTITUTO DE QUÍMICA MÉDICA   (Spain)

^b REGA INSTITUTE FOR MEDICAL RESEARCH   (Belgium)

Author keywords

[No Author keywords available]

Indexed keywords

1 ACYL BETA LACTAM; 1 BENZYLOXYCARBONYLAZETIDINE; ANTIRETROVIRUS AGENT; AZETIDINE DERIVATIVE; BETA LACTAM ANTIBIOTIC; CARBOXYLIC ACID; CIDOFOVIR; FOMIVIRSEN; FOSCARNET; GANCICLOVIR; PHENYLALANINE; PROTEINASE INHIBITOR; UNCLASSIFIED DRUG; VALGANCICLOVIR;

ANTIVIRAL ACTIVITY; ARTICLE; COVALENT BOND; CYTOMEGALOVIRUS; ENZYME ACTIVE SITE; ENZYME INHIBITION; GENE DELETION; HYDROPHOBICITY; PROPHYLAXIS; SITE DIRECTED MUTAGENESIS; STRUCTURE ANALYSIS; VIRUS REPLICATION; X RAY CRYSTALLOGRAPHY;

ALANINE; ANTIVIRAL AGENTS; AZETIDINES; CELLS, CULTURED; CYTOMEGALOVIRUS; HUMANS; LACTAMS; PROTEASE INHIBITORS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 17144408696     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm0492812     Document Type: Article

References (55)

1. Arvin, A. M.; Alford, C. A. Chronic intrauterine and perinatal infections. In Antiviral Agents and Viral Diseases of Man; Galasso, G. J., Whitley, R. J., Merigan, T. C., Eds.; Raven Press: New York, 1990; pp 497-580.
2. Falagas, M. E.; Paya, C.; Ruthazer, R.; Bradley, A.; Wiesner, R.; Griffith, J.; Freeman, R.; Rohrer, R.; Werner, B. G.; Snydman, D. R.; Wiesner, R.; Griffith, J.; Freeman, R.; Rohrer, R.; Werner, B. G.; Snydman, D. R. Significance of cytomegalovirus for long-term survival after orthotopic liver transplantation - A prospective derivation and validation cohort analysis. Transplantation 1998, 66, 1020-1028.
3. Casado, J. L.; Pérez-Elías, M. J.; Martí-Belda, P.; Antela, A.; Suárez, M.; Ciancas, E.; Frutos, B.; Pérez, M. D.; Guerrero, A. Improved outcome of cytomegalovirus retinitis in AIDS patients after introduction of protease inhibitors. J. Acq. Immune Def. Synd. 1998, 19, 130-134.
4. Torriani, F. J.; Freeman, W. R.; Macdonald, J. C.; Karavellas, M. P.; Duran, D. M.; Jeffrey, D. D.; Meyland, P. R. A.; Schrier, R. D. CMV retinitis recurs after stopping treatment in virological and immunological failures of potent antiretroviral therapy. AIDS 2000, 14, 173-180.
5. Field, A. K. Human Cytomegalovirus: Challenges opportunities and new drug development. Antiviral Chem. Chemother. 1999, 10, 219-232.
6. Martínez, A.; Castro, C.; Gil, C.; Pérez, C. Recent strategies in the development of new human cytomegalovirus inhibitors. Med. Chem. Rev. 2001, 21, 227-244.
7. De Clercq, E. New inhibitors of human cytomegalovirus (HCMV) on the horizon. J. Antimicrob. Chemother. 2003, 51, 1079-1083.
8. Jabs, D. A.; Enger, C.; Dunn, J. P.; Forman, M. Cytomegalovirus retinitis and viral resistance: Ganciclovir resistance. J. Infect. Dis. 1998, 177, 770-773.
9. Vaillancourt, V. A.; Cudahy, M. M.; Staley, S. A; Brideau, R. J.; Conrad, S. J.; Knechtel, M. L.; Oien, N. L.; Wieber, J. L.; Yoshihiko, Y.; Watchen, M. W. Naphthalene carboxamides as inhibitors of human cytomegalovirus DNA polymerase. Bioorg. Med. Chem. Lett. 2000, 10, 2079-2081.
10. Oien, N. L.; Brideau, R. J.; Hopkins, T. A.; Wieber, J. L.; Knechtel, M. L.; Shelly, J. A.; Anstadt, R. A.; Wells, P. A.; Poorman, R. A.; Huang, A.; Vaillancourt, V. A.; Clayton, T. L.; Tucker, J. A.; Wathen, M. W. Broad-spectrum anti-herpes activities of 4-hydroxyquinoline carboxamides, a novel class of herpesvirus polymerase inhibitors. Antimicrob. Agents Chemother. 2002, 46, 724-730.
11. Martinez, A.; Gil, C.; Perez, C.; Castro, A.; Prieto, C.; Otero, J.; Andrei, G.; Snoeck, R.; Balzarini, J.; De Clercq, E. Nonnucleoside human cytomegalovirus inhibitors: Synthesis and antiviral evaluation of (chlorophenylmethyl)benzothiadiazine dioxide derivatives J. Med. Chem. 2000, 43, 3267-3273.
12. Slater, M. J.; Baxter, R.; Bonser, R. W.; Cockerill, S.; Gohil, K.; Parry, N.; Robinson, E.; Randall, R.; Yeates, C.; Snowden, W.; Walters, A. Synthesis of N-alkyl substituted indolocarbazoles as potent inhibitors of human cytomegalovirus replication. Bioorg. Med. Chem. Lett. 2001, 11, 1993-1995.
13. Reefschlaeger, J.; Bender, W.; Hallenberger, S.; Weber, O.; Eckenberg, P.; Goldman, S.; Haerter, M.; Buerger, I.; Trappe, J.; Herrington, J. A.; Haebich, D.; Ruebsamen-Waigmann, H. Novel nonnucleoside inhibitors of cytomegaloviruses (BAY 38-4766): In vitro and in vivo antiviral activity and mechanism of action. J. Antimicrob. Chemother. 2001, 48, 757-767.
14. Snoeck, R.; Andrei, G.; Bodaghi, B.; Lagneaux, L.; Daelemans, D.; De Clercq, E.; Neytes, J.; Schols, D.; Naesens, L.; Michelson, S.; Bron, D.; Otto, M. J.; Bousseau, A.; Nemecek, C.; Roy, C. 2-Chloro-3-pyridin-3-yl-5,6,7,8- tetrahydroindolizine-1-carboxamide (CMV423), a new lead compound for the treatment of human cytomegalovirus infections. Antiviral Res. 2002, 55, 413-424.
15. Biron, K. K.; Harvey, R. J.; Chamberlain, S. C.; Good, S. S.; Smith, A. A., III; Davis, M. G.; Talarico, C. L.; Miller, W. H.; Ferris, R.; Dornsife, R. E.; Stanat, S. C.; Drach, J. C.; Townsend, L. B.; Koszalka, G. W. Potent and selective inhibition of human cytomegalovirus replication by 1263W94, a benzimidazole L-riboside with a unique mode of action. Antimicrob. Agents Chemother. 2002, 46, 2365-2372.
16. McGuigan, C.; Pathirana, R. N.; Snoeck, R.; Andrei, G.; De Clercq, E.; Balzarini, J. Discovery of a new family of inhibitors of human cytomegalovirus (HCMV) based upon lipophilic alkyl furano pyrimidine dideoxy nucleosides: Action via a novel nonnucleoside mechanism. J. Med. Chem. 2004, 47, 1847-1851.
17. (a) Bloom, J. D.; DiGrandi, M. J.; Dushin, R. G.; Curran, K. J.; Ross, A. A.; Norton, E. B.; Terefenko, E.; Jones, T. R.; Feld, B.; Lang, S. A. Thiourea inhibitors of herpes viruses. Part 1: Bis-(aryl)thiourea inhibitors of CMV. Bioorg. Med. Chem. Lett. 2003, 13, 2929-2932.
18. Bloom, J. D.; Dushin, R. G.; Curran, K. J.; Donahue, F.; Norton, E. B.; Terefenko, E.; Jones, T. R.; Ross, A. A.; Feld, B.; Lang, S. A.; DiGrandi, M. J. Thiourea inhibitors of herpes viruses. Part 2: N-Benzyl-N′-arylthiourea inhibitors of CMV. Bioorg. Med. Chem. Lett. 2004, 14, 3401-3406.
19. Jones, T. R.; Lee, S. W.; Johann, S. V.; Razinkov, V.; Visalli, R. J.; Feld, B.; Bloom, J. D.; O'Connell, J. Specific inhibition of human cytomegalovirus glycoprotein B-mediated fusion by a novel thiourea small molecule. J. Virol. 2004, 78, 1289-1300.
20. Welch, A. R.; Woods, A. S.; McNally, L. M.; Cotter, R. J.; Gibson, W. A. A herpesvirus maturational proteinase assembling: Identification of its gene, putative active site domain and cleavage site. Proc. Natl. Acad. Sci. U.S.A. 1991, 88, 10792-10796.
21. Tong, L.; Quian, C. G.; Massariol, M. J.; Bonneau, P. R.; Cordingley, M. G.; Lagace, L. A new serine-protease fold revealed by the crystal structure of human cytomegalovirus protease. Nature 1996, 383, 272-275.
22. 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. Three-dimensional structure of human cytomegalovirus protease. Nature 1996, 383, 279-282.
23. Shieh, H.-S.; Stallings, W. C.; Wittwer, A. J.; Hippenmeyer, P.; Kurumbail, R. G.; Holwerda, B. C. Crystal structure of human cytomegalovirus protease delineate a new target for antiherpes drug design. Int. Antiviral News 1997, 5, 71-73.
24. Holwerda, B. C. Herpesvirus proteases: Targets for novel antiviral drugs. Antiviral Res. 1997, 35, 1.
25. Waxman, L.; Darke, P. L. Recent advances in antiviral research: Identification of inhibitors of the herpesvirus proteases. Antiviral Chem. Chemother. 2000, 11, 1-21.
26. Ogilvie, W. W. Nonnucleoside inhibitors of the human cytomegalovirus. Curr. Med. Chem. Anti-Infective Agents 2002, 1, 177-191.
27. Liang, P.-H.; Brun, K. A.; Field, J. A.; O'Donnell, K.; Doyle, M. L.; Green, S. M.; Baker, A. E.; Blackburn, M. N.; Abdel-Meguid, S. S. Site-directed mutagenesis probing the catalytic role of arginines 165 and 166 of human cytomegalovirus protease. Biochemistry 1998, 37, 5923-5929.
28. Ogilvie, W.; Bailey, M.; Poupart, M.-A.; Abraham, A.; Bhavsar, A.; Bonneau, P.; Bordeleau, J.; Bousquet, Y.; Chabot, C.; Duceppe, J.-S.; Fazal, G.; Goulet, S.; Grand-Maitre, C.; Guse, I.; Halmos, T.; Lavallée, P.; Leach, M.; Malenfant, E.; O'Meara, J.; Plante, R.; Plouffe, C.; Poirier, M.; Soucy, F.; Yoakim, C.; Déziel, R. Peptidomimetic inhibitors of the human cytomegalovirus protease. J. Med. Chem. 1997, 40, 4113-4135.
29. LaPlante, S. R.; Bonneau, P.; Aubry, N.; Cameron, D. R.; Déziel, R.; Grand-Maitre, C.; Plouffe, C.; Tong, L.; Kawai, S. Characterization of the human cytomegalovirus protease as an induced-fit serine protease and the implications to the design of mechanism-based inhibitors. J. Am. Chem. Soc. 1999, 121, 2974-2978.
30. (a) Pinto, I. L.; Jarvest, R. L.; Clarke, B.; Dabrowski, C. E.; Fenwick, A.; Gorczyca, M. M.; Jennings, L. J.; Lavery, P.; Sternberg, E. J.; Tew, D. G.; West, A. Inhibition of human cytomegalovirus protease by enedione derivatives of thieno[2,3-d]oxazinones through a novel dual acylation/alkylation mechanism. Bioorg. Med. Chem. Lett. 1999, 9, 449-452.
31. Smith, D. G.; Gribble, A. D.; Haigh, D.; Ife, R. J.; Lavery, P.; Skett, P.; Slingsby, B. P.; Stacey, R.; Ward, R. W.; West, A. The inhibition of human cytomegalovirus (hCMV) protease by hydroxylamine derivatives. Bioorg. Med. Chem. Lett. 1999, 9, 3137-3142.
32. Borthwick, A. D.; Angier, S. J.; Crame, A. J.; Exall, A. M.; Haley, T. M.; Hart, G. J.; Mason, A. M.; Pennell, A. M. K.; Weingarten, G. G. Design and synthesis of pyrrolidine-5,5-trans-lactams (5-oxo-hexahydro-pyrrolo[3,2-6] pyrroles) as novel mechanism-based inhibitors of human cytomegalovirus protease. 1. The α-methyl-trans-lactam template. J. Med. Chem. 2000, 43, 4452-4464.
33. Borthwick, A. D.; Crame, A. J.; Erlt, P. F.; Exall, A. M.; Haley, T. M.; Hart, G. J.; Mason, A. M.; Pennell, A. M. K.; Sing, O. M. P.; Weingarten, G. G.; Woolven, J. M. Design and synthesis of pyrrolidine-5,5-trans-lactams (5-oxo-hexahydro-pyrrolo [3,2-6]-pyrroles) as novel mechanism-based inhibitors of human cytomegalovirus protease. 2. Potency and chirality. J. Med. Chem. 2002, 45, 1-18.
34. Borthwick, A. D.; Exall, A. M.; Haley, T. M.; Jackson, D. L.; Mason, A. M.; Weingarten, G. G. Pyrrolidine-5,5-trans-lactams as novel mechanism-based inhibitors of human cytomegalovirus protease. Part 3. Potency and plasma stability. Bioorg. Med. Chem. Lett. 2002, 12, 1719-1722.
35. Borthwick, A. D.; Davies, D. E.; Erlt, P. F.; Exall, A. M.; Haley, T. M.; Hart, G. J.; Jackson, D. L.; Parry, N. R.; Patikis, A.; Trivedi, N.; Weingarten, G. G.; Woolven, J. M. Design and synthesis of pyrrolidine-5,5-trans- lactams (5-oxo-hexahydro-pyrrolo[3,2-6]pyrroles) as novel mechanism-based inhibitors of human cytomegalovirus protease. 4. Antiviral activity and plasma stability. J. Med. Chem. 2003, 46, 4428-4449.
36. 0 with monocyclic β-lactams. Bioorg. Med. Chem. Lett. 1998, 8, 1437-1442.
37. Yoakim, C.; Ogilvie, W.; Cameron, D. R.; Chabot, C.; Guse, I.; Haché, B.; Naud, J.; O'Meara, J. A.; Plante, R.; Déziel, R. β-Lactam derivatives as inhibitors of human cytomegalovirus protease. J. Med. Chem. 1998, 41, 2882-2891.
38. Yoakim, C.; Ogilvie, W. W.; Cameron, D. R.; Chabot, C.; Grand-Maitre, C.; Guse, I.; Haché, B.; Kawai, S.; Naud, J.; O'Meara, J. A.; Plante, R.; Déziel, R. Potent β-lactmam inhibitors of human cytomegalovirus protease. Antiviral Chem. Chemother. 1998, 9, 379-387.
39. Ogilvie, W.; Yoakim, C.; Do, F.; Haché, B.; Lagacé, L.; Naud, J.; O'Meara, J. A.; Déziel, R. Synthesis and antiviral activity of monobactams inhibiting the human cytomegalovirus protease. Bioorg. Med. Chem. 1999, 7, 1521-1531.
40. Bonneau, P.; Hasani, F.; Plouffe, C.; Malenfant, E.; Laplante, S. R.; Guse, I.; Ogilvie, W. W.; Plante, R.; Davidson, W. C.; Hopkins, J. L.; Morelock, M. M.; Cordingley, M. G.; Déziel, R. Inhibition of human cytomegalovirus protease by monocyclic β-lactam derivatives: Kinetic characterization using a fluorescent probe. J Am. Chem. Soc. 1999, 121, 2965-2973.
41. Sanderson, P. E. J. Small, noncovalent serine protease inhibitors. Med. Res. Rev. 1999, 19, 179-197.
42. Leung, D.; Abbenante, G.; Faille, D. P. Protease inhibitors: Current status and future prospect. J. Med. Chem. 2000, 43, 305-441.
43. Gerona-Navarro, G.; Pérez de Vega, M. J.; García- López, M. T.; Andrei, G.; Snoeck, R.; De Clercq, E.; Balzarini, J.; González-Muñiz, R. Synthesis and anti-HCMV activity of 1-acyl-β-lactams and 1-acylazetidines derived from phenylalanine. Bioorg. Med. Chem. Lett. 2004, 14, 2253-2256.
44. α-cyclization strategy. J. Org. Chem. 2001, 43, 3538-3547.
45. Bonache, M. A.; Gerona-Navarro, G.; Martín-Martínez, M.; García-López, M. T.; López, P.; Cativiela, C.; González-Muñiz, R. Memory of chirality in the stereoselective synthesis of β-lactams derived from amino acids. Influence of the reaction conditions. Synlett 2003, 1007-1011.
46. Bonache, M. A.; Gerona-Navarro, G.; García-Aparicio, C.; Alías, M.; Martín-Martínez, M.; García-López, M. T.; López, P.; Cativiela, C.; González-Muniz, R. Memory of chirality in the stereoselective synthesis of β-lactams: Importance of the starting amino acid derivative. Tetrahedron: Asymmetry 2003, 14, 2161-2169.
47. Gerona-Navarro, G.; García-López, M. T.; Gonzalez-Muñiz, R. General approach for the stereocontrolled construction of the β-lactam ring in amino acid-derived 4-alkyl-4-carboxy-2- azetidinones. J. Org. Chem. 2002, 67, 3953-3956.
48. 8. Int. J. Pept. Protein Res. 1991, 37, 331-340.
49. Fournié-Zaluski, M. C.; Lucas-Soroca, E.; Devin, J.; Roques, B. P. Proton NMR configurational correlation for retro-inverso dipeptides: Application to the determination of the absolute configuration of enkephalinase inhibitors. Relationships between stereochemistry and enzyme recognition. J. Med. Chem. 1986, 29, 751-757.
50. Gerona-Navarro, G.; García-López, M. T.; Gonzalez-Muñiz, R. Easy access to orthogonally protected α-alkyl aspartic acid and α-alkyl asparagine derivatives by controlled opening of β-lactams. Tetrahedron Lett. 2003, 44, 6145-6148.
51. McGuigan, C.; Brancale, A.; Andrei, G.; Snoeck, R.; De Clercq, E.; Balzarini, J. Novel bicyclic furanopyrimidines with dual anti-VZV and -HCMV activity. Bioorg. Med. Chem. Lett. 2003, 13, 4511-4513.
52. Borthwick, A. D.; Weingarten, G.; Haley, T. M.; Tomaszewski, M.; Wang, W.; Hu, Z.; Bedard, J.; Jin, H.; Yuen, L.; Mansour, T. S. Design and synthesis of monocyclic β-lactams as mechanism-based inhibitors of human cytomegalovirus protease. Bioorg. Med. Chem. Lett. 1998, 8, 365-370.
53. Gerona-Navarro, G.; Bonache, M. A.; Alías, M.; Pérez de Vega, M. J.; García-López, M. T.; López, P.; Cativiela, C.; González-Muñiz, R. Simple access to novel azetidine-containing conformationally restricted amino acids by chemoselective reduction of β-lactams. Tetrahedron Lett. 2004, 45, 2193-2196.
54. Belvisi, L.; Gennari, C.; Mielgo, A.; Potenza, D.; Scolastico, C. Conformational preferences of peptides containing reverse-turn mimetic bicyclic lactams: Inverse γ-turn versus type-II′ β-turns. Insights into β-hairpin stability. Eur. J. Org. Chem. 1999, 389-400.
55. Gopalsamy, A.; Lim, K.; Ellingboe, J. W.; Mitsner, B.; Nikitenko, A.; Upeslacis, J.; Mansour, T. S.; Olson, M, W.; Bebernitz, G. A.; Grinberg, D.; Feld, B.; Moy, F. J.; O'Connell, J. Design and synthesis of 1,6-naphthalene derivatives as selective HCMV protease inhibitors. J. Med. Chem. 2004, 47, 1893-1899.