Aza-peptide analogs as potent human immunodeficiency virus type-1 protease inhibitors with oral bioavailability

Journal of Medicinal Chemistry

Volumn 39, Issue 16, 1996, Pages 3203-3216

  Fässler, Alexander ^a,b   Bold, Guido ^a   Capraro, Hans Georg ^a   Cozens, Robert ^a   Mestan, Jürgen ^a   Poncioni, Bernard ^a   Rösel, Johannes ^a   Tintelnot Blomley, Marina ^a   Lang, Marc ^a  

^a CIBA GEIGY LTD   (Switzerland)

^b Ciba Geigy PLC   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIVIRUS AGENT; PROTEINASE INHIBITOR;

ANIMAL EXPERIMENT; ANTIVIRAL ACTIVITY; ARTICLE; DOSE RESPONSE; DRUG BIOAVAILABILITY; DRUG CONFORMATION; DRUG FORMULATION; DRUG POTENCY; DRUG SYNTHESIS; FEMALE; HUMAN; HUMAN CELL; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; MOUSE; NONHUMAN; ORAL DRUG ADMINISTRATION; PROTEINASE INHIBITION; STEREOISOMERISM; STRUCTURE ACTIVITY RELATION;

ADMINISTRATION, ORAL; AMINO ACID SEQUENCE; AMINO ACIDS; ANIMALS; ANTIVIRAL AGENTS; BIOLOGICAL AVAILABILITY; CELLS, CULTURED; FEMALE; HIV PROTEASE; HIV PROTEASE INHIBITORS; HIV-1; HYDRAZINES; MAGNETIC RESONANCE SPECTROSCOPY; MICE; MICE, INBRED BALB C; MOLECULAR SEQUENCE DATA; MOLECULAR STRUCTURE; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 0029746483     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm960022p     Document Type: Article

References (65)

1. De Clercq, E. Toward Improved Anti-HIV Chemotherapy: Therapeutic Strategies for Intervention with HIV Infections. J. Med. Chem. 1995, 38, 2491-2517.
2. (a) Darke, P. L.; Huff, J. R. HIV Protease as an Inhibitor Target for the Treatment of AIDS. Adv. Pharmacol. 1994, 25, 399-454.
3. (b) Lang, M.; Rösel, J. HIV-1 Protease Inhibitors: Development, Status, and Potential Role in the Treatment of AIDS. Arch. Pharm. (Weinheim, Ger.) 1993, 326, 921-924.
4. (c) Martin, J. A. Recent advances in the design of HIV proteinase inhibitors. Antiviral Res. 1992, 17, 265-278.
5. (d) Debouck, C. The HIV-1 Protease as a Therapeutic Target for AIDS. AIDS Res. Human Retroviruses 1992, 8, 153-164.
6. (e) Huff J. R. HIV Protease: A Novel Chemotherapeutic Target for AIDS. J. Med. Chem. 1991, 34, 2305-2314.
7. (a) Boehme R. E.; Borthwick, A. D.; Wyatt, P. G. Antiviral Agents. In Annual Reports in Medicinal Chemistry; Bristol, J. A., Ed.; Academic Press: New York, 1995; Vol. 30, pp 139-144.
8. (b) Abdel-Meguid, S. S. Inhibitors of Aspartylproteinase. Med. Res. Rev. 1993, 13, 731-778.
9. (c) Meek, T. D. Inhibitors of HIV-1 Protease. J. Enzyme Inhib. 1992, 6, 65-98.
10. (a) Kay, J.; Dunn, B. M. Viral proteinases: weakness in strength. Biochim. Biophys. Acta 1990, 1048, 1-18.
11. (b) Navia, M. A.; Fitzgerald, P. M. D.; McKeever, B. M.; Leu, C.-T.; Heimbach, J. C.; Herber, W. K.; Sigal, I. S.; Darke, P. L.; Springer, J. P. Three-dimensional structure of aspartyl protease from human immunodeficiency virus HIV-1. Nature 1989, 337, 615-620.
12. (c) Wlodawer, A.; Miller, M.; Laskolski, M.; Sathyanarayana, B. K.; Baldwin, 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.
13. (a) Ahmad, S.; Ashfaq, A.; Alam, M.; Bisacchi, G. S.; Chen, P.; Cheng, P. T. W.; Greytok, J. A.; Hermsmeier, M. A.; Lin, P.-F.; Lis, K. A.; Merchant, Z.; Mitt, T.; Skoog, M.; Spergel, S. H.; Tino, J. A.; Vite, G. D.; Colonno, R. J.; Zahler, R.; Barrish, J. C. α-Hydroxyamide Derived Aminodiols as Potent Inhibitors of HIV Protease. Bioorg. Med. Chem. Lett. 1995, 5, 1729-1734.
14. (b) 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, J. N.; Chang, C.-H.; Weber, P. C.; Jackson, D. A.; Sharpe, T. R.; Erickson-Viitanen, S. Rational desing of potent, bioavailable, nonpeptide cyclic ureas as HIV protease inhibitors. Science 1994, 263, 380-384.
15. (c) Barrish, J. C.; Gordon, E.; Alam, M.; Lin, P.-F.; Bisacchi, G. S.; Chen, P.; Cheng, P. W. T.; Fritz, A. W.; Greytok, J. A.; Hermsmeier, M. A.; Humphreys, W. G.; Lis, K. A.; Marella, M. A.; Merchant, Z.; Mitt, T.; Morrison, R. A.; Obermeier, M. T.; Plusec, J.; Skoog, M.; Slusarchyk, W. A.; Spergel, S. H.; Stevenson, J. M.; Sun, C.-Q.; Sundeen, J. E.; Taunk, P.; Tino, J. A.; Warrack, B. M.; Colonne, R. J.; Zahler, R. Aminodiol HIV Protease Inhibitors. 1. Design, Synthesis, and Preliminary SAR. J. Med. Chem. 1994, 37, 1758-1768 and references cited therein.
16. (d) Babine, R. E.; Zhang, N.; Jurgens, A. R.; Schow, S. R.; Desai, P. R.; James, J. C.; Semmelhack, M. F. The Use of HIV-1 Protease Structure in Inhibitor Design. Bioorg. Med. Chem. Lett. 1992, 2, 541-546.
17. (e) 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.
18. 2 Symmetry. J. Am. Chem. Soc. 1991, 113, 9382-9384.
19. 2-Symmetric Diols. Bioorg. Med. Chem. 1995, 3, 559-571.
20. 2′ Ligands. Bioorg. Med. Chem. Lett. 1995, 5, 1707-1712.
21. 2-Symmetry. Bioorg. Med. Chem. Lett. 1994, 4, 2851-2856.
22. (d) Kempf, D. J.; Codacovi, L.; Wang, X. C.; Kohlbrenner, W. E.; Wideburg, N. E.; Saldivar, A.; Vasavanonda, S.; Marsh, K. C.; Bryant, P.; Sham, H. L.; Green, B. E.; Betebenner, D. A.; Erickson, J.; Norbeck, D. W. Symmetry-Based Inhibitors of HIV Protease. Structure-Activity Studies of Acylated 2,4-Diamino-1,5,diphenyl-3-hydroxypentane and 2,5-Diamino-1,6-diphenylhexane-2,4-diol. J. Med. Chem. 1993, 36, 320-330.
23. 2 Symmetric Inhibitors of the Human Immunodeficiency Virus Type 1 Protease. Antimicrob. Agents Chemother. 1991, 2209-2214.
24. 2-Symmetric Inhibitors of HIV-1 Proteinase: Structural and Modeling Studies. J. Med. Chem. 1993, 36, 3113-3119.
25. 2-Symmetric and Pseudosymmetric HIV-1 Protease Inhibitors from D-Mannitol and D-Arabitol. Bioorg. Med. Chem. Lett. 1991, 1, 219-222.
26. 2 Symmetric Inhibitors of HIV Protease. J. Med. Chem. 1990, 33, 2687-2689.
27. 2 Symmetric Inhibitor Complexed to HIV-1 Protease. Science 1990, 249, 527-533.
28. 2-Symmetric HIV-Protease Inhibitors with Sulfur-Containing Central Units. Tetrahedron Lett. 1993, 34, 1457-1460.
29. 2-Symmetric Phosphinate. Synthesis and Crystallographic Analysis. Biochemistry 1993, 32, 7972-7980.
30. 2-symmetrical Phosphinic Acid Amide. Bioorg. Med. Chem. Lett. 1994, 4, 1191-1194.
31. 2-symmetric Phosphinic Acid Inhibitors of HIV Protease. Tetrahedron Lett. 1992, 33, 4549-4552.
32. (a) Lecoq, A.; Marraud, M. Hydrazino and α-Amino peptides. Chemical and Structural Aspects. Tetrahedron Lett. 1991, 32, 2765-2768.
33. (b) Gante, J. Azapeptides. Synthesis 1989, 405-413.
34. (a) Fässler, A.; Bold, G.; Lang, M.; Schneider, P. EP-521827-A1, Pharmakologisch wirksame Hydrazinpräparate und Verfahren zu deren Herstellung; priority date, July 3, 1991; publication date, Jan. 7, 1993.
35. (b) Fässler, A.; Rösel, J.; Grütter, M.; Tintelnot-Blomley, M.; Alteri, E.; Bold, G.; Lang, M. Novel Pseudosymmetric Inhibitors of HIV-1 Protease. Bioorg. Med. Chem. Lett. 1993, 3, 2837-2842.
36. (c) Fässler, A.; Cozens, R.; Bold, G.; Capraro, H. G.; Mestan, J.; Rösel, J. Prodrug Esters of Pseudosymmetric HIV-1 Protease Inhibitors. Presented at the 210th ACS Meeting, Chicago, IL, 1995; Abstract Medi 28.
37. (d) Sham, H. L.; Betebenner, D. A.; Zhao, Ch.; Wideburg, N. E.; Saldivar, A.; Kempf, D. J.; Plattner, J. J.; Norbeck, D. W. Facile Synthesis of Potent HIV-1 Protease Inhibitors containing a Novel Pseudosymmetric Dipepide Isostere. J. Chem. Soc., Chem. Commun. 1993, 1052-1053.
38. (e) Sham, H. L; Zhao, Ch.; Marsh, K. C.; Betebenner, D. A; Lin, S.; McDonald, E.; Vasavanonda, S.; Wideburg, N.; Saldivar, A.; Robins, T.; Kempf, D. J.; Plattner, J. J.; Norbeck, D. W. Potent Inhibitors of the HIV-1 Protease with Good Oral Bioavailabilities. Biochem. Biophys. Res. Commun. 1995, 211, 159-165.
39. 2-symmetric ureas; see: Bold, G.; Bhagwat, S. S.; Fässler, A.; Lang, M. WO 95 02582, Cyclic hydrazine compounds; priority date, July 14, 1993; publication date, Jan. 26, 1995.
40. (g) Sham, H. L.; Zhao, C.; Stewart, K. D.; Betebenner, D. A.; Lin, S.; Park, C. H.; Kong, X.-P.; Rosenbrook, W., Jr.; Herrin, T.; Madigan, D.; Vasavanonda, S.; Lyons, N.; Molla, A.; Saldivar, A.; Marsh, K. C.; McDonald, E.; Wideburg, N. E.; Denissen, J. F.; Robins, T.; Kempf, D. J.; Plattner, J. J.; Norbeck, D. W. A Novel Picomolar Inhibitor of Human Immunodeficiency Virus Type 1 Protease. J. Med. Chem. 1996, 39, 392-397.
41. Priestle, J. P.; Fässler, A.; Rösel, J.; Tintelnot-Blomley, M.; Strop, P.; Grütter, M. Comparative Analysis of the X-ray Structures of HIV-1 and HIV-2 Proteases in Complex with CGP 53820, a Novel Pseudosymmetric Inhibitor. Structure 1995, 3, 381-389.
42. Dutta, A. S.; Morley, J. S. Preparation of α-Aza-amino-acid Derivatives and Intermediates for the Preparation of α-Aza-peptides. J. Chem. Soc., Perkin Trans. I 1975, 1712-1720.
43. Rutjes, F. P. J. T.; Teerhuis, N. M.; Hiemstra, H.; Speckamp, W. N. Synthesis of Cyclic α-Hydrazino Acid Derivatives via N-Acylhydrazonium Ions. Tetrahedron 1993, 49, 8605-8628.
44. 1′ Phenyl Substituents: X-ray Crystal Structure Assisted Design. J. Med. Chem. 1992, 35, 1685-1701.
45. (b) Thompson, W. J.; Vacca, J. P.; Huff, J. R.; Lyle, T. A.; Young, S. D.; Hungate, R. W.; Britcher, S. F.; Ghosh, A. K. HIV protease inhibitors useful for the treatment of AIDS. EP 434365 A2, Dec. 18, 1990.
46. (c) Luly, J. R.; Dellaria, J. F.; Plattner, J. J.; Soderquist, J. L.; Yi, N. A Synthesis of Protected Aminoalkyl Epoxids from α-Amino Acids. J. Org. Chem. 1987, 52, 1487-1492.
47. 1H-NMR spectroscopic method described by DeCamp, A. E.; Kawaguchi, A. T.; Volante, R. P.; Shinkai, I. Stereocontrolled Addition of Propionate Homoenolate Equivalents to Chiral α-Amino Aldehydes. Tetrahedron Lett. 1991, 32, 1867-1870.
48. All four possible stereoisomers of the Boc-protected epoxide could be separated on a chiral analytical HPLC column: stationary phase, Chiralcel OD; mobile phase, 98:2 hexane:2-propanol, detection at 210 nm; retention times in min, 2S3R-isomer 12.2, 2R3S-isomer 13.7, 2R3R-isomer 15.5, 2S3S-isomer 16.6. The reference compounds with 2R3S- and 2R3R-configurations were synthesized using commercially available D-phenylalaninol.
49. According to analytical HPLC analysis, both the threo and erythro isomers of trifluoroacetyl epoxide 15 were enantiomerically >98% pure: stationary phase, Chiralpak AD; mobile phase, 99:1 hexane:2-propanol, detection at 215 nm; retention times in min, 2R3S-isomer 22.1, 2S3R-isomer 24.4,2S3S-isomer 28.8, 2R3R-isomer 33.5.
50. 2 residue is a constituent of Ro 31-8959 as reported by Roberts, N. A.; Martin, J. A.; Kinchington, D.; Broadhurst, A. V.; Craig, J. C.; Duncan, I. B.; Galpin, S. A.; Handa, B. K.; Kay, J.; Kröhn, A.; Lambert, R. W.; Merrett, J. H.; Mills, J. S.; Parkes, K. E. B.; Redshaw, S.; Ritchie, A. J.; Taylor, D. L.; Thomas, G. J.; Machin, P. J. Rational Design of Peptide-Based HIV Proteinase Inhibitors. Science 1990, 248, 358-361.
51. Hydroxyethylamine-derived inhibitors like Ro 31-8959 show a marked preference for the R-stereochemistry at the hydroxyl group, whereas longer inhibitors with proline in P1′ position and extended C-terminus prefer the S-configuration for binding to the enzyme. Krohn, A.; Redshaw, S.; Ritchie, J. C.; Graves, B. J.; Hatada, M. H. Novel Binding Mode of Highly Potent HIV-Proteinase Inhibitors Incorporating the (R)-Hydroxyethylamine Isostere. J. Med. Chem. 1991, 34, 3340-3342.
52. (a) Getman, D. P.; DeCrescenzo, G. A.; Heintz, R. M.; Reed, K. L.; Talley, J. J.; Bryant, M. L.; Clare, M.; Houseman, K. A.; Marr, J. J.; Mueller, R. A.; Vazquez, M. L.; Shieh, H.-S.; Stallings, W. C.; Stegeman, R. A. Discovery of a Novel Class of Potent HIV-1 Protease Inhibitors Containing the (R)-(Hydroxyethyl)urea Isostere. J. Med. Chem. 1993, 36, 288-291.
53. (b) Vazquez, M. L.; Bryant, M. L.; Clare, M.; DeCrescenzo, G. A.; Doherty, E. M.; Freskos, J. N.; Getman, D. P.; Houseman, K. A.; Julien, J. A.; Kocan, G. P.; Mueller, R. A.; Shieh, H.-S.; Stallings, W. C.; Stegeman, R. A.; Talley, J. J. Inhibitors of HIV-1 Protease containing the Novel and Potent (R)-(Hydroxyethyl)sulfonamide Isostere. J. Med. Chem. 1995, 38, 581-584.
54. Alteri, E.; Bold, G.; Cozens, R.; Fässer, A.; Klimkait, T.; Lang, M.; Lazdins, J.; Poncioni, B.; Rosel, J. L.; Schneider, P.; Walker, M.; Woods-Cook, K. CGP 53437, an Orally Bioavailable Inhibitor of Human Immunodeficiency Virus Typ 1 Protease with Potential Antiviral Activity. Antimicrob. Agents Chemother. 1993, 37, 2087-2092.
55. 50 with increasing log P.
56. Simultaneous replacement of the two N-acetyl-L-valinyl substituents with two H-L-valinyl substituants removes two hydrogen bonds of the carbonyl groups to the amide nitrogens of Asp29 and Asp29′ of the enzyme. In a related series of aza-peptide analogs, this replacement resulted in a 3000-fold decrease in inhibitory potency as described in ref 11a.
57. The favorable oral bioavailability of cyclosporin, which contains several N-methylated and intramolecularly hydrogen-bonded amide moieties, supports the postulate that secondary amides principally hamper the oral bioavailability of peptidic compounds. Furthermore, transport into the cell is suggested to correlate inversely with the ability of a compound to form hydrogen bonds with water; see: Smith, A. B., III; Hirschmann, R.; Pasternak, A.; Akaishi, R.; Guzman, M. C.; Jones, D.; Keenan, T. P.; Sprengeler, P.; Darke, P. L.; Emini, E. A.; Holloway, M. K.; Schleif, W. A. Design and Synthesis of Peptidomimetic Inhibitors of HIV-1 Protease and Renin. Evidence for Improved Transport. J. Med. Chem. 1994, 37, 215-218 and references cited therein.
58. Several protease inhibitors containing the Quin-Asn moiety besides Ro 31-8959 have been described; see: (a) SC 52151, ref 21a. (b) LY 289612, Kaldor, S. W.; Hammond, M.; Dressman, B. A.; Fritz, J. E.; Crowell, T. A.; Hermann, R. A. Newdipeptide isosteres useful for the inhibition of HIV-1 protease. Bioorg. Med. Chem. Lett. 1994, 4, 1385-1390. (c) Girijavallabhan, V. M.; Bennett, F.; Patel, N. M.; Ganguly, A. K.; Basmahapatra, B.; Butkiewicz, N.; Hart, A. The synthesis of novel HIV-protease inhibitors. Bioorg. Med. Chem. 1994, 2, 1075-1083. (d) Haebisch, D. D.; Roebe, W. D.; Hansen, J. D.; Paessens, A. D. Trifluoromethyl containing pseudopeptides. EP 0528242 A, Feb. 24, 1993. (e) Tucker, T. J.; Lumma, W. C.; Payne, L. S.; Wai, J. M.; de Solms, S. J.; Giuliani, E. A.; Darke, P. L.; Heimbach, J. C.; Zugay, J. A.; Schleif, W. A.; Quintero, J. C.; Emini, E. A.; Huff, J. R.; Anderson, P. S. A Series of Potent HIV-1 Protease Inhibitors Containing a Hydroxyethyl Secondary Amine Transition State Isostere: Synthesis, Enzyme Inhibition, and Antiviral Activity. J. Med. Chem. 1992, 35, 2525-2533.
59. Several protease inhibitors containing the Quin-Asn moiety besides Ro 31-8959 have been described; see: (a) SC 52151, ref 21a. (b) LY 289612, Kaldor, S. W.; Hammond, M.; Dressman, B. A.; Fritz, J. E.; Crowell, T. A.; Hermann, R. A. Newdipeptide isosteres useful for the inhibition of HIV-1 protease. Bioorg. Med. Chem. Lett. 1994, 4, 1385-1390. (c) Girijavallabhan, V. M.; Bennett, F.; Patel, N. M.; Ganguly, A. K.; Basmahapatra, B.; Butkiewicz, N.; Hart, A. The synthesis of novel HIV-protease inhibitors. Bioorg. Med. Chem. 1994, 2, 1075-1083. (d) Haebisch, D. D.; Roebe, W. D.; Hansen, J. D.; Paessens, A. D. Trifluoromethyl containing pseudopeptides. EP 0528242 A, Feb. 24, 1993. (e) Tucker, T. J.; Lumma, W. C.; Payne, L. S.; Wai, J. M.; de Solms, S. J.; Giuliani, E. A.; Darke, P. L.; Heimbach, J. C.; Zugay, J. A.; Schleif, W. A.; Quintero, J. C.; Emini, E. A.; Huff, J. R.; Anderson, P. S. A Series of Potent HIV-1 Protease Inhibitors Containing a Hydroxyethyl Secondary Amine Transition State Isostere: Synthesis, Enzyme Inhibition, and Antiviral Activity. J. Med. Chem. 1992, 35, 2525-2533.
60. Several protease inhibitors containing the Quin-Asn moiety besides Ro 31-8959 have been described; see: (a) SC 52151, ref 21a. (b) LY 289612, Kaldor, S. W.; Hammond, M.; Dressman, B. A.; Fritz, J. E.; Crowell, T. A.; Hermann, R. A. Newdipeptide isosteres useful for the inhibition of HIV-1 protease. Bioorg. Med. Chem. Lett. 1994, 4, 1385-1390. (c) Girijavallabhan, V. M.; Bennett, F.; Patel, N. M.; Ganguly, A. K.; Basmahapatra, B.; Butkiewicz, N.; Hart, A. The synthesis of novel HIV-protease inhibitors. Bioorg. Med. Chem. 1994, 2, 1075-1083. (d) Haebisch, D. D.; Roebe, W. D.; Hansen, J. D.; Paessens, A. D. Trifluoromethyl containing pseudopeptides. EP 0528242 A, Feb. 24, 1993. (e) Tucker, T. J.; Lumma, W. C.; Payne, L. S.; Wai, J. M.; de Solms, S. J.; Giuliani, E. A.; Darke, P. L.; Heimbach, J. C.; Zugay, J. A.; Schleif, W. A.; Quintero, J. C.; Emini, E. A.; Huff, J. R.; Anderson, P. S. A Series of Potent HIV-1 Protease Inhibitors Containing a Hydroxyethyl Secondary Amine Transition State Isostere: Synthesis, Enzyme Inhibition, and Antiviral Activity. J. Med. Chem. 1992, 35, 2525-2533.
61. Several protease inhibitors containing the Quin-Asn moiety besides Ro 31-8959 have been described; see: (a) SC 52151, ref 21a. (b) LY 289612, Kaldor, S. W.; Hammond, M.; Dressman, B. A.; Fritz, J. E.; Crowell, T. A.; Hermann, R. A. Newdipeptide isosteres useful for the inhibition of HIV-1 protease. Bioorg. Med. Chem. Lett. 1994, 4, 1385-1390. (c) Girijavallabhan, V. M.; Bennett, F.; Patel, N. M.; Ganguly, A. K.; Basmahapatra, B.; Butkiewicz, N.; Hart, A. The synthesis of novel HIV-protease inhibitors. Bioorg. Med. Chem. 1994, 2, 1075-1083. (d) Haebisch, D. D.; Roebe, W. D.; Hansen, J. D.; Paessens, A. D. Trifluoromethyl containing pseudopeptides. EP 0528242 A, Feb. 24, 1993. (e) Tucker, T. J.; Lumma, W. C.; Payne, L. S.; Wai, J. M.; de Solms, S. J.; Giuliani, E. A.; Darke, P. L.; Heimbach, J. C.; Zugay, J. A.; Schleif, W. A.; Quintero, J. C.; Emini, E. A.; Huff, J. R.; Anderson, P. S. A Series of Potent HIV-1 Protease Inhibitors Containing a Hydroxyethyl Secondary Amine Transition State Isostere: Synthesis, Enzyme Inhibition, and Antiviral Activity. J. Med. Chem. 1992, 35, 2525-2533.
62. Several protease inhibitors containing the Quin-Asn moiety besides Ro 31-8959 have been described; see: (a) SC 52151, ref 21a. (b) LY 289612, Kaldor, S. W.; Hammond, M.; Dressman, B. A.; Fritz, J. E.; Crowell, T. A.; Hermann, R. A. Newdipeptide isosteres useful for the inhibition of HIV-1 protease. Bioorg. Med. Chem. Lett. 1994, 4, 1385-1390. (c) Girijavallabhan, V. M.; Bennett, F.; Patel, N. M.; Ganguly, A. K.; Basmahapatra, B.; Butkiewicz, N.; Hart, A. The synthesis of novel HIV-protease inhibitors. Bioorg. Med. Chem. 1994, 2, 1075-1083. (d) Haebisch, D. D.; Roebe, W. D.; Hansen, J. D.; Paessens, A. D. Trifluoromethyl containing pseudopeptides. EP 0528242 A, Feb. 24, 1993. (e) Tucker, T. J.; Lumma, W. C.; Payne, L. S.; Wai, J. M.; de Solms, S. J.; Giuliani, E. A.; Darke, P. L.; Heimbach, J. C.; Zugay, J. A.; Schleif, W. A.; Quintero, J. C.; Emini, E. A.; Huff, J. R.; Anderson, P. S. A Series of Potent HIV-1 Protease Inhibitors Containing a Hydroxyethyl Secondary Amine Transition State Isostere: Synthesis, Enzyme Inhibition, and Antiviral Activity. J. Med. Chem. 1992, 35, 2525-2533.
63. Martin, J. A.; Redshaw, S. Preparation of N-(asparaginyl-amino-hydroxyphenylbutyl)-decahydroisoquinoline-3-carboxamides as HIV protease inhibitors. EP 432695 A2, June 19, 1991.
64. Billich, S.; Knoop, M.-T.; Hansen, J.; Strop, P.; Sedlacek, J.; Mertz, R.; Moelling, K. Synthetic Peptides as Substrates and Inhibitors of Human Immune Deficiency Virus-1 Protease. J. Biol. Chem. 1988, 263, 17905-17908.
65. Richards, A.; Phylip, L. H.; Farmerie, W. G.; Scarborough, P. E.; Alvarez, A.; Dunn, B. M.; Hirel, P. H.; Konvalinka, J.; Strop, P.; Pavlickova, L.; Kostka, V.; Kay, J. Sensitive, Soluble Chromogenic Substrates for HIV-1 Proteinase. J. Biol. Chem. 1990, 265, 7733-7736.