Cyclic HIV protease inhibitors: Design and synthesis of orally bioavailable, pyrazole P2/P2' cyclic ureas with improved potency

Journal of Medicinal Chemistry

Volumn 41, Issue 12, 1998, Pages 2019-2028

  Han, Qi ^a   Chang, Chong Hwan ^a   Li, Renhua ^a   Ru, Yu ^a   Jadhav, Prabhakar K ^a   Lam, Patrick Y S ^a  

^a DUPONT COMPANY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

4,7 DIBENZYL 2,3,4,5,6,7 HEXAHYDRO 5,6 DIHYDROXY 1,3 BIS[4 (HYDROXYMETHYL)BENZYL] 2H 1,3 DIAZEPIN 2 ONE; ANTI HUMAN IMMUNODEFICIENCY VIRUS AGENT; MOZENAVIR; PROTEINASE INHIBITOR; PYRAZOLE DERIVATIVE; UNCLASSIFIED DRUG; UREA DERIVATIVE;

ANIMAL CELL; ANIMAL EXPERIMENT; ANTIVIRAL ACTIVITY; ARTICLE; CONTROLLED STUDY; DOG; DRUG BIOAVAILABILITY; DRUG DESIGN; DRUG HALF LIFE; DRUG SYNTHESIS; HUMAN IMMUNODEFICIENCY VIRUS 1; NONHUMAN; ORAL DRUG ADMINISTRATION; PROTEINASE INHIBITION; RAT; STRUCTURE ACTIVITY RELATION; VIRUS INHIBITION; X RAY CRYSTALLOGRAPHY;

ADMINISTRATION, ORAL; ANIMALS; ANTI-HIV AGENTS; AZEPINES; BIOLOGICAL AVAILABILITY; CRYSTALLOGRAPHY, X-RAY; DOGS; DRUG DESIGN; HIV PROTEASE INHIBITORS; MODELS, MOLECULAR; PYRAZOLES; RATS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 0001241103     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm9704199     Document Type: Article

References (35)

1. For recent reviews, see: (a) Debouck, C. The HIV-1 Protease as a Therapeutic Target for AIDS. AIDS Res. Hum. Retroviruses 1992, 8, 153-164. (b) Katz, R. A.; Skalka, A. M. Annu. Rev. Biochem. 1994, 63, 133-173.
2. For recent reviews, see: (a) Debouck, C. The HIV-1 Protease as a Therapeutic Target for AIDS. AIDS Res. Hum. Retroviruses 1992, 8, 153-164. (b) Katz, R. A.; Skalka, A. M. Annu. Rev. Biochem. 1994, 63, 133-173.
3. (a) Kohl, N. E.; Emini, E. A.; Schleif, W. A.; Davis, L. J.; Heimbach, J. C.; Dixon, R. A. F.; Scolnick, E. M.; Sigal, I. S. Active Human Immunodeficiency Virus Protease is Required for Viral Infectivity. Proc. Natl. Acad. Sci. U.S.A. 1988, 85, 4686- 4690.
4. (b) Peng, C.; Ho, B. K.; Chang, T. W.; Chang, N. T. Role of Human Immunodeficiency Virus Type 1-Specific Protease in Core Protein Maturation and Viral Infectivity. J. Virol. 1989, 63, 2550-2556.
5. (a) Vella, S. HIV Therapy Advances. Update on a Proteinase Inhibitor. AIDS 1994, 8 (Suppl. 3), S25-29.
6. (b) Pollard, R. B. Use of Proteinase Inhibitors in Clinical Practice. Pharmacotherapy 1994, 14, 21S-29S.
7. (c) Vacca, J. P.; Dorsey, B. D.; Schlief, 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.; Ostovic, D.; Anderson, P. S.; Emini, E. A.; Huff, J. R. An Orally Bioavailable Human Immunodeficiency Virus Type-1 Protease Inhibitor. Proc. Natl. Acad. Sci. U.S.A 1994, 91, 4096-4100.
8. (d) Wei, X.; Ghosh, S. K.; Taylor, M. E.; Johnson, V. A.; Emini, E. A.; Deutsch, P.; Lifson, J. D.; Bonhoeffer, S.; Nowak, M. A.; Hahn, B. H.; Saag, M. S.; Shaw, G. M. Viral Dynamics in Human Immunodeficiency Virus Type 1 Infection. Nature 1995, 373, 117-122.
9. (e) Kempf, D.; Marsh, K. C.; Denissen, J. F.; McDonald, E.; Vasavanonda, 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. M.; Norbeck, D. W. ABT-538 is a Potent Inhibitor of Human Immunodeficiency Virus Protease with High Oral Bioavailability in Humans. Proc. Natl. Acad. Sci. U.S.A, 1995, 92, 2484-2488.
10. (f) Ho, D. D.; Neumann, A. U.; Perelson, A. S.; Chen, W.; Leonard, J. M.; Markowitz, M. Rapid Turnover of Plasma Virions and CD4 Lymphocytes in HIV-1 Infection. Nature 1995, 373, 123-126.
11. (g) Kitchen, V. S.; Skinner, C.; Ariyoshi, K.; Lane, E. A.; Duncan, I. B.; Burckhardt, J.; Burger, H. U.; Bragman, K.; Pinching, A. J.; Weber, J. N. Safety and Acitivity of Saquinavir in HIV Infection. Lancet 1995, 345, 952-955.
12. (h) Reich, S. H.; Melnick, M.; Davies, J. F.; Appelt, K.; Lewis, K. K.; Fuhry, M. A.; Pino, M.; Trippe, A. J.; Nguyen, D.; Dawson, H.; Wu, B.; Musick, L.; Kosa, M.; Kahil, D.; Webber, S.; Gehlhaar, D. K.; Andrada, D.; Shetty, B. Protein Structure-based Design of Potent Orally Bioavailable, Nonpeptide Inhibitors of Human Immunodeficiency Virus Protease. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 3298-3302.
13. (i) Patick, A. K.; Mo, H.; Markowitz, M.; Appelt, K.; Wu, B.; Musick, L.; Kalish, V.; Kaldor, S.; Reich, S.; Ho, D.; Webber, S. Antiviral and Resistance Studies of AG1343, an Orally Bioavailable Inhibitors of Human Immunodeficiency Virus Protease. Antimicrob. Agents Chemother. 1996, 292-297.
14. (a) Wlodawer, A.; Erickson, J. W. Structure-based Inhibitors of HIV-1 Protease. Annu. Rev. Biochem. 1993, 62, 543-585.
15. (b)Appelt, K. Crystal Structures of HIV-1 Protease-inhibitor Complexes. Perspect. Drug Discovery Des. 1993, 1, 23-48.
16. (a) Kemf, D. J.; Sham, H. L. HIV Protease Inhibitors. Curr. Pharm. Des. 1996, 2, 225-246.
17. (b) De Lucca, G. V.; Erickson- Viitanen, S.; Lam, P. Y. S. Cyclic HIV Protease Inhibitors Capable of Displacing the Active-Site Structural Water Molecule. Drug Discovery Today 1997, 2, 6-18.
18. (c) Sham, H. L.; Zhao, C.; Stewart, K. D.; Betebenner, D. A.; Lin, S.; Park, C. H.; Kong, X.-P.; Rosenbrook, W., Jr.; Herrin, T.; Madigan, D.; Vasavanonda, S.; Lyons, N.; Molla, A.; Saldivar, A.; Marsh, K. C.; McDonald, E.; Wideburg, N. E.; Denissen, J. F.; Robins, T.; Kempf, D. J.; Plattner, J. J.; Norbeck, D. W. A Novel, Picomolar Inhibitor of Human Immunodeficiency Virus Type 1 Protease. J. Med. Chem. 1996, 39, 392.
19. (d) Sham, H. L.; Zhao, C.; Marsh, K. C.; Betebenner, D. A.; Lin, S.; Rosenbrook, W., Jr., Herrin, T.; Li, L.; Madigan, D.; Vasavanonda, S.; Molla, A.; Saldivar, A.; McDonald, E.; Wideburg, N. E.; Kempf, D. J.; Norbeck, D. W.; Plattner, J. J. Novel Azacyclic Ureas That Are Potent Inhibitors of HIV-1 Protease. Biochem. Biophys. Res. Commun. 1996, 225, 436.
20. (e) Kim, C. U.; McGee, L. R.; Krawczyk, S. H.; Harwood, E.; Harada, Y.; Swaminathan, S.; Bischofberger, N.; Chen, M. S.; Cherrington, J. M.; Xiong, S. F.; Griffin, L.; Cundy, K. C.; Lee, A.; Yu, B.; Gulnik, S.; Erickson, J. W. New Series of Potent, Orally Bioavailable, Non-Peptidic Cyclic Sulfones as HIV-1 Protease Inhibitors. J. Med. Chem. 1996, 39, 3431.
21. (a) Jacobsen, H.; Yasargil, K.; Winslow, D. L.; Craig, J. C.; Krohn, A.; Duncan, I. B.; Mous, J. Characterization of Human Immunodeficiency Virus Type 1 Mutants with Decreased Sensitivity to Proteinase Inhibitor Ro 31-8959. Virology 1995, 206, 527- 534.
22. (b) Markowitz, M. M.; Mo, H.; Kempf, D. J.; Norbeck, D. W.; Bhat, T. N.; Erickson, J. W.; Ho, D. Selection and Analysis of Human Immunodeficiency Virus Type 1 Variants with Increased Resistance to ABT-538, a Novel Protease Inhibitor. J. Virol. 1995, 69, 701-706.
23. (c) Condra, J. H.; Schleif, W. A.; Blahy, O. M.; Gabryelski, L. J.; Graham, D. J.; Quintero, J. C.; Rhodes, A.; Robbins, H. L.; Roth, E.; Shivaprakash, M.; Titus, D.; Yang, T.; Teppler, H.; Squires, K. E.; Deutsch, P. J.; Emini, E. A. In Vivo Emergence of HIV-1 Variants Resistant to Multiple Protease Inhibitors. Nature 1995, 374, 569-571.
24. (d) Ridky, T.; Leis, J. Development of Drug Resistance to HIV-1 Protease Inhibitors. J. Biol. Chem. 1995, 270, 29621-29623.
25. Lam, P. Y. S.; Jadhav, P. K.; Eyermann, C. J.; Hodge, C. N.; Ru, Y.; Bacheler, L. T.; Meek, J. L.; Otto, M. J.; Rayner, M. M.; Wong, N. Y.; Chang, C. H.; Weber, P. C.; Jackson, D. A.; Sharpe, T. R.; Erickson-Viitanen, S. Rational Design of Potent, Bioavailable, Nonpeptide Cyclic Ureas as HIV Protease Inhibitors. Science 1994, 263, 380-384.
26. Hodge, C. N.; Aldrich, P. E.; Bacheler, L. T.; Chang, C.-H.; Eyermann, C. J.; Grubb, M. F.; Jackson, D. A.; Jadhav, P. K.; Korant, B.; Lam, P. Y. S.; Maurin, M. B.; Meek, J. L.; Otto, M. J.; Rayner, M. M.; Sharpe, T. R.; Shum, L.; Winslow, D. L.; Erickson-Viitanen, S. DMP450: An Orally Bioavailable Cyclic Urea Inhibitor of the HIV Protease. Chem. Biol. 1996, 3, 301- 314. Avid Pharmaceutical Co. (Philadelphia, PA) has licensed DMP450 to continue the clinical trials.
27. Lam, P. Y. S.; Ru, Y.; Jadhav, P. K.; Aldrich, P. E.; DeLucca, G. V.; Eyermann, C. J.; Chang, C.-H.; Emmett, G.; Holler, E. R.; Daneker, W. F.; Li, L.; Confalone, P. N.; McHugh, R. J.; Han, Q.; Li, R.; Markwalder, J. A.; Seitz, S. P.; Sharpe, T. R.; Bacheler, L. T.; Rayner, M. M.; Habe, R. M.; Shum, L.; Winslow, D. L.; Kornhauser, D. M.; Jackson, D. A.; Erickson-Viitanen, S.; Hodge, C. N. Cyclic HIV Protease Inhibitors: Synthesis, Conformational Analysis, P2/P2′ Structure-Activity Relationship, and Molecular Recognition of Cyclic Ureas. J. Med. Chem. 1996, 39, 3514.
28. Chang, C.-H. Unpublished data.
29. (a) Kim, E. E.; Baker, C. T.; Dwyer, M. D.; Murcko, M. A.; rao, B. G.; Tung, R. D.; Navia, M. A. Crystal Structure of HIV-1 Protease in complex with VX-478, a Potent and Orally Bioavailable Inhibitor of the Enzyme. J. Am. Chem. Soc. 1995, 117, 1181.
30. (b) Hamilton, H. W.; Steinbaugh, B. A.; Stewart, B. H.; Chan, O. H.; Schmid, H. L.; Schroeder, R.; Ryan, M. J.; Reiser, J.; Taylor, M. D.; Blankley, C. J.; Kaltenbronn, J. S.; Wright, J.; Hicks, J. Evaluation of Physicochemical Parameters Important to the Oral Bioavailability of Peptide-like Compounds: Implications for the Synthesis of Renin Inhibitors. J. Med. Chem. 1995, 38, 1446.
31. Erickson-Viitanen, S.; Klabe, R. M.; Ciwood, P. G.; O'Neal, P. L.; Meek, J. L. Potency and Selectivity of Inhibition of Human Immunodeficiency Virus Protease by a Small Nonpeptide Cyclic Urea, DMP323. Antimicrob. Agents Chemother. 1994, 38, 1628- 1634.
32. Bacheler, L. T.; Paul, M.; Jadhav, P. K.; Otto, M.; Stone, B.; Miller, J. An Assay for HIV RNA in Infected Cell Lysates, and Its Use for the Rapid Evaluation of Antiviral Efficacy. Antiviral Chem. Chemother. 1994, 5 (2), 111-121.
33. 2 Symmetric Inhibitor Complexed to HIV-1 Protease. Science 1990, 249, 527-533.
34. Brunger, A. T.; Kuriyan, J.; Karplus, M. Crystallographic R Factor Refinement by Molecular Dynamics. Science 1987, 235, 458-460.
35. c| are the observed and calculated structure factor amplitudes, respectively.