Design and fast synthesis of C-terminal duplicated potent C2-symmetric P1/P1'-modified HIV-1 protease inhibitors

Journal of Medicinal Chemistry

Volumn 42, Issue 19, 1999, Pages 3835-3844

  Alterman, Mathias ^a   Andersson, Hans O ^a   Garg, Neeraj ^a   Ahlsén, Göran ^a   Lövgren, Seved ^a   Classon, Björn ^d   Danielson, U Helena ^a   Kvarnström, Ingmar ^c   Vrang, Lotta ^b   Unge, Torsten ^a   Samuelsson, Bertil ^d   Hallberg, Anders ^a  

^a UPPSALA UNIVERSITY   (Sweden)

^b MEDIVIR AB   (Sweden)

^c LINKÖPING UNIVERSITY   (Sweden)

^d STOCKHOLM UNIVERSITY   (Sweden)

Author keywords

[No Author keywords available]

Indexed keywords

ANTI HUMAN IMMUNODEFICIENCY VIRUS AGENT; INDINAVIR; NELFINAVIR; PROTEINASE INHIBITOR; RITONAVIR; SAQUINAVIR;

ANIMAL CELL; ANTIVIRAL ACTIVITY; ARTICLE; CONTROLLED STUDY; DRUG DESIGN; DRUG SYNTHESIS; HUMAN IMMUNODEFICIENCY VIRUS 1; MOUSE; NONHUMAN; PROTEINASE INHIBITION; STRUCTURE ACTIVITY RELATION; X RAY CRYSTALLOGRAPHY;

ANIMALS; CELL LINE; CRYSTALLOGRAPHY, X-RAY; DRUG DESIGN; ESCHERICHIA COLI; HIV PROTEASE INHIBITORS; HUMANS; KINETICS; MALE; MODELS, CHEMICAL; MODELS, MOLECULAR; PROTEIN CONFORMATION; RATS; RATS, SPRAGUE-DAWLEY; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 0033598384     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm9910371     Document Type: Article

References (70)

1. (a) Morrow, C. D.; Park, J.; Wakefield, J. K. Viral Gene Products and Replication of the Human Immunodeficiency Type 1 Virus. Am. J. Physiol. 1994, 266, C1135-1156.
2. (b) Clavel, F.; Guétard, D.; Brun-Vézinet, F.; Chamaret, S.; Rey, M.; Santos-Ferreira, M. O.; Laurent, A. G.; Dauguet, C.; Katlama, C.; Rouzioux, C.; Klatzmann, D.; Champalimaud, J. L.; Montagnier, L. Isolation of a New Human Retrovirus from West African Patients with AIDS. Science 1986, 233, 343-346.
3. (c) Gallo, R. C.; Salahuddin, S. Z.; Popovic, M.; Shearer, G. M.; Kaplan, M.; Haynes, B. F.; Palker, T. J.; Redfield, R.; Oleske, J.; Safai, B.; White, G.; Foster, P.; Markham, P. D. Frequent Detection and Isolation of Cytopathic Retroviruses (HTLV-III) from Patients with AIDS and at Risk for AIDS. Science 1984, 224, 500-503.
4. (d) Barré-Sinoussi, F.; Chermann, J. C.; Rey, M.; Nugeyre, M. T.; Chamaret, S.; Gruest, J.; Dauguet, C.; Axler-Blin, C.; Vézinet-Brun, F.; Rouzioux, C.; Rozenbaum, W.; Montagnier, L. Isolation of a T-Lymphotropic Retrovirus from a Patient at Risk for Acquired Immune Deficiency Syndrom (AIDS). Science 1983, 220, 868-871.
5. (e) Gallo, R. C.; Sarin, P. S.; Gelmann, E. P.; Robert-Guroff, M.; Richardson, E.; Kalyanaraman, V. S.; Mann, D.; Sidhu, G. D.; Stahl, R. E.; Zolla-Pazner, S.; Leibowitch, J.; Popovic, M. Isolation of Human T-Cell Leukemia Virus in Acquired Immune Deficiency Syndrome (AIDS). Science 1983, 220, 865-867.
6. (a) 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.
7. (b) Kempf, D. J.; Sham, H. L. HIV Protease Inhibitors. Curr. Pharm. Des. 1996, 2, 225-246.
8. (c) Boehme, R. E.; Borthwick, A. D.; Wyatt, P. G. Antiviral Agents. Annu. Rep. Med. Chem. 1995, 30, 139-149.
9. (d) Gait, M. J.; Karn, J. Progress in Anti-HIV Structurbased Drug Design. Trends Biotechnol. 1995, 13, 430-438.
10. (e) West, M. L.; Fairlie, D. P. Targeting HIV-1 Protease: a Test of Drug-design Methodologies. Trends Pharmacol. Sci. 1995, 16, 67-75.
11. (f) Thaisrivongs, S. HIV Proteas Inhibitors. Annu. Rep. Med. Chem. 1994, 29, 133-144.
12. (g) Vacca, J. P. Design of Tight-Binding Human Immunodeficiency Virus Type 1 Protease Inhibitors. Methods Enzymol. 1994, 241, 311-234.
13. (h) Kempf, D. J. Design of Symmetry-Based, Peptidomimetic Inhibitors of Human Immunodeficiency Virus Protease. Methods Enzymol. 1994, 241, 234-254.
14. (i) 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. Chim. Oggi 1991, 6-27.
15. (a) De Clercq, E. In Search of a Selective Antiviral Chemotherapy. Clin. Microbiol. Rev. 1997, 10, 674-693.
16. (b) 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.
17. (c) 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.
18. (d) Kitchen, V. S.; Skinner, C.; Ariyoshi, K.; Lane, E. A.; Duncan, I. B.; Burckhardt, J.; Burger, H. U.; Bragman, K.; Pinching, A. J.; Weber, L. N. Safty and Activity of Saquinavir in HIV Infection. Lancet 1995, 345, 952-955.
19. (a) Walli, R.; Herfort, O.; Michl, G. M.; Demant, T.; Jäger, H.; Dieterle, C.; Bogner, J. R.; Landgraf, R.; Goeble, F. D. Treatment with Protease Inhibitors Associated with Peripheral Insulin Resistance and Impaired Oral Glucose Tolerance in HIV-1-Infected Patients. AIDS 1998, 12, F167-173.
20. (b) Lo, J. C.; Mulligan, K.; Tai, V. W.; Algren, H.; Schambelan, M. "Buffalo Hump" in Men with HIV-1 Infection. Lancet 1998, 351, 867-870.
21. (c) Miller, K. D.; Jones, E.; Yanovski, J. A.; Shankar, R.; Feuerstein, I.; Falloon, J. Visceral Abdominal-Fat Accumulation Associated with use of Indinavir. Lancet 1998, 351, 871-875.
22. (d) Carr, A.; Samaras, K.; Burton, S.; Law, M.; Freund, J.; Chisholm, D. J.; Cooper, D. A. A Syndrome of Peripheral Lipodystrohy, Hyperlipidaemia and Insulin Resistance in Patients Receving HIV Protease Inhibitors. AIDS 1998, 12, F51-58.
23. (e) Viraben, R.; Aquilina, C. Indinavir-Associated Lipodystrophy. AIDS 1998, 12, F37-39.
24. (f) Martinez, E.; Casamitjana, R.; Conget, I.; Gatell, J. M. Protease Inhibitor-Associated Hyperinsulinaemia. AIDS 1998, 12, 2077-2079.
25. (a) Jacobsen, H.; Yasargil, K.; Winslow, D. L.; Craig, J. C.; Kröhn, A.; Duncan, I. B.; Mous, J. Characterization of Human Immunodeficieny Virus Type 1 Mutants with Decresed Sensitivity to Proteinase Inhibitor Ro 31-8959. Virology 1995, 206, 527-534.
26. (b) Markowitz, 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 Increased Resistance to ABT-538, a Novel Protease Inhibitor. J. Virol. 1995, 69, 701-706.
27. (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.; Shivapraksh, 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.
28. (d) Ridky, T.; Leis, J. Development of Drug Resistance to HIV-1 Protease Inhibitors. J. Biol. Chem. 1995, 270, 29621-29623.
29. (a) Zuccarello, G.; Bouzide, A.; Kvarnström, I.; Niklasson, G.; Svensson, S. C. T.; Brisander, M.; Danielson, U. H.; Nillroth, U.; Hallberg, A.; Classon, B.; Samuelsson, B. HIV-1 Protease Inhibitors Based on Acyclic Carbohydrates. J. Org. Chem. 1998, 63, 4898.
30. (b) Hultén, J.; Bonham, N. M.; Nillroth, U.; Hansson, T.; Zuccarello, G.; Bouzide, A.; Åqvist, J.; Classon, B.; Danielson, U. H.; Karlén, A.; Kvarnström, I.; Samuelsson, B.; Hallberg, A. Cyclic HIV-1 Protease Inhibitors Derived from Mannitol: Synthesis, Inhibitory Potencies, and Computational Predictions of Binding Affinities. J. Med. Chem. 1997, 40, 885-897.
31. (c) Bäckbro, K.; Löwgren, S.; Österlund, K.; Atepo, J.; Unge, T. Unexpected Binding Mode of a Cyclic Sulfamide HIV-1 Protease Inhibitor. J. Med. Chem. 1997, 40, 898-902.
32. (d) Alterman, M.; Björsne, M.; Mühlman, A.; Classon, B.; Kvarnström, I.; Danielson, H.; Markgren, P. O.; Nillroth, U.; Unge, T.; Hallberg, A.; Samuelsson, B. Design and Synthesis of New Potent C2-Symmetric HIV-1 Protease Inhibitors. Use of L-Mannaric Acid as a Peptidomimetic Scaffold. J. Med. Chem. 1998, 41, 3782-3792.
33. (a) Bold, G.; Fässler, A.; Capraro, H.; Cozens, R.; Klimkait, T.; Lazdins, J.; Mestan, J.; Poncioni, B.; Rösel, J.; Stover, D.; Tintelnot-Blomley, M.; Acemoglu, F.; Beck, W.; Boss, E.; Eschbach, M.; Hürlimann, T.; Masso, E.; Roussel, S.; Ucci-Stoll, K.; Wyss, D.; Lang, M. New Aza-Dipeptide Analoges as Potent and Orally Absorbed HIV-1 Protease Inhibitors: Candidates for Clinical Development. J. Med. Chem. 1998, 41, 3387-3401.
34. (b) Franchetti, P.; Perlini, P.; Abu Sheikha, G.; Cappellacci, L.; Grifantini, M.; Loi, A. G.; De Montis, A.; Pani, A.; Marongiu, M. E.; La Colla, L. Potent and Selective Inhibitors of Human Immunodeficiency Virus Protease Structurally Related to L-694,-746. Antiviral Chem. Chemother. 1998, 9, 303-309.
35. (c) Patel, M.; Bacheler, L. T.; Rayner, M. M.; Cordova, B. C.; Klabe, R. M.; Erickson-Viitanen, S.; Seitz, S. P. The Synthesis and Evaluation of Cyclic Ureas as HIV Protease Inhibitors: Modifications of the P1/P1' Residues. Bioorg. Med. Chem. Lett. 1998, 8, 823-828.
36. (d) Nugiel, D. A.; Jacobs, K; Cornelius, L.; Chang, C.; Jadhav, P. K.; Holler, E. R.; Klabe, R. M.; Bacheler, L. T.; Cordova, B.; Garber, S.; Reid, C.; Logue, K. A.; Gorey-Feret, L. J.; Lam, G. N.; Erickson-Viitanen, S.; Seitz, S. P. Improved P1/ P1'Substituents for Cyclic Urea Based HIV-1 Protease Inhibitors: Synthesis, Structure-Activity Relationship, and X-ray Crystal Structure Analysis. J. Med. Chem. 1997, 40, 1465-1474.
37. (e) Chen, P.; Cheng, P. T. W.; Alam, M.; Beyer, B. D.; Bisacchi, G. S.; Dejnecka, T.; Evans, A. J.; Greytok, J. A.; Hermsmeier, M. A.; Humphreys, W. G.; Jacobs, G. A.; Kocy, O.; Lin, P.; Lis, K. A.; Marella, M. A.; Ryono, D. E.; Sheaffer, A. K.; Spergel, S. H.; Sun, C.; Tino, J. A.; Vite, G.; Colonno, R. J.; Zahler, R.; Barrish, J. C. Aminodiol HIV Protease Inhibitors. Synthesis and Structure-Activity Relationships of P1/P1'Compounds: Correlation Between Lipophilicity and Cytotoxicity. J. Med. Chem. 1996, 39, 1991-2007.
38. (f) Ettmayer, P.; Billich, A.; Hecht, P.; Rosenwirth, B.; Gstach, H. Paracyclophanes: A Novel Class of Water-Soluble Inhibitors of HIV Proteinase. J. Med. Chem. 1996, 39, 3291-3299.
39. (g) Kaldor, S. W.; Appelt, K.; Fritz, J. E.; Hammond, M.; Crowell, T. A.; Baxter, A. J.; Hatch, S. D.; Wiskerchen, M.; Muesing, M. A. A Systematic Study of P1-P3 Spanning Side chains for the Inhibition of HIV-1 Protease. Bioorg. Med. Chem. Lett. 1995, 5, 715-720.
40. (h) Kroemer, R. T.; Ettmayer, P.; Hecht, P. 3D-Quantitative Structure-Activity Relationship of Human Immunodeficiency Virus Type-1 Proteinase Inhibitors: Comparative Molecular Field Analysis of 2-Heterosubstituted Staline Derivatives-Implications for the Design of Novel Inhibitors. J. Med. Chem. 1995, 38, 4917-4928.
41. (i) Schirlin, D.; Van Dorsselaer, V.; Tarnus, C.; Taylor, D. L.; Tyms, A. S.; Baltzer, S.; Weber, F.; Remy, J. M.; Brennan, T.; Farr, R.; Janowick, D. Beneficial Replacement of the P1 Phenylalanine Side Chain in HIV-1 Protease Inhibitors of the Difluorostatone Type. Bioorg. Med. Chem. Lett. 1994, 4, 241-246.
42. (j) Van Dorsselaer, V.; Schirlin, D.; Tarnus, C.; Taylor, D. L.; Tyms, A. S.; Weber, F.; Baltzer, S.; Remy, J. M.; Brennan, T.; Janowick, D. Increased Antiviral Activity of HIV Protease Inhibitors of the Difluorostatone Type Bearing (R)-Valinol Derivatives as Novel C-Termini. Bioorg. Med. Chem. Lett. 1994, 4, 1213-1218.
43. (k) Scholz, D.; Billich, A.; Charpiot, B.; Ettmayer, P.; Lehr, P.; Rosenwirth, B.; Schreiner, E.; Gstach, H. Inhibitors of HIV-1 Proteinase Containing 2-Heterosubstituted 4-Amino-3-hydroxy-5-phenylpentanoic Axid: Synthesis, Enzyme Inhibition, and Antiviral Activity. J. Med. Chem. 1994, 37, 3079-3089.
44. (l) Young, S. D.; Payne, L. S.; Thompson, W. J.; Gaffin, N.; Lyle, T. A.; Britcher, S. F.; Graham, S. L.; Shultz, T. H.; Deana, A. A.; Darke, P. L.; Zugay, J. A.; Schleif, W. A.; Quintero, J. C.; Emini, E. A.; Anderson, P. S.; Huff, J. R. HIV-1 Protease Inhibitors Based on Hydroxyethylene Dipeptide Isosteres: An Investigation into the Role of the P1' Side Chain on Structure Activity. J. Med. Chem. 1992, 35, 1702-1709.
45. (m) Thompson, W. J.; Fitzgerald, P. M. D.; Holloway, M. K.; Emini, E. A.; Darke, P. L.; McKeever, B. M.; Schleif, W. A.; Quintero, J. C.; Zugay, J. A.; Tucker, T. J.; Schwering, J. E.; Homnick, C. F.; Nunberg, J.; Springer, P.; Huff, J. R. Synthesis and Antiviral Activity of a Series of HIV-1 Proteas Inhibitors with Functionality Tethered to the P1 or P1' Phenyl Substituents: X-ray Crystal Structure Assisted Design. J. Med. Chem. 1992, 35, 1685-1701.
46. (n) Askin, D.; Wallace, M. A.; Vacca, J. P.; Reamer, R. A.; Volante, R. P.; Shinkai, I. Highly Diastereoselective Alkylations of Chiral Amide Enolates: New Routes to Hydroxyethylene Dipeptide Isostere Inhibitors of HIV-1 Protease. J. Org. Chem. 1992, 57, 2771-2773.
47. (o) Vacca, J. P.; Guare, J. P.; deSolms, S. J.; Sanders, W. M.; Giuliani, E. A.; Young, S. D.; Darke, P. L.; Zugay, J.; Sigal, I. S.; Schleif, W. A.; Quintero, J. C.; Emini, E. A.; Anderson, P. S.; Huff, J. R. L-687,908, a Potent Hydroxyethylene-Containing HIV Protease Inhibitor. J. Med. Chem. 1991, 34, 1225-1228.
48. (a) Gabriel, C.; Gabriel, S.; Grant, E. H.; Halstead, B. S. J.; Mingos, M. P. Dielectric Parameters Relevant to Microwave Dielectric Heating. Chem. Soc. Rev. 1998, 27, 213-223.
49. 11C]Alkyl Halides. J. Labelled Compd. Radiopharm. 1994, XXXIV, 949-959.
50. Larhed, M.; Hallberg, A. Microwave-Promoted Palladium-Catalyzed Coupling Reactions. J. Org. Chem. 1996, 61, 9582-9584.
51. (a) De Meijere, A. Palladium-catalyzed Coupling of Organyl Halides to Alkenes-the Heck Reaction. Metal-Catalyzed Cross-coupling Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VHC: Weinheim, 1997; pp 99-166.
52. (b) Suzuki, A. Cross-Coupling Reactions of Organoboron Compounds with Organic Halides. Metal-Catalyzed Cross-coupling Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VHC: Weinheim, 1997; pp 49-97.
53. (c) Farina, V.; Roth, G. P. Recent Advances in the Stille Reaction. Adv. Metal-Org. Chem. 1996, 5, 1-53.
54. Miyaura, N.; Ishikawa, M.; Suzuki, A. Stereoselective Synthesis of Exocyclic Alkenes via Hydroboration-Cross-Coupling Sequence. Tetrahedron Lett. 1992, 33, 2571-2574.
55. Gronowitz, S.; Björk, P.; Malm, J.; Hörnfeldt, A. The Effect of some Additives on the Stille Pd0-Catalyzed Cross-Coupling Reaction. J. Organomet. Chem. 1993, 127-129.
56. Garg, N.; Larhed, M.; Hallberg, A. Heck Arylation of 1,2-Cyclohexanedione and 2-Ethoxy-2-cyclohexenone. J. Org. Chem. 1998, 63, 4158-4162.
57. Danielson, U. H.; Lindgren, M. T.; Markgren, P. O.; Nillroth, U. Investigation of an Allosteric Site of HIV-1 Proteinase Involved in Inhibiton by Cu2+. Adv. Exp. Med. Biol. 1998, 463, 99-103.
58. Nillroth, U.; Vrang, L.; Markgren, P. O.; Hultén, J.; Hallberg, A.; Danielson, U. H. Human Immunodeficiency Virus Type 1 Proteinase Resistance to Symmetric Cyclic Urea Inhibitor Analogues. Antimicrob. Agents Chemother. 1997, 41, 2383-2388.
59. Atkinson, J. G.; Giraud, Y.; Rokach, J.; Rooney, C. S.; McFarlane, C. S.; Rackham, A.; Share, N. N. Kojic Amine-a Novel γ-Aminobutyric Acid Analogue. J. Med. Chem. 1979, 22, 99.
60. (a) Ladbury, J. E. Just Add Water! The Effect of Water on the Specificity of Protein-Ligand Binding Sites and Its Potential Aplication to Drug Design. Chem, Biol. 1996, 3, 973-980.
61. (b) Dunitz, J. D. The Entropic Cost of Bound Water in Crystals and Biomolecules. Science 1994, 264, 670.
62. Kraulis, P. J. MOLSCRIPT: a Program to Produce Both Detailed and Schematic Plots of Protein Structures. J. Appl. Crystallogr. 1991, 24, 946-590.
63. For preparation of palladium tetrakis(triphenylphosphine), see pp 2-3 in: Heck, R. F. Palladium Reagents in Organic Syntheses; Academic Press: London, 1985.
64. Yamamoto, Y.; Yanagi, A. Studies on Organometallic Compounds. II. Facile and Convenient Method for the synthesis of Iodoazines Through Iododestannation of Trimethylstannylazines. Chem. Pharm. Bull. 1982, 30, 1731-1737.
65. Otwinovski, Z.; Minor, W. The HKL Program Suite.
66. Gewirth, D.; Otwinovski, Z. The SCALEPACK Manual;; 1995.
67. i is an observation of the intensity of an individual reflection and 〈I〉 is the average intensity over symmetry equivalents.
68. Brünger, A. T.; Kuriyan, J.; Karplus, M. Crystallographic R Factor Refinement by Moleculardynamics. Science 1987, 235, 458-460.
69. crystal but calculated for a randomly chosen set of reflections that were omitted from the refinement process.
70. Jones, T. A.; Zou, J.-Y.; Cowan, S. W.; Kjeldgaard, M. Improved Methods for Building Protein Models in Electron Density Maps and the Location of Errors in These Models. Acta Crystallogr. A 1991, 47, 110-119.