Nonpeptide cyclic cyanoguanidines as HIV-1 protease inhibitors: Synthesis, structure - Activity relationships, and X-ray crystal structure studies

Journal of Medicinal Chemistry

Volumn 41, Issue 9, 1998, Pages 1446-1455

  Jadhav, Prabhakar K ^a   Woerner, Francis J ^a   Lam, Patrick Y S ^a   Nicholas Hodge, C ^a   Eyermann, Charles J ^a   Man, Hon Wah ^a   Daneker, Wayne F ^a   Bacheler, Lee T ^a   Rayner, Marlene M ^a   Meek, James L ^a   Erickson Viitanen, Susan ^a   Jackson, David A ^a   Calabrese, Joseph C ^a   Schadt, Margaret ^a   Chang, Chong Hwan ^a  

^a DUPONT COMPANY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

[HEXAHYDRO 5,6 DIHYDROXY 1,3 BIS[[4 (HYDROXYMETHYL)PHENYL]METHYL] 4,7 BIS(PHENYLMETHYL) 2H 1,3 DIAZEPIN 2 YLIDENE]CYANAMIDE; CIMETIDINE; CYANAMIDE; GUANIDINE DERIVATIVE; PROTEINASE INHIBITOR; UNCLASSIFIED DRUG; UREA DERIVATIVE;

ARTICLE; CRYSTAL STRUCTURE; DRUG DESIGN; DRUG SYNTHESIS; HUMAN IMMUNODEFICIENCY VIRUS 1; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; STRUCTURE ACTIVITY RELATION;

ANTI-HIV AGENTS; CELL LINE; CRYSTALLOGRAPHY, X-RAY; GUANIDINES; HIV PROTEASE; HIV PROTEASE INHIBITORS; HIV-1; HUMANS; HYDROGEN BONDING; MODELS, MOLECULAR; STRUCTURE-ACTIVITY RELATIONSHIP; UREA;

EID: 14444267317     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm970524i     Document Type: Article

References (18)

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. (c) Wlodawer, A.; Erickson, J. W. Structure-based inhibitors of HIV-1 proteaae. Annu. Rev. Biochem. 1993, 62, 543-585.
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. (c) Wlodawer, A.; Erickson, J. W. Structure-based inhibitors of HIV-1 proteaae. Annu. Rev. Biochem. 1993, 62, 543-585.
3. 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. (c) Wlodawer, A.; Erickson, J. W. Structure-based inhibitors of HIV-1 proteaae. Annu. Rev. Biochem. 1993, 62, 543-585.
4. 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.
5. Ganellin, C. R. In Chron. Drug Discovery; Bindra, J. S., Lednicer, D., Eds.; Wiley: New York, 1982; Vol. 1, pp 1-38.
6. (a) Navia, M. A.; Fitzgerald, P. M. D.; McKeever, B. M.; Leu, C.-T.; Heimbach, J. C.; Herber, W. K.; Sigal, I. S.; Darke, I. L.; Springer, J. P. Three-dimensional structure of aspartyl protease from human immunodeficiency virus HIV-1. Nature 1989, 337, 615-620.
7. (b) Wlodawer, A.; Miller, M.; Jaskolski, N.; Sathyanarayana, B. K.; Balwin, E.; Weber, I. T.; Selk, L. M.; Clawson, L.; Schneider, J.; Kent, S. B. H. Conserved folding in retroviral proteases: crystal structure of a synthetic HIV-1 protease. Science 1989, 245, 616-621.
8. (c) Fitzgerald, P. M. D.; McKeever, B. M.; VanMiddlesworth, J. F.; Springer, J. P.; Heimbach, J. C.; Leu, C.-T.; Herber, W. K.; Dixon, R. A. F.; Darke, P. L. Crystallographic analysis of a complex between human immunodeficiency virus type 1 protease and acetylpepstatin at 2.0-Å resolution. J. Biol. Chem. 1990, 265, 14209-14219.
9. Jadhav, P. K.; Woerner, F. J.; Man, H.-W. Synthesis of seven-membered Cyclic Hydroxyguanidine: Novel HIV-1 Protease Inhibitors. Bioorg. Med. Chem. Lett. 1997, in press.
10. (a) 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.
11. (b) 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 Structure-Activity Relationship of Novel P1/ P1′-Substituted Cyclic Urea-Based Human Immunodeficiency Virus Type-1 Protease Inhibitors. J. Med. Chem. 1996, 39, 2156-2169.
12. (c) 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.
13. Burpitt, B. E.; Crawford, L. P.; Davies, B. J.; Mistry, J.; Mitchell, M. B.; Pancholi, K. D. 6-(Substituted phenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-ones of Medicinal interest. The synthesis of SK&F 94836 and SK&F 95654. J. Heterocycl. Chem. 1988, 25, 1689-1695.
14. 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.
15. 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.
16. Nicholson, L. K.; Yamazaki, T.; Torchia, D. A.; Grzesiek, S.; Bax, A.; Stahl, S. J.; Kaufman, J. D.; Wingfield, P. T.; Lam, P. Y. S.; Jadhav, P. K.; Hodge, C. N.; Domaille, P. J.; Chang, C.-H. Flexibility and function in HIV-1 protease. Nature Struct. Biol. 1995, 2, 274-280.
17. Ala, P.; Huston, E.; Klabe, R. M.; McCabe, D. D.; Duke, J. L.; Rizzo, C. J.; Korant, B. D.; DeLoskey, R. J.; Lam, P. Y. S.; Hodge, C. N.; Chang, C.-H. Molecular Basis of HIV-1 Protease Drug Resistance: Structural Analysis of Mutant Proteases Complexed with Cyclic Urea Inhibitors. Biochemistry 1997, 1573-1580.
18. Brünger, A. T.; Kuriyan, J.; Karplus, M. Crystallographic R Factor Refinement by Molecular Dynamics. Science 1987, 235, 458-460.