Nonsymmetric P2/P2' cyclic urea HIV protease inhibitors. Structure- activity relationship, bioavailability, and resistance profile of monoindazole-substituted P2 analogues

Journal of Medicinal Chemistry

Volumn 41, Issue 13, 1998, Pages 2411-2423

  De Lucca, George V ^a   Kim, Ui T ^a   Liang, Jing ^a   Cordova, Beverly ^a   Klabe, Ronald M ^a   Garber, Sena ^a   Bacheler, Lee T ^a   Lam, Gilbert N ^a   Wright, Matthew R ^a   Logue, Kelly A ^a   Erickson Viitanen, Susan ^a   Ko, Soo S ^a   Trainor, George L ^a  

^a DUPONT COMPANY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1 [(3 AMINOPHENYL)METHYL]HEXAHYDRO 5,6 DIHYDROXY 3 (1H INDAZOL 5 YL METHYL) 4,7 BIS(PHENYLMETHYL) 2H 1,3 DIAZEPIN 2 ONE; 1 [(4 AMINOPHENYL)METHYL]HEXAHYDRO 5,6 DIHYDROXY 3 (1H INDAZOL 5 YL METHYL) 4,7 BIS(PHENYLMETHYL) 2H 1,3 DIAZEPIN 2 ONE; 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; HUMAN SERUM ALBUMIN; INDINAVIR; OROSOMUCOID; PROTEINASE INHIBITOR; RITONAVIR; UNCLASSIFIED DRUG; UREA DERIVATIVE;

AMINO ACID SUBSTITUTION; ANIMAL EXPERIMENT; ANTIVIRAL ACTIVITY; ARTICLE; CONTROLLED STUDY; CRYSTAL STRUCTURE; DOG; DRUG BIOAVAILABILITY; DRUG DESIGN; DRUG IDENTIFICATION; DRUG POTENCY; DRUG PROTEIN BINDING; DRUG RESISTANCE; DRUG SOLUBILITY; DRUG SYNTHESIS; HUMAN IMMUNODEFICIENCY VIRUS 1; HYDROGEN BOND; LIPOPHILICITY; MOLECULAR WEIGHT; NONHUMAN; ORAL DRUG ADMINISTRATION; STRUCTURE ACTIVITY RELATION; VIRUS INHIBITION; VIRUS MUTANT; X RAY CRYSTALLOGRAPHY;

ADMINISTRATION, ORAL; ANIMALS; ANTI-HIV AGENTS; AZEPINES; BIOLOGICAL AVAILABILITY; CELL LINE; CHROMATOGRAPHY, HIGH PRESSURE LIQUID; DOGS; DRUG DESIGN; DRUG RESISTANCE, MICROBIAL; HIV PROTEASE INHIBITORS; HIV-1; INDAZOLES; MUTATION; RITONAVIR; RNA, VIRAL; STRUCTURE-ACTIVITY RELATIONSHIP; TRANSCRIPTION, GENETIC; UREA;

EID: 15644373221     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm980103g     Document Type: Article

References (54)

1. For recent reviews, see: (a) Norbeck, D. W.; Kempf, D. J. HIV Protease Inhibitors. Annu. Rep. Med. Chem. 1991, 26, 141-160.
2. (b) Tomasselli, A. G.; Howe, W. J.; Sawyer, T. K.; Wlodawer, A.; Heinrikson, R. L. The Complexities of AIDS: An Assessment of the HIV Protease as a Therapeutic Target. ChimicaOggi. 1991, 6-27.
3. Huff, J. R. HIV Protease A Novel Chemotherapeutic Target for AIDS. J. Med. Chem. 1991, 34, 2305-2314.
4. Martin, J. A. Recent Advances in the Design of HIV Proteinase Inhibitors. Antiviral Res. 1992, 17, 265-278.
5. (e) Thaisrivaongs, S. HIV Protease Inhibitors. Annu. Rep. Med. Chem. 1994, 29, 133-144.
6. (f) Kempf, D. J. Progress in the Discovery of Orally Bioavailable Inhibitors of HIV Protease. Perspect. Drug Discovery Des. 1994, 2, 427-436.
7. (g) Kempf, D. J. Design of Symmetry-Based, Peptidomimetic Inhibitors of Human Immunodeficiency Virus Protease. Methods Enzymol. 1994, 241, 334-354.
8. (h) Vacca, J. P. Design of Tight-Binding Human Immunodeficiency Virus Type 1 Protease Inhibitors. Methods Enzymol. 1994, 241, 311-334.
9. Wlodawer, A. Rational Drug Design: The Proteinase Inhibitors. Pharmacotherapy 1994, 14 (suppl), 9S-20S.
10. (j) Erickson, J.; Kempf, D. Structure-Based Design of Symmetric Inhibitors of HIV-1 Protease. Arch. Virol. 1994, Suppl 9, 19-29,
11. (k) Darke, P. L.; Huff, J. R. HIV Protease as an Inhibitor Target for the Treatment of AIDS. Adv. Pharmacol. 1995, 25, 399-454.
12. Romines, K. R.; Chrusciel, R. A. 4-Hydroxypyrones and Related Templates as Nonpeptic HIV Protease Inhibitors. Curr. Med. Chem. 1995, 2, 825-838.
13. Gait, M. J.; Karn, J. Progress in Anti-HIV Structure-Based Drug Design. Trends Biotechnol. 1995, 13, 430-437.
14. (n) West, M. L.; Fairlie, D. P. Targeting HIV-1 Protease: A Test of Drug-Design Methodologies. Trends Pharmacol Sci. 1995, 16, 67-74.
15. (o) De Clercq, E. Toward Improved Anti-HIV Chemotherapy: Therapeutic Strategies for Intervention With HIV Infections. J. Med. Chem. 1995, 38, 2491-2517.
16. (p) Boehme, R. E.; Borthwick, A. D.; Wyatt, P. G. Antiviral Agents. Annu. Rep. Med. Chem. 1995, 30, 139-149.
17. (q) Chong, K. T. Recent Advances in HIV-1 Protease Inhibitors. Exp. Opin. Invest. Drugs 1996, 5, 115-124.
18. (r) Kempf, D. J.; Sham, H. L. HIV Protease Inhibitors. Curr. Pharm. Des. 1996, 2, 225-246.
19. (s) 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.
20. (a) Vella, S. HIV Therapy Advances. Update on a Proteinase Inhibitor. AIDS 1994, 8 (Suppl 3), S25-29.
21. (b) Pollard, R. B. Use of Proteinase Inhibitors in Clinical Practice. Pharmacotherapy 1994, 14, 21S-29S.
22. 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. L; Condra, J. H.; Gotlib, L.; Holloway, M. K.; Lin, J.; Chen, I.-W.; Ostovic, D.; Anderson, P. S.; Emini, E. A.; Huff, J. R. L-735,524: an Orally Bioavailable Human Immunodeficiency Virus Type 1 Protease Inhibitor. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 4096-4100.
23. 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.
24. (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.
25. (f) Ho, D. D.; Neumann, A. U.; Perelson, A. S.; Chen, W.; Leonard, J. M.; Markowitz, M. Rapid Turnover of Plasma Virons and CD4 Lymphocytes in HIV-1 Infection. Nature 1995, 373, 123-126.
26. (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 Activity of Saquinavir in HIV Infection. Lancet 1995, 345, 952-955.
27. (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.
28. (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.
29. 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.
30. Ridky, T.; Leis, J. Development of Drug Resistance to HIV-1 Protease Inhibitors. J. Biol. Chem. 1995, 270, 29621-29623.
31. 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.
32. Lam, P. Y. S.; Ru, Y.; Jadhav, P. K.; Aldrich, P. E.; De Lucca, 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.
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.; Reid, C.; Sharpe, T. R.; Shum, L.; Winslow, D. L.; Erickson-Viitanen, S. Improved Cyclic Urea Inhibitors of the HIV-1 Protease: Synthesis, Potency, Resistance Profile, Human Pharmacokinetics and X-ray Crystal Structure of DMP450. Chem. Biol. 1996, 3, 301-314.
34. Christ, D. D.; Meek, J. L.; Farmer, A. R.; Larsen, B. S. Oxidative metabolism of the novel HIV protease inhibitor DMP 323 by rat, dog and human systems. ISSX Proceedings 1993, 4, 230.
35. Bryant, M.; Getman, D.; Smidt, M.; Marr, J.; Clare, M.; Dillard, R.; Lansky, D.; DeCrecenzo, G.; Heintz, R.; Houseman, K.; Reed, K.; Stoszenbach, J.; Talley, J.; Vazquez, M.; Mueller, R. SC- 52151, a novel inhibitor of the human immunodeficiency virus protease. Antimicrob. Agents Chemother. 1995, 39, 2239-2234.
36. (a) Jadhav, P. K.; Ala, P.; Woerner, F. J.; Chang, C.-H.; Garber, S. S.; Anton, E. D.; Bacheler, L. T. Cyclic Urea Amides: HIV-1 Protease Inhibitors with Low Nanomolar Potency against both Wild Type and Protease Inhibitor Resistant Mutants of HIV. J. Med. Chem. 1997, 40, 181-191.
37. (b) For a schematic diagram of the hydrogen bond interactions of the benzamides with HIVPR based on the X-ray structure, see Figure 4 in ref 9a.
38. Wilkerson, W. W.; Akamike, E.; Cheatham, W. W.; Hollis, A. Y.; Collins, D.; DeLucca, I.; Lam, P. Y. S.; Ru, Y. HIV Protease Inhibitory Bis-benzamide Cyclic Ureas: A Quantitative StructureActivity Relationship Analysis. J. Med. Chem. 1996, 39, 4299-4312.
39. (a) Rodgers, J. D.; Johnson, B. L.; Wang, H.; Greenburg, R. A.; Erickson-Viitanen, S.; Klabe, R. M.; Cordova, B. C.; Rayner, M. M.; Lam, G. N.; Chang, C.-H. Potent Cyclic Urea HIV Protease Inhibitors with Benzofused Heterocycles as P2/P2′ Groups. Bioorg. Med. Chem. Lett 1996, 6, 2919-2924.
40. (b) Sun, J.-H.; Teleha, C. A.; Yan, J.-S.; Rodgers, J. D.; Nugiel, D. A. Efficient Synthesis of 5-(Bromomethyl) and 5-(AminomethyI)-1-THF-Indazole. J. Org. Chem. 1997, 62, 5627-5629.
41. (a) De Lucca, G. V.; Liang, J.; Aldrich, P. E.; Calabrese, J.; Cordova, B.; Klabe, R. M.; Rayner, M. M.; Chang, C.-H. Design, Synthesis, and Evaluation of Tetrahydropyrimidinones As An Example Of A General Approach to Non-peptide HIV Protease Inhibitors. J. Med. Chem. 1997, 40, 1707-1719.
42. fb) For a schematic diagram of the hydrogen bond interactions of the amidoxime with HIVPR based on the X-ray structure, see Figure 8 in ref 12a.
43. Erickson-Viitanen, S.; Klabe, R. M.; Cawood, P. G.; O'Neal, P. L.; Meek, J. L. Potency and Selectivity of Inhibitor of Human Immunodeficiency Virus Protease by a Small Nonpeptide Cyclic Urea, DMP323. Antimicrob. Agents Chemother. 1994, 38, 1628-1634.
44. Bacheler, L. T.; Paul, M.; Jadhav, P. K.; Otto, M.; Stone, B.; Miller, J. A. An assay for HIV RNA in Infected Cell Lysates, and Its Use for the Rapid Evaluation of Antiviral Efficacy. Antiviral Chem. Chemother. 1994, 5, 111-121.
45. Wong, Y. N.; Burcham, D. L.; Saxton, P. L.; Erickson-Viitanen, S.; Grubb, M. F.; Quon, C. Y.; Huang, S.-M. A Pharmacokinetic Evaluation of HIV Protease Inhibitors, Cyclic Ureas, in Rats and Dogs. Biopharm. Drug Dispos. 1994, 15, 535-544.
46. Pierce, M. E.; Harris, G. D.; Islam, Q.; Radesca, L. A.; Storace, L.; Waltermire, R. E.; Wat, E.; Jadhav, P. K.; Emmett, G. C. Stereoselective Synthesis of HIV-1 Protease Inhibitor, DMP 323. J. Org. Chem. 1996, 61, 444-450.
47. Rodgers, J. D.; Sun, J. H. Method for preparing HIV-protease-inhibiting N-monosubstituted and N,N′-disubstituted unsymmetrical cyclic ureas via alkylation and dealkylation of intermediate isoureas. US 5, 532, 357, 1996.
48. Katritzky, A. R.; Pilarski, B.; Urogdi, L. Efficient Conversion of Nitriles to Amides with Basic Hydrogen Peroxide in Dimethyl Sulfoxide. Synthesis 1989, 949-950.
49. Nahm, S.; Weinreb, S. M. N-Methoxy-N-Methylamides as Effective Acylating Agents. Tetrahedron Lett. 1981, 22, 3815-3818.
50. Einhorn, J.; Einhorn, C.; Luche, J.-L. A convenient method for the Preparation of N-Methoxyamides. Synth. Commun. 1990, 20, 1105-1112.
51. 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.
52. Otto, M. J.; Reid, C.; Garber, S.; Lam, P. Y. S.; Scaranti, H.; Bacheler, L. T.; Rayner, M. M.; Winslow, D. In vitro anti-human immunodeficiency virus (HIV) activity of XM323, a novel HIV protease inhibitor. Antimicrob. Chemother. 1993, 37, 2606-2611.
53. King, R. W.; Garber, S.; Winslow, D. L.; Reid, C.; Bacheler, L. T.; Anton, E.; Otto, M. J. Multiple mutations in the human immunodeficiency virus protease gene are responsible for decreased susceptability to HIV protease inhibitors. Antiviral Chem. Chemother. 1995, 6, 80-88.
54. Lin, Y.-i.; Lang, S. A., Jr.; Lovell, M. F.; Perkins, N. A. New Synthesis of 1,2,4-Triazolee and 1,2,4-Oxadiazoles. J. Org. Chem. 1979, 44, 4160-4164.