Structure based design: Novel spirocyclic ethers as nonpeptidal P2- ligands for HIV protease inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 8, Issue 8, 1998, Pages 979-982

  Ghosh, Arun K ^a   Krishnan, K ^a   Walters, D Eric ^b   Cho, Wonhwa ^a   Cho, Hanna ^a   Koo, Yumee ^a   Trevino, Jose ^a   Holland, Louis ^c   Buthod, Jim ^c  

^a UNIVERSITY OF ILLINOIS AT CHICAGO   (United States)

^b ROSALIND FRANKLIN UNIVERSITY OF MEDICINE AND SCIENCE   (United States)

^c IIT RESEARCH INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMPRENAVIR; ETHER DERIVATIVE; HYDROGEN; LIGAND; OXYGEN; PROTEINASE INHIBITOR; SAQUINAVIR;

ARTICLE; CONFORMATION; CRYSTAL STRUCTURE; DRUG DESIGN; DRUG POTENCY; DRUG STRUCTURE; ENZYME ACTIVE SITE; HUMAN IMMUNODEFICIENCY VIRUS 1; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; HYDROGEN BOND; STEREOCHEMISTRY; SYNTHESIS;

CRYSTALLOGRAPHY, X-RAY; DRUG DESIGN; ETHERS, CYCLIC; HIV PROTEASE; HIV PROTEASE INHIBITORS; HIV-1; HUMANS; KINETICS; LIGANDS; MODELS, MOLECULAR; MOLECULAR CONFORMATION; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 0032554691     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(98)00139-5     Document Type: Article

References (21)

1. 1. (a) Katz, R. A.; Skalka, A. M. Ann. Rev. Biochem. 1994, 63, 133;
2. (b) Debouck, C. AIDS Res. Human Retroviruses 1992, 8, 153 and references cited therein.
3. 2. (a) Kempf, D. J; Marsh, K. C.; Denissen, J. F.; McDonald, E.; Vasavononda, S.; Flentge, C. A.; Green, B. G.; Fino, L.; Park, C. H.; Kong, X.-P.; Wideburg, N. E.; Saldivar, A.; Ruiz, L.; Kati, W. M.; Sham, H. L.; Robins, T.; Stewart, K. D.; Hsu, A.; Plattner, J. J.; Leonard, J.; Norbeck, D. Proc. Natl. Acad. Sci. U. S. A. 1995, 92, 2484;
4. (b) Vacca, J. P.; Dorsey, B. D.; Schleif, W. A.; Levin, R. B.; McDaniel, S. L.; Darke, P. L.; Zugay, J.; Quintero, J. C.; Blahy, O. M.; Roth, E.; Sardana, V. V.; Schlabach, A. J.; Graham, P. I.; Condra, J. H.; Gotlib, L.; Holloway, M. K.; Lin, J.; Chen, I-W.; Vastag, K.; Ostovic, D.; Anderson, P. S.; Emini, E. A.; Huff, J. R. Proc. Natl. Acad. Sci., U.S.A. 1994, 91, 4096;
5. (c) Roberts, N. A., Martin, J. A.; Kinchington, D.; Broadhurst, A. V.; Craig, J. C.; Duncan, I. B.; Galpin, S. A.; Handa, B. K.; Kay, J.; Krohn, A.; Lambert, R. W.; Merrett, J. H.; Mills, J. S.; Parkes, K. E. B.; Redshaw, S.; Ritchie, A. J.; Taylor, D. L.; Thomas, G. J.; Machin, P. J. Science 1990, 248, 358 and references cited therein.
6. 3. (a) Ghosh, A. K.; Kincaid, J. F.; Walters, D. E.; Chen, Y.; Chaudhuri, N. C.; Thompson, W. J.; Culberson, C.; Fitzgerald, P. M.D.; Lee, H. Y.; McKee, S. P.; Munson, P. M.; Duong, T. T.; Darke, P. L.; Zugay, J. A.; Schleif, W. A.; Axel, M. G.; Lin, J.; Huff, J. R. J. Med. Chem., 1996, 39, 3278;
7. (b) Ghosh, A. K.; Thompson, W. J.; Munson, P. M.; Liu, W.; Huff, J. R. Bioorg. Med. Chem. Lett. 1995, 5, 83;
8. (c) Ghosh, A. K.; Thompson, W. J.; Fitzgerald, P. M.D.; Culberson, C. J.; Axel, M. G.; McKee, S. P.; Huff, J. R.; Anderson, P. S. J. Med. Chem. 1994, 37, 2506;
9. (d) Ghosh, A. K.; Lee, H. Y.; Thompson, W. J.; Culberson, C; Holloway, M. K.; McKee, S. P.; Munson, P. M.; Duong, T. T.; Smith, A. M.; Darke, P. L.; Zugay, J. A.; Emini, E. A.; Schleif, W. A.; Huff, J. R.; Anderson, P. S. J. Med. Chem. 1994, 37, 1177;
10. (e) Ghosh, A. K.; Thompson, W. J.; Holloway, M. K.; Mckee, S. P.; Duong, T. T.; Lee, H. Y.; Munson, P. M.; Smith, A. M.; Wai, J. M.; Darke, P. L.; Zugay, J. A.; Emini, E. A.; Schleif, W. A.; Huff, J. R.; Anderson, P. S. J. Med. Chem. 1993, 36, 2300;
11. (f) Ghosh, A. K.; Thompson, W. J.; Lee, H. Y.; McKee, S. P.; Munson, P. M.; Duong, T. T.; Darke, P. L.; Zugay, J. A.; Emini, E. A.; Schleif, W. A.; Huff, J. R.; Anderson, P. S. J. Med. Chem. 1993, 36, 924;
12. (g) Ghosh, A. K.; Thompson, W. J.; McKee, S. P.; Duong, T. T.; Lyle, T. A.; Chen, J. C.; Darke, P. L.; Zugay, J. A.; Emini, E. A.; Schleif, W. A.; Huff, J. R.; Anderson, P. S. J. Med. Chem. 1993, 36, 292.
13. 4. (a) Kim, E. E.; Baker, C. T.; Dwyer, M. D.; Murcko, M. A.; Rao, B. G.; Tung, R. D.; Navia, M. A. J. Am. Chem. Soc. 1995, 117, 1181;
14. (b) Chen, X.; Li, L.; Kemp, D. J.; Sham, H.; Wideburg, N. E.; Saldivar, A.; Vasavanonda, S.; Marsh, K. C.; McDonald, E.; Norbeck, D. W. Bioorg. Med. Chem. Lett. 1996, 6, 2847.
15. 5. Danishefsky, S.; Kobayashi, S.; Kerwin, J. F. J. Org. Chem. 1982, 47, 1981.
16. 3 to provide the corresponding azide. Catalytic hydrogenation of the azide over 10% Pd-C in EtOAc afforded the amine 12. For the development of (R)-(hydroxyethylamino)sulfonamide isostere based protease inhibitors, see, Vazquez, M. L.; Bryant, M. L.; Clare, M.; DeCrescenzo, G. A.; Doherty, E. M.; Freskos, J. N.; Getman, D. P.; Houseman, K. A.; Julien, J. A.; Kocan, G. P.; Mueller, R. A.; Shieh, Huey-Sheng.; Stallings, W. C.; Stegeman, R. A.; Talley, J. J. J. Med. Chem. 1995, 38, 581.
17. 7. All new compounds gave satisfactory spectroscopic and analytical results.
18. 8. Maloney Huss, K. E. Syn. Comm. 1985, 15, 273.
19. 9. Toth, M. V.; Marshall, G. R. Int. J. Pep. Prot. Res. 1990, 36, 544.
20. 4 were employed.
21. 11. Craig, J. C.; Duncan, I. B.; Hockley, D.; Grief, C.; Roberts, N. A.; Mills, J. S. Antiviral Res. 1991, 16, 295, and references cited therein.