Discovery of pentacyclic compounds as potent inhibitors of hepatitis C virus NS5B RNA polymerase

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 3, 2009, Pages 633-638

  Habermann, Jörg ^a   Capitò, Elena ^a   Ferreira, Maria del Rosario Rico ^a   Koch, Uwe ^a   Narjes, Frank ^a  

^a IRBM   (Italy)

Author keywords

1,3 Dipolar cycloaddition; HCV; HCV NS5B polymerase inhibitor; Pauson Khand reaction

Indexed keywords

BENZAZEPINE DERIVATIVE; HETEROCYCLIC COMPOUND; INDOLE DERIVATIVE; NONSTRUCTURAL PROTEIN 5B; PLASMA PROTEIN; PYRROLE DERIVATIVE; RNA POLYMERASE;

ARTICLE; DRUG POTENCY; ENZYME ASSAY; HEPATITIS C VIRUS; HUMAN; HUMAN CELL; HYDROPHOBICITY; NONHUMAN; REPLICON; RING CLOSING METATHESIS; STEREOCHEMISTRY; STRUCTURE ACTIVITY RELATION;

BENZAZEPINES; CHEMISTRY, PHARMACEUTICAL; DNA-DIRECTED RNA POLYMERASES; DRUG DESIGN; ENZYME INHIBITORS; HUMANS; INHIBITORY CONCENTRATION 50; LIVER; MODELS, CHEMICAL; MODELS, MOLECULAR; MOLECULAR CONFORMATION; RNA, VIRAL; STRUCTURE-ACTIVITY RELATIONSHIP; VIRAL NONSTRUCTURAL PROTEINS;

HEPATITIS C VIRUS;

EID: 58849165652     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2008.12.039     Document Type: Article

References (45)

1. WHO, J. Viral Hepatitis 1999, 6, 35.
2. Cohen J. Science 285 (1999) 26
3. WHO Factsheet No. 164: Hepatitis C, accessed 09 May 2007, http://www. who.int/mediacentre/factsheets/fs164/en/print.html.
4. Steedman S.A., and Younossi Z.M. J. Clin. Gastroenterol. 30 (2000) 125
5. Beaulieu P.L. Curr. Opin. Invest. Drugs 7 (2006) 618 and references cited therein
6. Koch U., and Narjes F. Curr. Top. Med. Chem. 7 (2007) 1302 and references cited therein
7. De Francesco R., and Carfi A. Adv. Drug Deliv. Rev. 59 (2007) 1242 and references cited therein
8. Beaulieu P.L. Curr. Opin. Invest. Drugs 8 (2007) 614 and references cited therein
9. Toniutto P., Fabris C., Bitetto D., Fornasiere E., Rapetti R., and Pirisi M. Curr. Opin. Invest. Drugs 8 (2007) 150
10. Kwong A.D., McNair L., Jacobson I., and George S. Curr. Opin. Pharm. 8 (2008) 522 and references cited therein
11. McCown M.F., Rajyaguru S., Le Pogam S., Ali S., Jiang W.-R., Kang H., Symons J., Cammack N., and Najera I. Antimicr. Agents Chemother. 52 (2008) 1604
12. Beaulieu P.L., Boes M., Bousquet Y., DeRoy P., Fazal G., Gauthier J., Gillard J., Goulet S., McKercher G., Poupart M.-A., Valois S., and Kukolj G. Bioorg. Med. Chem. Lett. 14 (2004) 967
13. Harper S., Pacini B., Avolio S., Di Filippo M., Migliaccio G., Laufer R., De Francesco R., Rowley M., and Narjes F. J. Med. Chem. 48 (2005) 1314
14. Ontoria J.M., Martin Hernando J.I., Malancona S., Attenni B., Stansfield I., Conte I., Ercolani C., Habermann J., Ponzi S., Di Filippo M., Koch U., Rowley M., and Narjes F. Bioorg. Med. Chem. Lett. 16 (2006) 4026
15. Tomei L., Altamura S., Bartholomew L., Biroccio A., Ceccacci A., Pacini L., Narjes F., Gennari N., Bisbocci M., Incitti I., Orsatti L., Harper S., Stansfield I., Rowley M., De Francesco R., and Migliaccio G. J. Virol. 77 (2003) 13225
16. Di Marco S., Volpari C., Tomei L., Altamura S., Harper S., Narjes F., Koch U., Rowley M., De Francesco R., Migliaccio G., and Carfi A. J. Biol. Chem. 280 (2005) 29765
17. Ikegashira K., Oka T., Hirashima S., Noji S., Yamanaka H., Hara Y., Adachi T., Tsuruha J.-I., Doi S., Hase Y., Noguchi T., Ando I., Ogura N., Ikeda S., and Hashimoto H. J. Med. Chem. 49 (2006) 6950
18. Hirashima S., Oka T., Ikegashira K., Noji S., Yamanaka H., Hara Y., Goto H., Mizojiri R., Niwa Y., Noguchi T., Ando I., Ikeda S., and Hashimoto H. Bioorg. Med. Chem. Lett. 17 (2007) 3181
19. Stansfield, I.; Ercolani, C.; Mackay, A.; Conte, I.; Pompei, M.; Koch, U.; Giuliano, C.; Rowley, M.; Narjes, F. Accompanying paper..
20. Although for the compounds in question this property has not been evaluated, in some cases aromatic amines may constitute a potential risk for being mutagenic and/or carcinogenic. For some studies see: (a) Franke, R.; Gruske, A.; Giuliani, A.; Benigni, R. Carcinogenesis 2001, 22, 1561; (b) Turesky, R.J. Drug Metab. Rev. 2002, 34, 625.
21. All compounds were profiled as racemic mixture if not denoted otherwise.
22. 50 values are the average of at least two independent determinations. Cell-based data was obtained in the presence of 10% fetal calf serum (FCS) or 50% normal human serum (NHS).
23. Olson R.E., and Christ D.D. Annu. Rep. Med. Chem. 31 (1996) 327
24. Boffito M., Back D.J., Blaschke T.F., Rowland M., Bertz R.J., Gerber J.G., and Miller V. AIDS Res. Hum. Retrovir. 19 (2003) 825
25. Raboisson P., Manthey C.L., Chaikin M., Lattanze J., Crysler C., Leonard K., Pan W., Tomczuk B.E., and Marugán J.J. Eur. J. Med. Chem. 41 (2006) 847
26. Calculated physicochemical properties were determined using the ACD/Labs 8.0 package by Advanced Chemistry Development, Inc.
27. A conformational analysis was performed on the pentacyclic structures 10 and 11 in the absence of the protein. This analysis was carried out with Maestro 7.5.112 generating 10.000 conformations and using the MMFFs force field for minimisation. The indole scaffold of the global minimum conformation was superimposed onto the corresponding scaffold of the crystal structure.
28. Detailed synthesis protocols and spectroscopic data for the compounds are described in: (a) Ercolani, C.; Habermann, J.; Narjes, F.; Ponzi, S.; Rowley, M.; Stansfield, I. WO 2006046039 A2, 2006; (b) Capitò, E.; Habermann, J.; Narjes, F.; Rico Ferreira, Maria d. R.; Stansfield, I. WO 2007129119 A1, 2007.
29. Khand I.U., Knox G.R., Pauson P.L., Watts W.E., and Foreman M.I. J. Chem. Soc., Perkin Trans. 1 (1973) 977
30. Exon C., and Magnus P. J. Am. Chem. Soc. 105 (1983) 2477
31. Hua D.H. J. Am. Chem. Soc. 108 (1986) 3835
32. Schore N.E., and Rowley E.G. J. Am. Chem. Soc. 110 (1988) 5224
33. Rausser R., Weber L., Hershberg E.B., and Oliveto E.P. J. Org. Chem. 31 (1966) 1342
34. Rausser R., Finckenor C.G., Weber L., Hershberg E.B., and Oliveto E.P. J. Org. Chem. 31 (1966) 1346
35. Secrist III J.A., and Logue M.W. J. Org. Chem. 37 (1972) 335
36. Wrobel J., Dietrich A., Gorham B.J., and Sestanj K. J. Org. Chem. 55 (1990) 2694
37. Beeson C., and Dix T.A. J. Org. Chem. 57 (1992) 4386
38. Tsuge O., Kanemasa S., Ohe M., and Takenaka S. Chem. Lett. (1986) 973
39. Tsuge O., Kanemasa S., Ohe M., and Takenaka S. Bull. Chem. Soc. Jpn. 60 (1987) 4079
40. Amal Raj A., and Raghunathan R. Tetrahedron 57 (2001) 10293
41. Subramaniyan G., Raghunathan R., and Nethaji M. Tetrahedron 58 (2002) 9075
42. Nyerges M., Bendell D., Arany A., Hibbs D.E., Coles S.J., Hursthouse M.B., Groundwater P.W., and Meth-Cohn O. Synlett (2003) 947
43. Poornachandran M., and Raghunathan R. Tetrahedron Lett. 46 (2005) 7197
44. Coldham I., and Hufton R. Chem. Rev. 105 (2005) 2765 and references cited therein
45. Super-critical fluid chromatography (SFC) was performed using a Berger system equipped with a Berger ALS 719.