Inhibitors of the C2-symmetric HIV-1 protease: Nonsymmetric binding of a symmetric cyclic sulfamide with ketoxime groups in the P2/P2' side chains

Journal of Medicinal Chemistry

Volumn 42, Issue 20, 1999, Pages 4054-4061

  Hultén, Johan ^a   Andersson, Hans O ^a   Schaal, Wesley ^a   Danielson, Helena U ^a   Classon, Björn ^b   Kvarnström, Ingemar ^c   Karlén, Anders ^a   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

2,7 BIS[(3 METHYLOXIMOPHENYL)METHYL] 4,5 DIHYDROXY 3,6 BIS(PHENOXYMETHYL) 1,27 THIADIAZEPINE 1,1 DIOXIDE; PROTEINASE INHIBITOR; UNCLASSIFIED DRUG;

ANTIVIRAL ACTIVITY; ARTICLE; BINDING SITE; CRYSTAL STRUCTURE; DRUG CONFORMATION; DRUG STRUCTURE; HUMAN IMMUNODEFICIENCY VIRUS 1; NONHUMAN; PROTEINASE INHIBITION; STRUCTURE ACTIVITY RELATION;

CRYSTALLOGRAPHY, X-RAY; HIV PROTEASE; HIV PROTEASE INHIBITORS; MODELS, MOLECULAR; MOLECULAR CONFORMATION; PHENYLUREA COMPOUNDS; SPECTROMETRY, FLUORESCENCE; SULFONAMIDES;

EID: 0033533880     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm991054q     Document Type: Article

References (50)

1. 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.
2. 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, 273, 117-122.
3. 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.
4. 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 Inhibitor of Human Immunodeficiency Virus Protease. Antimicrob. Agents Chemother. 1996, 40, 292-297.
5. Palella, F. J., Jr.; Delaney, K. M.; Moorman, A. C.; Loveless, M. O.; Fuhrer, J. S. G. A.; Aschman, D. J.; Holmberg, S. D. Declining Morbidity and Mortality Among Patients with Advanced Human Immunodeficiency Virus Infection. N. Engl. J. Med. 1998, 338, 853-860.
6. Ala, P. J.; Huston, E. E.; Klabe, R. M.; McCabe, D. D.; Duke, J. L.; Rizzo, C. J.; Korant, B. D.; DeLoskey, R. J.; Lam, P. Y. S.; Hodge, N.; Chang, C.-H. Molecular Basis of HIV-1 Protease Drug Resistance: Structural Analysis of Mutant Protease Complexed with Cyclic Urea Inhibitors. Biochemistry 1997, 36, 1573-1580.
7. Mellors, J. W.; Larder, B. A.; Schinazi, R. F. Mutations in HIV-1 Reverse Transcriptase and Protease Associated with Drug Resistance. Int. Antivir. News 1995, 3, 8-13.
8. Erickson, J. W. The Not-So-Great Escape. Nature Struct. Biol. 1995, 2, 523-529.
9. Tisdale, M. HIV Protease Inhibitors-Resistance Issues. Int. Antivir. News 1996, 4, 41-43.
10. Appelt, K. Crystal Structures of HIV-1 Protease-Inhibitor Complexes. Perspect. Drug Discovery Des. 1993, 1, 23-48.
11. Jadhav, P. K.; Woerner, F. J.; Lam, P. Y. S.; Hodge, C. N.; Eyermann, C. J.; Man, H.-W.; Daneker, W. F.; Bacheler, L. T.; Rayner, M. M.; Meek, J. L.; Erickson-Viitanen, S.; Jackson, D. A.; Calabrese, J. C.; Schadt, M.; Chang, C.-H. Nonpeptide Cyclic Cyanoguanidines as HIV-1 Preotease Inhibitors: Sythesis, Structure-Activity Relationships and Crystal Structure Studies. J. Med. Chem. 1998, 41, 1446-1455.
12. Turner, S. R.; Strohbach, J. W.; Tommasi, R. A.; Aristoff, P. A.; Johnson, P. D.; Skulnich, H. I.; Dolak, L. A.; Seest, E. P.; Tomich, P. K.; Bohanon, M. J.; Horng, M.-M.; Lynn, J. C.; Chong, K.-T.; Hinshaw, R. R.; Watenpaugh, K. D.; Janakiraman, M. N.; Thaisrivongs, S. Tipranavir (PNU 140960): A potent, Orally Bioavailable nonpeptidic HIV Protease Inhibitor of the 5,6-Dihydro-4-hydroxy-2-pyrone Sulfonamide Class. J. Med. Chem. 1998, 41, 3467-3476.
13. Wlodawer, A.; Erickson, J. W. Structure-Based Inhibitors of HIV-1 Protease . Annu. Rev. Biochem. 1993, 62, 543-585.
14. Wang, Y.-X.; Freedberg, D. I.; Wingfield, P. T.; Stahl, S. J.; Kaufman, J. D.; Kiso, Y.; Bhat, T. N.; Erickson, J. W.; Torchia, D. A. Bound Water Molecules at the Interface Between the HIV-1 Protease and a Potent Inhibitor, KNI-272, Determined by NMR. J. Am. Chem. Soc. 1996, 118, 12287-12290.
15. Wang, Y.-X.; Freedberg, D. I.; Grzesik, S.; Torchia, D. A.; Wingfield, P. T.; Kaufman, J. D.; Stahl, S. J.; Chang, C.-H.; Hodge, C. N. Mapping hydration Water Molecules in the HIV-1 Protease/DMP 323 Complex in Solution By NMR Spectroscopy. Biochemistry 1996, 35, 12694-12704.
16. Yamazaki, T.; Hinck, A. P.; Wang, Y.-X.; Nicholson, L. K.; Torchia, D. A.; Wingfield, P. S., S. J.; Kaufman, J. D.; Chang, C.-H.; Domaille, P. J.; Lam, P. Y. S. Three-Dimensional Solution Structure of the HIV-1 Protease Complexed withDMP323, a Novel Cyclic Urea-Type Inhibitor, Determined by Nuclear MagneticResonance Spectroscopy. Protein Sci. 1996, 5, 495-506.
17. Grezesiek, S.; Bax, A.; Nicholson, L. K.; Yamazaki, T.; Wingfield, P.; Stahl, S. J.; Eyermann, C. J.; Torchia, D. A.; Hodge, C. H.; Lam, P. Y. S.; Jadhav, P. K.; Chang, C.-H. NMR Evidence for the Displacement of a Conserved Interior Water Molecule in HIV Protease by a Non-Peptide Cyclic Urea-Based Inhibitor. J. Am. Chem. Soc. 1994, 116, 1581-1582.
18. Ishima, R.; Wingfield, P. T.; Stahl, S. J.; Kaufman, J. D.; Torchia, D. A. Using Amide 1H and 15N Transverse relaxation To Detect Millisecond Time-Scale Motions in Predeuterated Proteins: Applications to HIV-1 Protease. J. Am. Chem. Soc. 1998, 120, 10534-10542.
19. 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.
20. Hultén, J.; Bonham, N. M.; Nillroth, U.; Hansson, T.; Zuccarello, G.; Bouzide, A.; Åqvist, J.; Classon, B.; Danielson, H. U.; 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.
21. Bäckbro, K.; Löwgren, S.; Österlund, K.; Atepo, J.; Unge, T.; Hultén, J.; Bonham, N. M.; Schaal, W.; Karlén, A.; Hallberg, A. Unexpected Binding Mode of a Cyclic Sulfamide HIV-1 Protease Inhibitor. J. Med. Chem. 1997, 40, 898-902.
22. Hallberg, A.; Westfelt, L.; Holm, B. Palladium-Catalyzed Arylation of Methyl Vinyl Ether. J. Org. Chem. 1981, 46, 5414-5415.
23. Cabri, W.; Candiani, I.; Bedeschi, A.; Santi, R. Ligand-Controlled α-Regioselectivity in Palladium-Catalyzed Arylation of Butyl Vinyl Ether. J. Org. Chem. 1990, 55, 3654-3655.
24. Larhed, M.; Hallberg, A. Direct Synthesis of Cyclic Ketals of Acetophenones by Palladium-Catalyzed Arylation of Hydroxyalkyl Vinyl Ethers. J. Org. Chem. 1997, 62, 7858-7862.
25. Harada, T.; Ohno, T.; Kobayashi, S.; Mukaiyama, T. The Catalytic Friedel-Crafts Acylation Reaction and the Catalytic Beckmann Rearangement Promoted by a Gallium(III) or a Antimony(V) Cationic Species. Synthesis 1991, 1216-1220.
26. Andersson, C.-M.; Larsson, J.; Hallberg, A. J. Org. Chem. 1990, 55, 5757.
27. Brown, H. S.; Narasimhan, S.; Choi, Y. M. Selective Reductions. 30. Effect on Cation and Solvent on the Reactivity of Saline Borohydrides for Reduction of Carboxylic Esters. Improved Procedures for the Conversion of Esters to Alcohols by Metal Borohydrides. J. Org. Chem. 1982, 47, 4702-4708.
28. 2+. Adv. Exp. Med. Biol. 1998, 463, 99-103,
29. Nillroth, U.; Vrang, L.; Markegren, 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.
30. Abola, E. E.; Sussman, J. L.; Prilusky, J.; Manning, N. O. Protein Data Bank Archives of Three-Dimensional Macromolecular Structures. In Methods in Enzymology; Carter, Jr., C. W., Sweet, R. M., Eds.; Academic Press: San Diego, 1997; Vol. 277, pp 556-571.
31. Sussman, J. L.; Lin, D. J.; Manning, N. O.; Prilusky, J.; Ritter, O.; Abola, E. E. Protein Data Bank (PDB): Database of Three-Dimensional Structural Information of Biological Macromolecules. Acta Crystallogr. 1998, D54, 1078-1084.
32. Lam, P. Y. S.; Ru, Y.; Jadhav, P. K.; Aldrich, P. E.; DeLucca, G. V.; Eyermann, C. J.; Chang, C.-H.; Emmet, 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.; Klabe, R. M.; Shum, L.; Winslow, D. L.; Kornhauser, D. M.; Jackson, D. A.; Erikson-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, 3514-3525.
33. Allen, F. H.; Kennard, O. 3D Search and Research Using the Cambridge Structural Database. Chem. Des. Autom. News 1993, 8, 1 and 31-37.
34. Energy calculations were conducted to test the hypothesis of a more stable E isomer. Under the MMFF empirical force field of MacroModel, the E isomer was calculated to be 3.4 kcal/mol more stable than the Z isomer. Since oximes are not well parametrized with the above force field, an ab initio calculation was performed. At the B3LYP/6-31G* level of theory, the E isomer was calculated to be 2.6 kcal/mol more stable than the Z isomer. Assuming that the reaction was not overwhelmingly kinetically controlled, we used the E isomer in our models.
35. Han, Q.; Chang, C.-H.; Li, R.; Ru, Y.; Jadhav, P. K.; Lam, P. Y. S. Cyclic HIV Protease Inhibitors: Design and Synthesis of Orally Bioavailable, Pyrazole P2/P2'Cyclic Ureas with Improved Potency. J. Med. Chem. 1998, 41, 2019-2028.
36. For a discussion on the displacement of corresponding structural water molecules in other systems, see: Melnick, M.; Reich, S. H.; Lewis, K. K.; Mitchell, L. J., Jr.; Nguyen, D.; Trippe, A. J.; Dawson, H.; Davies, J. F., II; Appelt, K.; Wu, B.-W.; Musick, L.; Gehlaar, D. K.; Webber, S.; Shetty, B.; Kosa, M.; Kahil, D.; Andrada, D. Bis Tertiary Amide Inhibitors of the HIV-1 Protease Generated via Protein Structure-Based Iterative Design. J. Med. Chem. 1996, 39, 2795-2811.
37. Mohamadi, F.; Richards, N. G. J.; Guida, W. C.; Liskamp, R.; Lipton, M.; Caufield, C.; Chang, G.; Hendrickson, T.; Still, W. C. MacroModel - An Integrated Software System for Modeling Organic and Bioorganic Molecules Using Molecular Mechanics. J. Comput. Chem. 1990, 11, 440-467.
38. Halgren, T. A. Merck Molecular Force Field. 1. Basis, Form, Scope, Parametrization, and Performance of MMFF94. J. Comput. Chem. 1996, 17, 490-519.
39. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Gill, P. M. W.; Johnson, B. G.; Robb, M. A.; Cheeseman, J. R.; Keith, T.; Petersson, G. A.; Montgomery, J. A.; Raghavachari, K.; Al-Laham, M. A.; Zakrzewski, V. G.; Ortiz, J. V.; Foresman, J. B.; Cioslowski, J.; Stefanov, B. B.; Nanayakkara, A.; Challacombe, M.; Peng, C. Y.; Ayala, P. Y.; Chen, W.; Wong, M. W.; Andres, J. L.; Replogle, E. S.; Gomperts, R.; Martin, R. L.; Fox, D. J.; Binkley, J. S.; Defrees, D. J.; Baker, J.; Stewart, J. P.; Head-Gordon, M.; Gonzalez, C.; Pople, J. A. Gaussian 94, Revision D. 4; Gaussian, Inc.: Pittsburgh, PA, 1995.
40. McDonald, D. Q.; Still, W. C. AMBER* Torsional Parameters for the Peptide Backbone. Tetrahedron Lett. 1992, 33, 7743-7746.
41. Still, W. C.; Tempczyk, A.; Hawley, R. C.; Hendrickson, T. Semianalytical Treatment of Solvation for Molecular Mechanics and Dynamics. J. Am. Chem. Soc. 1990, 112, 6127-6129.
42. Bäckbro, K.; Zhang, H.; Vrang, L.; Öberg, B.; Unge, T. Unpublished results.
43. Taylor, A.; Brown, D. P.; Kadam, S. M.; Kohlbrenner, W. E.; Weigl, D.; Turon, M. C.; Katz, L. High-level expression and purification of mature HIV-1 protease in Escherichia coli under control of the araBAD promoter. Appl. Microbiol. Biotechnol. 1992, 205-210.
44. Gewirth, D.; Otwinovski, Z. The SCALEPACK Manual.
45. Otwinovski, Z.; Minor, W. The HKL Program Suite.
46. Brunger, A. T.; Adams, P. D.; Clore, G. M.; Delano, W. L.; Gros, P.; Grosse-Kunstleve, R. W.; Jiang, J.-S.; Kuszewski, J.; Nilges, M.; Pannu, N. S.; Read, R. J.; Rice, L. M.; Simonson, T.; Warren, G. L. Crystallography & NMR System: A New Software Suite for Macromolecular Structure Determination. Acta Crystallogr. 1998, D54, 905-921.
47. Brünger, A. T.; Kuriyan, J.; Karplus, M. Crystallographic R factor refinement by molecular dynamics. Science 1987, 235, 458-460.
48. 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. 1991, A47, 110-119.
49. crystal but calculated for a randomly chosen set of reflections that were omitted from the refinement process.
50. Kraulis, P. J. MOLSCRIPT: a program to produce both detailed and schematic plots of protein structures. J. Appl. Crystallogr. 1991, 24, 946-950.