Nonpeptidic potent HIV-1 protease inhibitors

Drug Design and Discovery

Volumn 13, Issue 3-4, 1996, Pages 15-28

  Vara Prasad, J V N ^a   Lunney, Elizabeth A ^a   Para, Kimberly S ^a   Tummino, Peter J ^a   Ferguson, Donna ^a   Hupe, Donald ^a   Domagala, John M ^a   Erickson, John W ^b  

^a PFIZER INC   (United States)

^b SAIC FREDERICK INC   (United States)

Author keywords

HIV protease inhibitors; Peptidomimetics; Pyran 2 ones; Structure based design; X ray crystal structures of protease inhibitors

Indexed keywords

2 PYRONE DERIVATIVE; PROTEINASE INHIBITOR;

CHIRALITY; CONFERENCE PAPER; DRUG BINDING; DRUG POTENCY; DRUG STRUCTURE; HUMAN IMMUNODEFICIENCY VIRUS 1; X RAY CRYSTALLOGRAPHY;

CACO-2 CELLS; CELL MEMBRANE PERMEABILITY; CRYSTALLOGRAPHY, X-RAY; DRUG DESIGN; DRUG EVALUATION, PRECLINICAL; HIV PROTEASE INHIBITORS; HUMANS; MODELS, MOLECULAR; MOLECULAR STRUCTURE; PROTEIN BINDING; PYRANS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 0342854936     PISSN: 10559612     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Conference Paper

References (44)

1. Gallo, R.C., Salahuddin, S.Z., Popovic, M., Shearer, G.M., Kaplan, M., Haynes, B.F., Palker, T.J., Redfield, R., Oleske, G., Safai, B., White, G., Foster, P. and Markham, P.D. (1984) Frequent detection and isolation of cytopathic retrovimses (HTLV-III) from patients with AIDS, Science, 224, 500-503 and references therein.
2. Mitsuya, H., Yarchoan, R. and Broder, S. (1990) Molecular Targets for AIDS Therapy, Science, 249, 1533-1544.
3. Romero, D.L. Chapter 13. (1994) Advances in the development of HIV Reverse Transcriptase Inhibitors, Annu. Rep. Med. Ckem., 29, 123-132.
4. Dyda, F., Hickman, A.B., Jenkins, T.M., Engelman, A., Craigie, R. and Davies, D.R. (1994) Crystal structure of the Catalytic Domian of HIV-1 Integrase: Similarlity to Other Polynucleotidyl Transferases, Science, 266, 1981-1986.
5. Darke, P.L., Nutt, R.F., Brady. S.F., Garsky, V.M., Ciccarone, T.M., Liu, C-T, Lumma, P.K., Freidinger, R.M., Veber, D.F. and Sigal, I.S. (1988) HIV-1 Protease Specificity of Peptide Cleavage is Sufficient for Processing of GAG and POL Polyproteins, Biochem. Biophys. Res Commun., 156, 297-303.
6. Kohl, N.E., Emini, E.A., Schlief, W.A., Heimbach. J.C., Dixon, R.A., Scolnik, E.M. and Sigal, I.S. (1988) Active Human Immunodeficiency Virus is Required for Viral Infectivity, Proc. Nail. Acad. Sci., USA, 85, 4686-4690.
7. McQuade, T.J., Tomasselli, A.G., Liu, L., Karacostas, V., Moss, B., Sawyer, T.K., Heinrinkson, R.L., Tarpley, W.G.A (1990) Synthetic HIV-1 Protease Inhibitor with Antiviral Activity HIV-like Particle Maturation, Science. 247, 454-456.
8. Seelmeier, S., Schmidt, H., Turk, V. and von der Helm, K. (1988) Human Immunodeficicency Virus Has an Aspartic-type Protease that can be Inhibited by Pepstatin-A, Proc. Natl. Acad. Sci., USA, 85, 6612-6616.
9. For nomenclature of the enzyme binding pockets refer: Schechter, I. and Berger, A. (1967) On the Size of the Active Site in Protease. I. Papain, Biochem. Biophys. Res. Commun., 27, 157-162.
10. Thaisrivongs, S. (1994) Chapter 14. HIV Protease Inhibitors, Annu. Rep. Med. Chem., 29, 133-144 and references therein.
11. Kempf, D.J. (1994) Design of Symmetry-Based Peptidomimetic Inhibitors of Human Immunodeficiency Virus Protease, Methods of Enzymology, 241, 334-354, New York: Academic Press.
12. (a) Friedman, S.H., DeCamp, D.L., Sijbesma, R.P., Srdanov, G., Wudl, F. and Kenyon, G.L. (1993) Inhibition of the HIV-1 Protease by Fullerene Derivatives: Model Building Studies and Experimental Verification, J. Amer. Chem. Soc., 115, 6506-6509 and references therein,
13. (b) DeCamp, D.L., Babe, L.M., Salto, R., Lucich, J.L., Koo, M-S., Kahl. S.B. and Craik, C.S. (1992) Specific Inhibition of HIV-1 Protease by Boronated Porphyrins, J. Med. Chem., 35, 3426-3428.
14. (c) Brinkworth, R.I., Stoermer, M.J. and Fairlie, D.P. (1992) Flavones Are Inhibitors of HIV-1 Proteinase, Biochem. Biophys. Res. Commun., 188, 631-637 and references therein,
15. (d) Humber, D.C., Bamford, M.J., Bethell, R.C., Cammack, N., Orr, D.C., Storer, R., Weingarten, G.G. and Wyatt, P.G. (1994) Synthesis and Structure Activity Relationships of a series of Pencillin-derived Pseudosymmetric Inhibitors of HIV-1 Proteinase, Antiviral Chemistry & Chemotherapy, 5, 197-200 and references therein,
16. (e) Pans, A., Strukelj, B., Renko, M., Turk, V., Pukl, M., Umerk, A. and Korant, B.D. (1993) Inhibitory Effect of Carnosolic Acid on HIV-1 Protease In Cell-Free Assays, J. Natural Products, 56, 1426-1430 and references therein.
17. (a) Fitzgerald, P.M.D. (1993) HIV Protease-ligand Complexes, Curr. Opin. Struct. Biol., 3, 868-874.
18. (b) Wlodawer, A., Erickson. J.W. (1993) Structure-Based Inhibitors of HIV-1 Protease, Annu. Rev. Biochem., 62, 543-585.
19. Condra, J.H., Schleif, W.A., Blahy, O.M., Gabryelski, L.J., Graham, DJ., Quintero, J.C., Rhodes, A., Robbins, H.L., Roth, E., Shivaprakash, M., Titus, D., Yang, T., Teppler, H., Squires, K.E., Deutsch, P.J. and Emini, E.A. (1995) In vivo emegence of HIV-1 Variants Resistant to Multiple Protease Inhibitors, Nature, 374, 569-571 and references therein.
20. Sarin, P.S., Goldstern, A., Agrawal, S. and Zamecnik, P. (1992) Use of Drugs Targeted to Inhibit Different Stages of the HIV Life Cycle in the Treatement of AIDS Combination Therapies, edited by Goldstein, A.L. and Garaci, E., pp. 123-129. New York: Plenum Press.
21. Tummino, P.J., Ferguson, D., Hupe, L. and Hupe, D. (1994) Competitive Inhibition of HIV-1 Protease by 4-Hydroxy-2H-pyran-2-ones, Biochem. Biophys. Res Commun., 200, 1658-1664.
22. Vara Prasad, J.V.N., Para, K.S., Lunney, E.A., Ortwine, D.F., Dunbar, Jr., J.B., Ferguson, D., Tummino, P.J., Hupe, D., Tait, B.D., Domagala, J.M., Humblet, C., Bhat, T.N., Liu, B., Guerin, D.M.A., Baldwin, E.T., Erickson, J.W. and Sawyer, T.K. (1994) Novel Series of Achiral, Low Molecular Weight, and Potent HIV-1 Protease Inhibitors, J. Am. Chem. Soc., 116, 6989-6990.
23. (a) Luly, J.R., Yi, N., Soderquist, J., Stein, H., Cohen, J., Perun, T.J. and Plattner, J.J. (1987) New Inhibitors of Human Renin That Contain Novel Leu-Val Replacements, J. Med. Chem., 30, 1609-1616.
24. (b) Vara Prasad, J.V.N., Houseman, K., Mueller, R. and Rich, D.H. (1993) Synthesis of Hydroxyethyl Sulfide Peptides For HIV Protease Inhibition. Structure-Activity Relationships of Inhibitors. Peptides Chemistry, Structure and Biology, Proceedings of 22nd EPS, edited by Schneider, C.H. and Eberle, A.N., pp. 629-630, Lieden, the Netherlands : Escom Science Publishers B.V.
25. Ortwine, D.F., Lunney, E.A., Dunbar, Jr., J.B., Bhat, T.N., Liu, B., Guerin, D.M.A., Baldwin, E.T. and Erickson, J.W. (1994) Molecular Modelling of HIV Protease Inhibitors: A Comparison of Docking Approaches. Poster given at the 10th European Symposium on Structure-Activity Relationships: QSAR and Molecular Modeling, Barcelona, Spain, September, 4-9.
26. Griffiths, J.T., Phylip, L.H., Konvalinka, J., Strop, P., Gutchina, A., Wlodawer, A., Davenport, R.J., Briggs, R., Dunn, B.M. and Kay, J. (1992) Different Requirements for Productive Interaction Between the Active Site of HIV-1 Proteinase and Substrates Containing Hydrophobic * Hydrophobic or Aromatic *Pro Clevage Sites, Biochemistry, 31, 5193.
27. Erickson, J.W. et al. (Unpublished results).
28. Molecular modeling studies were performed using SYBYL version 6.0 commercially available from Tripos Associates, Inc., 1699 Hanley Road, Suite 303, St. Louis, Missouri 63 144.
29. 2′ Subsites in a Unique Mode of Active Site Binding, J. Med. Chem., 38, 898-905.
30. Thaisrivongs, S., Tomich, P.K., Watenpaugh, K.D., Chong, K-T., W.J., Howe, W.J., Yang, C-P, Strohbach, J.W., Turner, S.R., McGrath, J.P., Bohanon, M.J., Lynn, J.C., Mulichak, A.M., Pagano, P.J., Moon, J.B., Ruwart, M.J., Wilkinson, K.F., Rush, B.D., Zipp, G.L., Dalga, R.J., Schwende, F.J., Howard, G.M., Padbury, G.E., Toth, L.N., Zhao, Z., Koeplinger, K.A., Kakuk, T.J., Cole, S.L., Zaya, R.M., Piper, R.C. and Jeffrey, P. (1994) Structure-Based Design of HIV Protease Inhibitors: 4-Hydroxycoumarins and 4-Hydroxy-2-pyrones as Non-peptidic Inhibitors, J. Med. Chem., 37, 3200-3204.
31. Kaldor, S.W., Hammond, M., Dressman, B.A., Fritz, I.E., Crowell, T.A. and Hermann, R.A. (1994) New Dipeptide Isosteres Useful for the Inhibition of HIV-1 Protease, Bioorg. Med. Chem. Lett., 4, 1385-1390.
32. 2 ′ligand with Unique Pattern of In vitro Resistance. Importance of Conformationally-restricted Tempate in the Design of Enzyme Inhibitors, J Am. Chem. Soc., 117, 11070-11074.
33. 1′ Phenyl Substitutents: X-ray Crystal Structure Assisted Design, J. Med. Chem., 35, 1685-1701.
34. Rich, D.H., Vara Prasad, J.V.N., Sun, C.Q., Green, J., Mueller, R.D., Mckenzie, D. and Malkovsky, M. (1992) New Hydroxyethylamine HIV Protease Inhibitors That Suppress Viral Replication, J. Med. Chem., 35, 3803-3812.
35. (a) While our work is in progress the following publication appeared, which contains enol moiety as transition state analogue: Vaillancourt, M., Vanasse, B., Cohen, E. and Sauve, G. (1993) Difunctional Enols of N-Protected Amino Acids as Low Molecular Weight and Novel Inhibitors of HIV-1 Protease, Bioorg. Med. Chem. Lett., 3, 1169-1174.
36. (b) Vaillancourt, M., Vanasse, B., Berre, N.L., Cohen, E. and Sauve, G. (1994) Synthesis of Novel Inhibitors of the HIV-1 Protease: Difunctional Enols of Simple N-Protected Amino Acids, Bioorg. Med. Chem. Leu., 5, 343-355.
37. Rich, D.H., Sun, C.-Q., Vara Prasad, J.V.N., Pathiasseril, A., Toth, M.V., Marshall, G.R., Clare, M., Mueller, R.A. and Houseman, K. (1991) Effect of Hydroxyl Group in Hydroxyethylamine Isosteres on HIV Protease Inhibition. Evidence for Multiple Binding Modes, J. Med. Chem., 34, 1222-1225.
38. Hosur, M.V., Bhat, T.N., Kempf, D.J., Baldwin, E.T., Liu, B., Gulnik, S., Wideburg, N.E., Norbeck, D.W., Appelt, K. and Erickson, J.W. (1994) Influence of Stereochemistry on Activity and Binding Modes for C2 Symmetry-Based Diol Inhibitors of HIV-1 Protease, J. Am. Chem. Soc., 116, 847-855.
39. 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. and Sharpe, T.R., Erickson-Viitanen, S. (1994) Rational Design of Potent, Bioavailable, Nonpeptide Cyclic Ureas as HIV Protease Inhibitors, Science, 283, 380-384.
40. Olson, G.L., Bolin, D.R., Bonner, M.P., Bos, M., Cook, C.M., Fry, D.C., Graves, B.J., Hatada, M., Hill, D.E., Kahn, M., Madison V.S., Rusiecki, V.K., Sarabu, R., Sepinwall, J., Vincent, G.P. and Voss, M.E. (1993) Concepts and Progress in the Development of Peptide Mimetics, J. Med. Chem., 36, 3039-3049.
41. Para, K.S., Ellsworth, E.L. and Vara Prasad, J.V.N (1994) A Simple Procedure for the Synthesis of 3-(Substituted-sulfanyl)-4-hydroxy-6-substituted-pyran-2-ones, J. Heterocyclic Chem., 31, 1619-1624.
42. Harris, R.F., Dunbar, J.E. U.S. Patent No. 3,931.235. Chem. Abstr., (1976) 84, 150505s.
43. Stewart, B.H., Chan, O.H., Lu, R.H., Reyner, E.L., Schmid, H.L., Hamilton, H.W., Steinbaugh, B.A. and Taylor, M.D. (1995) Comparison of Intestinal Permeabilities Determined in Multiple in Vitro and in situ Models: Relationship to Absorption in Humans, Pharmaceutical Research, 12, 693-699.
44. Tummino, P.J., Ferguson, D. (Unpublished results).