Phenethylthiazolylthiourea (PETT) compounds as a new class of HIV-1 reverse transcriptase inhibitors. 2. Synthesis and further structure-activity relationship studies of PETT analogs

Journal of Medicinal Chemistry

Volumn 39, Issue 21, 1996, Pages 4261-4274

  Cantrell, Amanda S ^a   Engelhardt, Per ^b   Högberg, Marita ^b   Jaskunas, S Richard ^a   Johansson, Nils Gunnar ^b   Jordan, Christopher L ^a   Kangasmetsä, Jussi ^b   Kinnick, Michael D ^a   Lind, Peter ^b   Morin Jr , John M ^a   Muesing, M A ^a   Noreén, Rolf ^b   Öberg, Bo ^b,c   Pranc, Paul ^a   Sahlberg, Christer ^b   Ternansky, Robert J ^a   Vasileff, Robert T ^a   Vrang, Lotta ^b   West, Sarah J ^a   Zhang, Hong ^b  

^a ELI LILLY AND COMPANY   (United States)

^b MEDIVIR AB   (Sweden)

^c KAROLINSKA INSTITUTE   (Sweden)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIVIRUS AGENT; RNA DIRECTED DNA POLYMERASE INHIBITOR; THIOUREA DERIVATIVE; TROVIRDINE;

ANTIVIRAL ACTIVITY; ARTICLE; DRUG EFFECT; DRUG SCREENING; DRUG SYNTHESIS; HUMAN IMMUNODEFICIENCY VIRUS 1; NONHUMAN; STRUCTURE ACTIVITY RELATION;

ANIMALS; ANTI-HIV AGENTS; CELLS, CULTURED; HIV-1 REVERSE TRANSCRIPTASE; INTERCALATING AGENTS; STRUCTURE-ACTIVITY RELATIONSHIP; THIAZOLES; THIOUREA;

EID: 10244222420     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm950639r     Document Type: Article

References (27)

1. Sandström, E.; Öberg B. Antiviral Therapy in Human Immunodeficiency Virus Infections: Part 1. Drugs 1993, 45 (4), 488-508.
2. Accelerated Approval Recommended for D4T Treatment of HIV-Infection. Antiviral Agents Bull. 1994, 7 (6), 161.
3. Staduvine approved in the US. Scrip 1994, 1937, 23.
4. (a) Grob, P. M.; Wu, J. C.; Cohen, K. A.; Ingraham, R. H.; Shih, C. K.; Hargrave, K. D.; Mctague, T. L.; Merluzzi, V. J. Nonnucleoside inhibitors of HIV-1 reverse transcriptase: nevirapine as a prototype drug. AIDS Res. Hum. Retroviruses 1992, 8 (2), 145-52.
5. (b) Hargrave, K. D.; Proudfood, J. R.; Grozinger, K. G.;Cullen, E.; Kapadia, S. R.; Patel, U. R.; Fuchs, V. U.; Mauldin, S. C.; Vitous, J.; Behnke, M. L.; Klunder, J. M.; Pal, K.; Skiles, J. W.; McNeil, D. W.; Rose, J. M.; Chow, G. C.; Skoog, M. T.; Wu, J. C.; Schmidt, G.; Engel, W. W.; Eberlein, W. G.; Saboe, T. D.; Campbell, S. J.; Rosenthal, A. S.; Adams, J. Novel Non-Nucleoside Inhibitors of HIV-1 Reverse Transcriptase. 1. Tricyclic Pyridobenzo- and Dipyrido-diazepinones. J. Med. Chem. 1991, 34, 2231-2241.
6. (a) Goldman, M. E.; O'Brien, J. A.; Ruffing, T. L.; Schleif, W. A.; Sardana, V. V.; Byrnes, V. W.; Condra, J. H.; Hoffman, J. M.; Emini, E. A. A Nonnucleoside Reverse Transcriptase Inhibitor Active on Human Immunodeficiency Virus Type 1 Isolates Resistant to Related Inhibitors. Antimicrob. Agents Chemother. 1993, 37 (5), 947-949.
7. (b) Hoffman, J. M.; Wai, J. S.; Thomas, C. M.; Levin, R. B.; O'Brien, J. A.; Goldman, M E. Synthesis and evaluation of 2-pyridinone derivatives as HIV-1-specific reverse transcriptase inhibitors. 1. Phthalimidoalkyl and -alkylamino analogs. J. Med. Chem. 1992, 35, 3784-91.
8. (c) Saari, W. S.; Wai, J. S.; Fisher, T. E.; Thomas, C. M.; Hoffman, J. M.; Rooney, C. S.; Smith, A. M.; Jones, J. H.; Bamberger, D. L.; et al. Synthesis and evaluation of 2-pyridinone derivatives as HIV-1-specific reverse transcriptase inhibitors. 2. Analogs of 3-aminopyridin-2(1H)-one. J. Med. Chem. 1992, 35, 3792-3802.
9. (d) Wai, J. S.; Williams, T. M.; Bamberger, D. L.; Fisher, T. E.; Hoffman, J. M.; Hudcosky, R. J.; MacTough, S. C.; Rooney, C. S.; Saari, W. S.; et al. Synthesis and evaluation of 2-pyridinone derivatives as HIV-1-specific reverse transcriptase inhibitors. 3. Pyridyl and phenyl analogs of 3-aminopyridin-2(1H)-one. J. Med. Chem. 1993, 36, 249-255.
10. (e) Hoffman, J. M.; Smith, A. M.; Rooney, C. S.; Fisher, T. E.; Wai, J. S.; Thomas, C. M.; Bamberger, D. L.; Barnes, J. L.; Williams, T. M.; et al. Synthesis and evaluation of 2-pyridinone derivatives as HIV-1-specific reverse transcriptase inhibitors. 4. 3-[2-(Benzoxazol-2-yl)ethyl]-5-ethyl-6-methylpyridin-2(1H)-one and analogs. J. Med. Chem. 1993, 36, 953-966.
11. White, E. L.; Buckheit, R. W., Jr.; Ross, L. J.; Germany, J. M.; Andries, K.; Pauwels, R.; Janssen, P. A. J.; Shannon, W. M.; Chirigos, M. A. A TIBO derivative, R82913, is a potent inhibitor of HIV-1 reverse transcriptase with heteropolymer templates. Antiviral Res. 1991, 16, 257-266.
12. Romero, D. L.; Morge, R. A.; Biles, C.; Berrios-Péna, N.; May, P. D.; Palmer, J. R.; Johnson, P. D.; Smith, H. W.; Busso, M.; Tan, C.-K.; Voorman, R. L.; Reusser, F.; Althaus, I. W.; Downey, K. M.; So, A. G.; Resnick, L.; Tarpley, W. G.; Aristoff, P. A. Discovery, Synthesis, and Bioactivity of Bis(heteroaryl)-piperazines. 1. A Novel Class of Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors. J. Med. Chem. 1994, 37, 999-1014.
13. Pauwels, R.; Andries, K.; Debyser, Z.; Van Daele, P.; Schols, D.; Stoffels, P.; De Vreese, K.; Woestenborghs, R.; Vandamme, A.-M.; Janssen, C. G. M.; Anne, J.; Cauwenbergh, G.; Desmyter, J.; Heykants, J.; Janssen, M. A. C.; De Clercq, E.; Janssen, P. A. J. Potent and highly selective human Immunodeficiency virus type 1 (HIV-1) inhibition by a series of alpha-anilinophenyl-acetamide derivatives targeted at HIV-1 reverse transcriptase. Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 1711-1715.
14. Young, S. D. Non-nucleoside inhibitors of HIV-1 reverse transcriptase. Perspect. Drug Disc. Des. 1993, 1, 181-192.
15. Smerdon, S. J.; Jäger, J.; Wang, J.; Kohlstaedt, L. A.; Chirino, A. J.; Friedman, J. M.; Rice, P. A.; Steizt, P. A. Structure of the binding site for nonnucleoside inhibitors of the reverse transcriptase of human immunodeficiency virus type 1. Proc. Natl. Acad. Sci. U.S.A., 1994, 91, 3911-3915.
16. Ternansky, R. J.; Morin, J. M., Jr.; Bell, F. W.; Cantrell, A.; Jaskunas, R.; Jordan, C. L.; Kinnick, M. D.; Lopez, C.; Paget, C. J., Jr.; Palkowitz, J.; Parrish, C.; Pranc, P.; Vasileff, R. T.; West, S. J.; Engelhardt, P.; Högberg, M.; Johansson, N. G.; Kangasmetsä, J.; Lind, P.; Norèen, R.; Rydegård, C.; Sahlberg, C.; Vrang, L.; Zhang, H.; Zhou, X.-X.; Åhgren, C.; Öberg, B. A Novel Class of Potent Non-nucleoside Reverse Transcriptase Inhibitors, a poster presentation, 6th ICAR, Venice, April 25-30, 1993.
17. Johansson, N. G.; Lind, P.; Noréen, R.; Morin, J. M., Jr.; Ternansky, R. J.; et al. a poster presentation, IXth Int. Conf. AIDS, Berlin, June 6-11, 1993.
18. Ahgren, C.; Backro, K.; Bell, F. W.; Cantrell, A. S.; Clemens, M.; Colacino, J. M.; Deeter, J. B.; Engelhardt, J. A.; Hogberg, M.; Jaskunas, S. R.; Johansson, N. G.; Jordan, C. L.; Kasher, J. S.; Kinnick, M. D.; Lind, P.; Lopez, C.; Morin, J. M., Jr.; Muesing, M. A.; Noreen, R.; Oberg, B.; Paget, C. J.; Palkowitz, J. A.; Parrish, C. A.; Pranc, P.; Rippy, M. K.; Rydergard, C.; Sahlberg, C.; Swanson, S.; Ternansky, R. J.; Unge, T.; Vasileff, R. T.; Vrang, L. West, S. J.; Zhang, H.; Zhou, X.-X. The PETT Series, a New Class of Potent Nonnucleoside Inhibitors of Human Immunodeficiency Virus Type 1 Reverse Transcriptase. Antimicrob. Agents Chemother. 1995, 39, 1329-1335.
19. Bell, F. W.; Cantrell, A. S.; Högberg, M.; Jaskunas, S. R.; Johansson, N. G.; Jordan, C. L.; Kinnick, M. D.; Lind, P.; Morin, J. M., Jr.; Noréen, R.; Öberg, B.; Palkowitz, J. A.; Parrish, C. A.; Pranc, P.; Sahlberg, C.; Ternansky, R. J.; Vasileff, R. T.; Vrang, L.; West, S. J.; Zhang, H.; Zhou, X.-X, PETT Compounds, a New Class of HIV-1 Reverse Transcriptase Inhibitors. 1. Synthesis and Basic SAR Studies of PhenEthylThiazoleThiourea (PETT) Analogs. J. Med. Chem. 1995, 38, 4929-4936.
20. Zhang, H.; Vrang, L.; Unge, T.; Öberg, B. Characterization of HIV reverse transcriptase with Tyr181→Cys and Leu 100→Ile mutations. Antiviral Chem. Chemother. 1993, 4 (5), 301-308.
21. Staab, H. A.; Walther, G. Synthese von Isothiocyanaten. Liebigs Ann. Chem. 1962, 657, 104-107.
22. Wallingford, V. H.; Krueger, P. A.; Organic Syntheses; John Wiley & Sons: New York, 1957; Collect. Vol. II, pp 349-351.
23. Vogel's Textbook of Practical Organic Chemistry, 4th ed.; Longman: London and New York, 1978; p 796.
24. Garst, J. E.; Wilson, B. J. Synthesis and analysis of various 3-furyl ketones from Perilla frutescens. J. Agric. Food Chem. 1984, 32, 1083-1087.
25. Weislow, O. S.; Kiser, R.; Fine, D. L.; Bader, J.; Shoemaker, R. H.; Boyd, M. R. New Soluble-Formazan Assay for HIV-1 Cytopathic Effects: Application to High-Flux Screening of Synthetic and Natural Products for AIDS-Antiviral Activity. J. Nat. Cancer Inst. 1989, 81 (8), 577-586.
26. Richman, D. D.; Havlir, D.; Corbeil, J.; Looney, D.; Ignario, C.; Spector, S.A.; Sullivan, J.; Cheeseman, S.; Barringer, K.; Pauletti, D.; Shih, C.-K; Myers, M.; Griffin, J. Nevirapine Resistance Mutations of Human Immunodeficiency Virus Type 1 Selected during Therapy. J. Virol. 1994, 68, 1660-1666.
27. Zhang, H.; Vrang, L.; Bäckbro, K.; Lind, P.; Sahlberg, C.; Unge, T.; Öberg, B. Inhibition of human immunodeficiency virus type 1 wild-type and mutant reverse transcriptases by the phenyl ethyl thiazolyl thiourea derivatives trovirdine and MSC-127. Antiviral Res. 1995, 28, 331-342.