Cyclic urea amides: Hiv-1 protease inhibitors with low nanomolar potency against both wild type and protease inhibitor resistant mutants of HIV

Journal of Medicinal Chemistry

Volumn 40, Issue 2, 1997, Pages 181-191

  Jadhav, Prabhakar K ^a   Ala, Paul ^a   Woerner, Francis J ^a   Chang, Chong Hwan ^a   Garber, Sena S ^a   Anton, Elizabeth D ^a   Bacheler, Lee T ^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; CYCLIC UREA AMIDE DERIVATIVE; PROTEINASE INHIBITOR; SD 143; SD 146; SD 152; UNCLASSIFIED DRUG; XV 638; XV 651; XV 655;

ARTICLE; BINDING SITE; DRUG POTENCY; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; HYDROGEN BOND; MOLECULAR INTERACTION; MOLECULAR MODEL; PROTEINASE INHIBITION; STRAIN DIFFERENCE; VIRUS MUTATION;

AMIDES; ANTI-HIV AGENTS; CELLS, CULTURED; CRYSTALLOGRAPHY, X-RAY; DRUG RESISTANCE, MICROBIAL; HIV PROTEASE; HIV PROTEASE INHIBITORS; HIV-1; HUMANS; MUTATION; PROTEIN CONFORMATION; SENSITIVITY AND SPECIFICITY; UREA;

EID: 0031022510     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm960586t     Document Type: Article

References (51)

1. (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. and 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. and Skalka, A. M. Annu. Rev. Biochem. 1994, 63, 133-173.
3. (a) Ho, D. D.; Toyoshima, T.; Mo, H.; Kempf, D. J.; Norbeck, D. W.; Chen, C. M; Wideburg, N. E.; Burt, S. K.; Erickson, J. W.; Singh, M. K. Characterization of Human Immunodeficiency Virus Type 1 Variants with Increased Resistance to a C2-Symmetric Protease Inhibitor. J. Virol. 1994, 68, 2016-2020.
4. (b) 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.
5. (c) Kaplan, A. H.; Michael, S. F.; Wehbie, R. S.; Knigge, M. F.; Paul, D. A.; Everitt, L.; Kempf, D. J.; Norbeck, D. W.; Erickson, J. W.; Swanstrom, R. Selection of multiple human immunodeficiency virus type 1 variants that encode viral proteases with decreased sensitivity to an inhibitor of viral protease. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 5597-5601.
6. (d) King, R. W.; Garber, S.; Winslow, D. L.; Reid, C. D.; Bacheler, L. T.; Anton, E.; Otto, M. J. Multiple mutations in the human immunodeficiency virus protease gene are responsible for decreased susceptibility to protease inhibitors. Antiviral Chem. Chemother. 1995, 6, 80-88.
7. (e) Otto, M. J.; Garber, S.; Winslow, D. L.; Reid, C. D.; Aldrich, P.; Jadhav, P. K.; Patterson, C. E.; Hodge, C. N.; Cheng, Y.-SE. In vitro isolation and identification of human immunodeficiency virus (HIV) variants with reduced sensitivity to C-2 symmetrical inhibitors of HIV type 1 protease. Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 7543-7547.
8. (f) Tisdale, M.; Myers, R. E.; Blair, E.; Kohli, A.; Kemp, S. D.; Larder, B. A. In Vitro Studies Support Combination Therapy with HIV Protease Inhibitors. Fourth International Workshop on Drug Resistance, Sardinia Italy, 1995, Abstract No. 61.
9. (g) El-Farrash, M. A.; Kuroda, M. J.; Kitazaki, T.; Masuda, T.; Kato, K.; Hatanaga, M.; Harada, S. Generation and characterization of human immunodeficiency virus type-1 (HIV-1) mutant resistant to HIV-1 protease inhibitor. J. Virol. 1994, 68, 233-239.
10. (h) Partaledis, J. A.; Yamaguchi, K.; Tisdale, M.; Blair, E.; Falcione, C.; Maschera, B.; Myers, R. E.; Pazhanisamy, S.; Futer, O.; Cullinan, A. B.; Stuver, C. M.; Byrn, R. A.; Livingston. D. J. In vitro selection and characterization of human immunodeficiency virus type-1 (HIV-1) isolates with reduced sensitivity to hydroxyethylamino sulfonamide inhibitors of HIV-1 aspartyl protease. J. Virol. 1995, 69, 5228-5235.
11. (i) 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.; Shivapraksh, M.; Titus, D.; Yang, T.; Toppler, 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.
12. (j) Norbeck, D.; Hsu, A.; Granneman, R.; Denissen, J.; Kempf, D.; Molla, A.; Leonard, J. Virologic and immunologic response to ritonavir (ABT-538), an inhibitor of HIV protease. Fourth International Workshop on Drug Resistance, Sardinia Italy, 1995, Abstract No. 70.
13. (a) Mansky, L. M.; Temin, H. M. Lower in vivo mutation rate of human immunodeficiency virus type 1 than that predicted from the fidelity of purified reverse transcriptase. J. Virol. 1995, 69, 5087-94.
14. (b) Roberts, J. D.; Bebenek, K.; Kunkel, T. A. The accuracy of reverse transcriptase from HIV-1. Science 1988, 242, 1171-3.
15. (c) Hubner, A.; Kruhoffer, M.; Grosse, F.; Krauss, G. Fidelity of human immunodeficiency virus type I reverse transcriptase in copying RNA. J. Mol. Biol. 1992, 223, 595-600.
16. (d) Ji, J.; Loeb, L. A. Fidelity of HIV-1 reverse transcriptase copying RNA in vitro. Biochemistry 1992, 31, 954-8.
17. (e) Boyer, J. C.; Bebenek, K.; Kunkel, T. A. Unequal human immunodeficiency virus type I reverse transcriptase error rate with RNA and DNA templates. Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 6919-6923.
18. (a) Perelson, A. S.; Neumann, A. U.; Markowitz, M.; Leonard, J. M.; Ho, D. D HIV-1 Dynamics in Vivo: Virion Clearance Rate, Infected Cell Life-Span, and Viral Generation Time. Science 1996, 271, 1582-1586.
19. (b) 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.
20. (c) 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 infection. Nature 1995, 373, 117-122.
21. Coffin, J. M. HIV Population Dynamics in Vivo: Implications for Genetic Variation, Pathogenesis, and Therapy. Science 1995, 267, 483-489.
22. (b) Kozal, M. J.; Shah, N.; Yang, R.; Shen, N.; Fucini, R.; Merigan, T. C.; Richman, D. D.; Chee, M. S.; Gingeras, T. R. Natural polymorphism of HIV-1 clade B protease gene and the implications for therapy. Fourth International Workshop on Drug Resistance, Sardinia, Italy, 1995, Abstract No. 76.
23. (a) Baldwin, E. T.; Bhat, T. N.; Liu, B.; Pattabiraman, N.; Erickson, J. W. Structural basis of drug resistance for the V82A mutant of HIV-1 proteainase. Struct. Biol. 1995, 2, 244-249.
24. (b) Erickson, J. W. The not-so-great escape. Struct. Biol. 1995, 2, 523-529.
25. (a) Markowitz, M. M.; Mo, H.; Kempf, D. J.; Norbeck, D. W.; Bhat, T. N.; Erickson, J. W.; Ho, D. D. Selection and analysis of human immunodeficiency virus type 1 variants with increase resistance to ABT-538, a novel protease inhibitor. J. Virol. 1995, 69, 701-706.
26. (b) Anton, E. D.; Bacheler, L.; Garber, S.; Reid, C.; Buckery, R.; Scarnati, H.; Korant, B.; Winslow, D. L. Replicative ability of HIV variants with substitutions in the active site of protease is dependent on compensatory mutations outside the active site. Fourth International Workshop on Drug Resistance, Sardinia, Italy, 1995, Abstract No. 60.
27. (c) Rose, R. E.; Gong, Y., Greytok, J. A.; Bechtold, C. M.; Terry, B. J.; Robinson, B. S.; Alam, M.; Colono, R. J.; Lin, P. Human immunodeficiency virus type 1 viral background plays a major role in development of resistance to protease inhibitors. Proc. Natl. Acad. Sci. U.S.A. 1996, 93, 1648-1653.
28. 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, Y, N.; 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.
29. 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.; Markwalder, J. A.; Seitz, S. P.; Bacheler, L. T.; Rayner, M. M.; Klabe, R. M.; Shum, L.; Winslow, D. L.; Kornhauser, D. M.; Jackson, D. A.; Erickson-Viitanen, S.; Sharpe, T. R.; 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, 3514-3525.
30. Nugiel, D. A.; Jacobs, K.; Worley, T.; Patel, M.; Kaltenbach, R. F., III; Meyer, D. T.; Jadhav, P. K.; DeLucca, G. V.; Smyser, T. E.; Klabe, R. M.; Bacheler, L. T.; Rayner, M. M.; Seitz, S. P. Preparation and Strcuture-Activity Relationship of Novel P1/ P1′-Substituted Cyclic Urea-Based Human Immunodeficiency Virus Type-1 Protease Inhibitors. J. Med. Chem. 1996, 39, 2156-2169.
31. Bodanszky, M. Peptide Chemistry: A Practical Textbook; Springer-Verlag: New York, 1986; pp 63-68.
32. Winslow, D.; Horlick R. A.; Anton, E. A.; Tritch, R. J.; Zagursky, R. J.; Bacheler, L. T. A novel method for construction of infectious molecular clones of HIV-1 containing defined mutations in the HIV protease gene. Biochem. Biophys. Res. Commun. 1994, 205, 1651-1657.
33. Hodge, C. N.; Aldrich, P. E.; Bacheler, L. T.; Chang, C-H.; Eyermann, C. J.; Garber, S.; Grubb, M.; 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: Improved cyclic urea inhibitors of the HIV-1 protease: synthesis, potency, resistance profile, human pharmacokinetics and x-ray crystal structure of DMP 450. Chem. Biol. 1996, 3, 301-314.
34. (a) Jadhav, P. K.; Woerner, F. J. Synthesis of C2-Symmetric HIV-1 Protease Inhibitors from D-Mannitol. Bioorg. Med. Chem. Lett. 1992, 2, 353-356. Q8024 is the same as compound 3 reported in this reference.
35. (b) Jadhav, P. K.; McGee, L. R.; Shenvi, A.; Hodge, C. N. U.S. Patent 5,294,720, issued March 15, 1994.
36. Kempf, D. J.; Marsh, K. C.; Denissen, J. F.; McDonald, E.; Vasavanonda, S.; Flentge, C. A.; Green, B. E.; Fino, L.; Park, C. H.; et al. ABT-538 is a potent inhibitor of human immunodeficiency virus protease and has high oral bioavailability in humans. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 2484-2488.
37. Dorsey, Bruce D.; Levin, R. B.; McDaniel, S. L.; Vacca, J. P.; Guare, J. P.; Darke, P. L.; Zugay, J. A.; Emmi, E. A.; Schleif, W. A.; et al. L-735,524: The Design of a Potent and Orally Bioavailable HIV Protease Inhibitor. J. Med. Chem. 1994, 37, 3443-51
38. Kim, E. E.; Baker, C. T.; Dwyer, M. D.; Mureko, 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, 1181-1182.
39. 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.; et al. Rational design of peptide-based HIV proteinase inhibitors. Science 1990, 248, 358-361.
40. A NL4-3-based reconstructed virus (10R/46I/63P/82T/84V) with reduced senstivity to multiple protease inhibitors was provided by W. Schleif of Merck Research Laboratories.
41. Geng, X.; Chang, X. High-performance hydrophobic interaction chromatography as a tool for protein folding. J. Chromatogr. 1992, 599, 185-194.
42. Wlodawer, A.; Erickson, J. W. Structure-based inhibitors of HIV-1 protease. Annu. Rev. Biochem. 1993, 62, 543-585.
43. 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.
44. (a) Loeb D. D.; Swanstrom, R.; Everitt, L.; Manchester, M.; Stamper, S. E.; Hutchison, C. A., III. Complete mutagenesis of the HIV-1 protease. Nature 1989, 340, 397-400.
45. (b) Manchester, M.; Everitt, L.; Loeb, D. D.; Hutchison, C. A., III; Swanstrom, R. Identification of temperature-sensitive mutants of the human immunodeficiency virus type 1 protease through saturation mutagenesis. Amino acid side chain requirements for temperature sensitivity. J. Biol. Chem. 1994, 269, 7689-7695.
46. Patick, A. K.; Duran, M.; Cao, Y.; Ho, T.; Fei, Z.; Keller, M. R.; Peterkin, J.; Chapman, S.; Anderson, B.; Ho, D.; Markowitz, M. Genotypic and phenotypic characterization of HIV-1 variants isolated from in vitro selection studies and from patients treated with the protease inhibitor, nelfinavir. Fifth International Workshop on Drug Resistance, Whistler, Canada, 1996, Abstract No. 29.
47. Erickson-Viitanen, S.; Klabe, R. M.; Cawood, 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.
48. 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 Evalution of Antiviral Efficacy. Antiviral Chem. Chemother. 1994, 5, 111-121.
49. Wong N. Y.; Burcham, D. L.; Saxton, P. L., Erickson-Viitanen, S.; Grubb, M.F.; Quon, C. Y.; and Huang, S.-M. A Pharmacokinetic Evalution of HIV Protease Inhibitors, Cyclic Ureas, in Rats and Dogs. Biopharm. Drug Dispos. 1994, 15, 535-544.
50. Erickson, J.; Neidhart, D. J.; VanDrie, J.; Kempf, D. J.; Wang, X. C.; Norbeck, D.; Plattner, J. J.; Rittonhouse, J.; Turon, M.; Wideburg, N.; Kohlbrenner, W. E.; Simmer, R.; Helfrich, R.; Paul, D.; Knigge, M. Design, Activity, and 2.8 Å Crystal Structure of a C2 Symmetric Inhibitor Complexed to HIV-1 Protease. Science 1990, 249, 527-533.
51. Brünger, A. T.; Kuriyan, J.; Karplus, M. Crystallographic R Factor Refinement by Molecular Dynamics. Science 1987, 235, 458-460.