Improved P1/P1' substituents for cyclic urea based HIV-1 protease inhibitors: Synthesis, structure-activity relationship, and X-ray crystal structure analysis

Journal of Medicinal Chemistry

Volumn 40, Issue 10, 1997, Pages 1465-1474

  Nugiel, David A ^a   Jacobs, Kim ^a   Cornelius, Lyndon ^a   Chang, Chong Hwan ^a   Jadhav, Prabhakar K ^a   Holler, Edward R ^a   Klabe, Ronald M ^a   Bacheler, Lee T ^a   Cordova, Beverly ^a   Garber, Sena ^a   Reid, Carol ^a   Logue, Kelly A ^a   Gorey Feret, Lorraine J ^a   Lam, Gilbert N ^a   Erickson Viitanen, Susan ^a   Seitz, Steven P ^a  

^a DUPONT COMPANY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ARGININE; DRUG ANALOG; GUANIDINE; HEXAHYDRO 5,6 DIHYDROXY 1,3 BIS[[3 (METHYLAMINO)PHENYL]METHYL] 4,7 BIS[[3,4 (ETHYLENEDIOXY)PHENYL]METHYL] 2H 1,3 DIAZEPIN 2 ONE; HYDROGEN; OXYGEN; PROTEIN; PROTEINASE; PROTEINASE INHIBITOR; UNCLASSIFIED DRUG; UREA; VIRUS RNA;

ANIMAL EXPERIMENT; ANTIVIRAL ACTIVITY; ARTICLE; BINDING AFFINITY; BIOAVAILABILITY; CRYSTAL STRUCTURE; DOG; DRUG BLOOD LEVEL; DRUG HALF LIFE; DRUG POTENCY; DRUG RESISTANCE; DRUG SYNTHESIS; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; HUMAN; HUMAN CELL; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; HYDROGEN BOND; LIPOPHILICITY; NONHUMAN; ORAL DRUG ADMINISTRATION; PROTEIN BINDING; RAT; STRUCTURE ACTIVITY RELATION; X RAY CRYSTALLOGRAPHY;

ANIMALS; ANTI-HIV AGENTS; BIOLOGICAL AVAILABILITY; CELL LINE; CRYSTALLOGRAPHY, X-RAY; DOGS; HIV PROTEASE INHIBITORS; HUMANS; MAGNETIC RESONANCE SPECTROSCOPY; MASS SPECTROMETRY; STRUCTURE-ACTIVITY RELATIONSHIP; UREA;

EID: 14444287797     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm960839i     Document Type: Article

References (31)

1. Richman, D. D. HIV Therapeutics. Science 1996, 272, 1886-8.
2. (a) Parkes, K. E. B.; Bushnell, D. J.; Crackett, P. H.; Dunsdon, S. J.; Freeman, A. C.; Gunn, M. P.; Hopkins, R. A.; Lambert, R. W.; Martin, J. A.; Merrett, J. H.; Redshaw, S.; Spurden, W. C.; Thomas, G. J. Studies toward the large-scale synthesis of the HIV proteinase inhibitor Ro 31-8959. J. Org. Chem. 1994, 59, 3656-64 and references cited therein.
3. (b) Dorsey, B. D.; Levin, R. B.; McDaniel, S. L.; Vacca, J. P.; Guare, J. P.; Darke, P. L.; Zugay, J. A.; Emini, E. A.; Schleif, W. A.; Quintero, J. C.; Lin, J. H.; Chen, I.-W.; Holloway, M. K.; Fitzgerald, P. M. D.; Axel, M. G.; Ostovic, D.; Anderson, P. S.; Huff, J. R. L-735,524: The Design of a Potent and Orally Bioavailable HIV Protease Inhibitor. J. Med. Chem. 1994, 37, 3443-51.
4. Kempf, D. J.; Marsh, K. C.; Denissen, J.; McDonald, E.; Vasavanonda, S.; Flentge, C.; Green, B. G.; Fino, L.; Park, C.; Kong, X.; Wideburg, N. E.; Saldivar, A.; Ruiz, L.; Kati, W. M.; Sham, H. L.; Robins, T.; Stewart, K. D.; Plattner, J. J.; Leonard, J.; Norbeck, D. 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, 2484-8.
5. Roberts, N. A. Drug-resistance Patterns of Saquinavir and other HIV Protease Inhibitors. AIDS 1995, 9, S27-S32.
6. (a) Boehme, R. E.; Borthwick, A. D.; Wyatt, P. G. Antiviral Agents. Annu. Rep. Med. Chem. 1995, 30, 139-45.
7. (b) Thaisrivongs, S. HIV Protease Inhibitors. Annu. Rep. Med. Chem. 1994, 29, 133-44.
8. (a) Lam, P. Y. S.; Jadhav, P. K.; Eyerman, 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, 380-4.
9. (b) Lam, P. Y. S.; Ru, Y.; Jadhav, P. K.; Aldrich, P. E.; DeLucca, G. E.; Eyermann, C. J.; Chang, C.-H.; Emmett, 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.; Erickson-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, 3514-25.
10. Dax, S. L.; Cook, S. C. Cyclic urea HIV protease inhibitors containing alkynyl- and alkenyl-tethered heterocycles in the P2 region. Bioorg. Med. Chem. Lett. 1996, 6, 797-802.
11. Wilkerson, W. W.; Hollis, A. Y.; Cheatham, W. W.; Lam, G. N.; Erickson-Viitanen, S.; Bacheler, L. T.; Cordova, B. C.; Klabe, R. M.; Meek, J. L. A bis-[N-3(1-hydroxy-1-methylethyl)benzyl]cyclic urea as a HIV protease inhibitor. Bioorg. Med. Chem. Lett. 1995, 5, 3027-32.
12. (e) Jadhav, P. K.; Man, H.-W. Synthesis of 7-membered cyclic oxamides: novel HIV-1 protease inhibitors. Tetrahedron Lett. 1996, 37, 1153-6.
13. Hodge, C. N.; Aldrich, P. E.; Bacheler, L. T.; Chang, C.-H.; Eyerman, C. J.; 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. 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, 301-14.
14. 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 HIV-1 Protease Inhibitors. J. Med. Chem. 1996, 39, 2156-69.
15. Mitsunobu, O. The Use of Diethyl Azodicarboxylate and Triphenylphosphine in Synthesis and Transformation of Natural Products. Synthesis 1981, 1-28.
16. 2-Symmetric and Pseudosymmetric HIV-1 Protease Inhibitors from D-Mannitol and D-Arabitol. Bioorg. Med. Chem. Lett. 1991, 1, 219-22.
17. 2-Symmetric and Pseudosymmetric HIV-1 Protease Inhibitors from D-Mannitol and D-Arabitol. Bioorg. Med. Chem. Lett. 1991, 1, 219-22.
18. Ronald, R. C. A New Stereoselective Synthesis of (±)-Debromoaplysin and (±)-Aplysin. Tetrahedron Lett. 1976, 49, 4413-6. For an alternative synthesis, see: Bradsher, C. K.; Reames, D. C. Oxygen Heterocycles by the Parham Cyclialkylation. J. Org. Chem. 1981, 46, 1384-8.
19. Ronald, R. C. A New Stereoselective Synthesis of (±)-Debromoaplysin and (±)-Aplysin. Tetrahedron Lett. 1976, 49, 4413-6. For an alternative synthesis, see: Bradsher, C. K.; Reames, D. C. Oxygen Heterocycles by the Parham Cyclialkylation. J. Org. Chem. 1981, 46, 1384-8.
20. 2 Symmetric Bis-(phospholanes): Production of α-Amino Acid Derivatives via Highly Enantioselective Hydrogenation Reactions. J. Am. Chem. Soc. 1993, 115, 1001-5.
21. 2 Symmetric Bis-(phospholanes): Production of α-Amino Acid Derivatives via Highly Enantioselective Hydrogenation Reactions. J. Am. Chem. Soc. 1993, 115, 1001-5.
22. Tapia, R.; Torres, G.; Valderama, J. A. Nitric Acid on Silica Gel: A Useful Nitrating Reagent for Activated Aromatic Compounds. Synth. Commun. 1986, 16, 681-7.
23. Coudert, G.; Guillaumet, G.; Boubinoux, B. A New Synthesis of 3,4-Dihydro-2H-1,4-benzoxazines Using Solid-Liquid Phase-Transfer Catalysis. Synthesis 1979, 541-3.
24. This alkylating agent was prepared from commercially available 2-fluoro-5-methyl benzonitrile using N-bromosuccinimide. See: Moorthy, B. K. Organoinsecticide synergists. Part-I. Synthesis of substituted-benzyl-2-propynyl ethers and their synergistic activity. J. Indian Chem. Soc. 1990, 67 (11), 909-11.
25. α trace is 0.4 Å.
26. Condra, J. H.; Schleif, W. A.; Blahy, O. M.; Gabryelski, L. J.; Grahm, 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, 569-71.
27. 2 Symmetric Inhibitor Complexed to HIV-1 Protease. Science 1990, 249, 527-33.
28. Brünger, A. T.; Kuriyan, J.; Karplus, M. Crystallographic R Factor Refinement by Molecular Dynamics. Science 1987, 235, 458-60.
29. Erickson-Viitanen, S.; Klabe, R. M.; Cawood, P. G.; O'Neal, P. L.; Meek, J. L. Potency and Selectivity of Inhibition of the HIV Protease by a Small Nonpeptide Cyclic Urea, DMP 323. Antimicrob. Agents Chemother. 1994, 38, 1628-34.
30. 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 Evaluation of Antiviral Efficacy. Antiviral Chem. Chemother. 1994, 5 (2), 111-21.
31. 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. Agents Chemother. 1993, 37, 2606-11.