Inhibitors of Hepatitis C NS5b RNA Polymerase
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 3 1045
(18) Young, D. C.; Bailey, T. R. Methods for Treating or Preventing Viral
Infections and Associated Disease. PCT Int. Appl. WO-00018231,
2000.
(19) Hashimoto, H.; Mizutani, K.; Yoshida, A. Preparation of Heterocyclic
Compounds as Remedies for Hepatitis C. PCT Int. Appl. WO-
0147883, 2001.
(20) Baginski, S. G.; Pevear, D. C.; Seipel, M.; Sun, S. C. C.; Benetatos,
C. A.; Chunduru, S. K.; Rice, C. M.; Collet, M. S. Mechanism of
Action of a Pestivirus Antiviral Compound. Proc. Nat. Acad. Sci.
2000, 97, 7981-7986.
(21) A preliminary account of this work has been described: Powers, J.
P.; Anzola, J.; Chen, J.; Jaen, J. C.; Li, Y.; Lee, G.; McNally, J.;
Mayorga, V.; Peterson, M. G.; Piper, D.; Walker, N.; Wang, Z. SAR
and Mechanism of Novel HCV NS5b RNA Polymerase Inhib-
itors. Presented at the 5th Annual Winter Conference on Medici-
nal and Bioorganic Chemistry, Steamboat Springs, CO, Jan 26-31,
2003.
(22) Chan, L.; Reddy, T. J.; Proulx, M.; Das, S. K.; Pereira, O.; Wang,
W.; Siddiqui, A.; Yannopoulos, C. G.; Poisson, C.; Turcotte, N.;
Drouin, A.; Alaoui-Ismaili, M. H.; Bethell, R. Hamel, M.; L’Heureux,
L.; Bilimoria, D. Nguyen-Ba, N. Identification of N,N-Disubstituted
Phenylalanines as a Novel Class of Inhibitors of Hepatitis C NS5B
Polymerase. J. Med. Chem. 2003, 46, 1283-1285.
(23) Dhanak, D.; Duffy, K. J.; Johnston, V. K.; Lin-Goerke, J.; Darcy,
M.; Shaw, A. N.; Gu, B.; Silverman, C.; Gates, A. T.; Nonnemacher,
M. R.; Earnshaw, D. L.; Casper, D. J.; Kaura, A.; Baker, A.;
Greenwood, C.; Gutshall, L. L.; Maley, D.; DelVecchio, A.;
Macarron, R.; Hofmann, G. A.; Alnoah, Z.; Cheng, H.-Y.; Chan,
G.; Khandekar, S.; Keenan, R. M.; Sarisky, R. T. Identification and
Biological Characterization of Heterocyclic Inhibitors of the Hepatitis
C Virus RNA-dependent RNA Polymerase. J. Biol. Chem. 2002, 277,
38322-38327.
(24) Wang, M.; Ng, K. K._S.; Cherney, M. M.; Chan, L.; Yannopoulos,
C. G.; Bedard, J.; Morin, N.; Nguyen-Ba, N.; Alaoui-Ismaili, M. H.;
Bethell, R. C.; James, M. N. G. Non-Nucleoside Analogue Inhibitors
Bind to an Allosteric Site on HCV NS5b Polymerase. J. Biol. Chem.
2003, 278, 9489-9495.
(25) Beaulieu, P. L.; Bos, M.; Bousquest, Y.; Fazal, G.; Gauthier, J.;
Gillard, J.; Goulet, S.; LaPlante, S.; Poupart, M.-A.; Lefebvre, S.;
McKercher, G.; Pellerin, C.; Austel, V.; Kukolj, G. Non-Nucleoside
Inhibitors of the Hepatitis C Virus NS5B Polymerase: Discovery
and Preliminary SAR of Benzamidazole Derivitives. Bioorg. Med.
Chem. Lett. 2004, 14, 119-124.
(26) Chan, L.; Das, S. K.; Reddy, T. J.; Poisson, C.; Proulx, M.; Pereira,
O.; Courchesne, M.; Roy, C.; Wang, W.; Siddqui, A.; Yannopoulos,
C. G.; Nguyen-Ba, N.; Labrecque, D.; Bethell, R.; Hamel, M.;
Courtmanche-Asselin, P.; L’Heureux, L.; David, M.; Nicolas, O.;
Brunette, S.; Bilimoria, D.; Bedard, J. Discovery of Thiophene-2-
carboxylic Acids as Potent Inhibitors of HCV NS5B Polymerase and
HCV Subgenomic RNA Replication. Part 1: Sulfonamides. Bioorg.
Med. Chem. Lett. 2004, 14, 793-796.
(27) Chan, L.; Pereira, O.; Reddy, T. J.; Das, S. K.; Poisson, C.;
Courchesne, M.; Proulx, M.; Siddiqui, A.; Yannopoulos, C. G.;
Nguyen-Ba, N.; Roy, C.; Nasturica, D.; Moinet, C.; Bethell, R.;
Hamel, M.; L’Heureux, L.; David, M.; Nicolas, O.; Courtmanche-
Asselin, P.; Brunette, S.; Bilimoria, D.; Bedard, J. Discovery of
Thiophene-2-carboxylic Acids as Potent Inhibitors of HCV NS5B
Polymerase and HCV subgenomic RNA Replication. Part 2: Tertiary
Amides. Bioorg. Med. Chem. Lett. 2004, 14, 797-800.
(28) Pace, P.; Nizi, E.; Pacini, B.; Pesci, S.; Matassa, V.; De Francesco,
R.; Altamura, S.; Summa, V. The Monomethyl Ester of Meconic
Acid is an Active Site Inhibitor of HCV NS5B RNA-Dependent RNA
Polymerase. Bioorg. Med. Chem. Lett. 2004, 14, 3257-3261.
(29) Summa, V.; Petrocchi, A.; Pace, P.; Matessa, V. G.; De Francesco,
R.; Altamura, S.; Tomei, L.; Koch, U.; Neuner, P. Discovery of R,γ-
Diketo Acids as Potent Selective Inhibitors of Hepatitis C Virus NS5b
RNA-Dependent RNA Polymerase. J. Med. Chem. 2004, 47, 14-
17.
(30) Summa, V.; Petrocchi, A.; Matassa, V. G.; Taliani, M.; Laufer, R.;
De Francesco, R.; Altamura, S.; Pace, P. HCV NS5b RNA-Dependent
RNA Polymerase Inhibitors: From R,γ-Diketoacids to 4,5-Dihy-
droxypyrimidine- or 3-Methyl-5-hydroxypyrimidinonecarboxylic ac-
ids. Design and Synthesis. J. Med. Chem. 2004, 47, 5336-5339.
(31) Ships, G. W., Jr.; Deng, Y.; Wang, T.; Popovici-Muller, J.; Curran,
P. J.; Rosner, K. E.; Cooper, A. B.; Griijavallabhan, V.; Butkiewicz,
N.; Cable, M. Aminothiazole Inhibitors of HCV RNA Polymerase.
Bioorg. Med. Chem. Lett. 2005, 15, 115-119.
Diffraction data were collected at 90 Kelvin at ALS Beamline 5.0.2,
and processed using Denzo and Scalepack.61 The NS5b structure
was solved by molecular replacement with EPMR62 using NS5b
(1QUV)39,63 as the search model. NS5b-inhibitor complex struc-
tures were determined by rigid-body refinement using the unli-
ganded NS5b structure as the starting model. Structure improvement
proceeded with multiple rounds of manual model building in
Quanta, followed by refinement using CNX.64 Ligands were fitted
into clear Fo-Fc electron density in the later stages of refinement.
Data and refinement statistics are given in the Supporting Informa-
tion.
Acknowledgment. We thank Mario Cardozo and John
McNally for technical assistance. The Advanced Light Source
at the Lawrence Berkeley National Laboratory is supported by
the Director, Office of Science, Office of Basic Sciences,
Materials Sciences Division, of the US Department of Energy.
Supporting Information Available: C, H, N, S analysis for
all compounds and X-ray data and refinement statistics for
NS5b+5h, NS5b+5ee, and NS5b+5x. This material is available
References
(1) Choo, Q.-L.; Kuo, G.; Weiner, A. J.; Overby, L. R.; Bradley, D. W.;
Houghton, M. Isolation of a cDNA Clone Derived from a Blood-
Bourne Non-A, Non-B Viral Hepatitis Genome. Science 1989, 244,
359-362.
(2) Kuo, G.; Choo, Q.-L.; Alter, H. J.; Gitnick, G. L.; Redeker, A. G.;
Purcell, R. H.; Miyamura, T.; Dienstag, J. L.; Alter, M. J.; Stevens,
C. E.; Tegtmeir, G. E.; Bonino, F.; Colombo, M,; Lee, W.-S.; Kuo,
C.; Berger, K.; Shuster, J. R.; Overby, L. R.; Bradley, D. W.;
Houghton, M. An Assay for Circulating Antibodies to a Major
Etiologic Virus of Non-A, Non-B Hepatitis. Science 1989, 244, 362-
364.
(3) Hoofnagle, J. H. Hepatitis C: The Clinical Spectrum of Disease.
Hepatology 1997, 26, 15S-20S.
(4) Monto, A.; Wright, T. L. The Epidemiology and Prevention of
Hepatocellular Carcinoma. Semin. Oncol. 2001, 28, 441-449.
(5) Di Bisceglie, A. M. Hepatitis C and Hepatocellular Carcinoma.
Hepatology 1997, 26, 34S-38S
(6) McHutchison, J. G.; Gordon, S. C.; Schiff, E. R.; Shiffman, M. L.;
Lee, W. M.; Rustgi, V. K.; Goodman, Z. D.; Ling, M.-H.; Cort, S.;
Albrecht, J. K. Interferon Alfa-2b Alone or in Combination with
Ribavirin as Initial Treatment for Chronic Hepatitis C. N. Engl. J.
Med. 1998, 339, 1485-1492.
(7) Zeuzem, S.; Feinman, S. V.; Rasenack, J.; Heathcote, E. J.; Lai, M.-
Y.; Gane, E.; O’Grady, J.; Reichen, J.; Diago, M.; Lin, A.; Hoffman,
J.; Brunda, M. J. Peginterferon Alfa-2a in Patients with Chronic
Hepatitis C. N. Engl. J. Med. 2000, 343, 1666-1672.
(8) Lauer, G. M.; Walker, B. D. Hepatitis C Virus Infection. N. Engl. J.
Med. 2001, 345, 41-52.
(9) Perni, R. B.; Kwong, A. D. Inhibitors of Hepatitis C Virus NS3‚4A
Protease: An Overdue Line of Therapy. In Progress in Medicinal
Chemistry; King, F. D., Oxford, A. W., Eds.; Elsevier Science: New
York, 2002; Volume 39, pp 215-255.
(10) Kadow, J. F.; Scola, P. M. Antiviral Agents. In Annual Reports in
Medicinal Chemistry; Doherty, A. M., Ed.; Academic Press: San
Francisco, 2002; Volume 37, pp 133-147.
(11) Wang, W.; Preville, P.; Morin, N.; Mounir, S.; Cai, W.; Siddiqui,
M. A. Hepatitus C Viral IRES Inhibition by Phenazine and Phenazine-
like Molecules. Bioorg. Med. Chem. Lett. 2000, 10, 1151-1154
(12) Witherell, G. W. ISIS-14803, Isis Pharmaceuticals. Curr. Opin. InVest.
Drugs. 2001, 2, 1523-1529.
(13) Jaen, J. C.; Piper, D. E.; Powers, J. P.; Walker, N. P.; Li, Y. NS5b
HCV Polymerase Inhibitors. PCT Int. Appl. WO-0177091, 2001.
(14) Altamura, S.; Tomei, L.; Koch, U.; Neuner, P. J. S.; Summa, V.
Diketoacid Derivitives as Inhibitors of Polymerases. PCT Int. Appl.
WO-00006529, 2000.
(15) Gardelli, C.; Ciuliano, C.; Harperr, S.; Koch, U.; Narjes, F.; Ontoria,
U.; Jesus, M.; Poma, M.; Ponz, S.; Stansfield, I.; Summa, V.
Preparation of 2-Aryldihydroxypyrimidine-4-carboxylic Acids as
Hepatitis C Viral Polymerrase Inhibitors. PCT Int. Appl. WO-
0206246, 2002.
(16) Bailey, T. R.; Young, D. C. Methods for Treating or Preventing Viral
Infections and Associated Diseases. PCT Int. Appl. WO-00013708,
2000.
(32) Beaulieu, P. L.; Bousquet, Y.; Gauthier, J.; Gillard, J.; Marquis, M.;
McKercher, G.; Pellerin, C.; Valois, S.; Kukolj, G. Non-Nucleoside
Benzimidazole-Based Allosteric Inhibitors of the Hepatitis C Virus
NS5B Polymerase: Inhibition of Subgenomic Hepatitis C Virus RNA
Replicons in Huh-7 Cells. J. Med. Chem. 2004, 47, 6884-6892.
(17) Bailey, T. R.; Young, D. C. Compounds, Compositions and Methods
for Treating or Preventing Viral infections and Associated Diseases.
PCT Int. Appl. WO-00010573, 2000.