Novel P2-P4 macrocyclic inhibitors of HCV NS3/4A protease by P3 succinamide fragment depeptidization strategy

Bioorganic and Medicinal Chemistry Letters

Volumn 20, Issue 1, 2010, Pages 168-174

  Pompei, Marco ^a   Francesco, Maria Emilia Di ^b   Pesci, Silvia ^a   Koch, Uwe ^c   Vignetti, Sue Ellen ^a   Veneziano, Maria ^a   Pace, Paola ^a   Summa, Vincenzo ^a  

^a IRBM   (Italy)

^b MERCK RESEARCH LABORATORIES   (United States)

^c Lead Discovery Center GmbH   (Germany)

Author keywords

Bioisosters; HCV; Hepatitis C; MK 7009; NS3; Protease inhibitor; Succinamide depeptidization

Indexed keywords

NONSTRUCTURAL PROTEIN 3; PROTEINASE INHIBITOR; QUINOLINE DERIVATIVE; SUCCINAMIDE DERIVATIVE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; AREA UNDER THE CURVE; ARTICLE; CONTROLLED STUDY; DRUG BINDING; DRUG BLOOD LEVEL; DRUG HYDROLYSIS; DRUG STRUCTURE; DRUG SYNTHESIS; HUMAN; HUMAN CELL; HYDROGENATION; NONHUMAN; NUCLEAR MAGNETIC RESONANCE; RAT; REVERSED PHASE HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; RING CLOSING METATHESIS; STRUCTURE ACTIVITY RELATION;

ADMINISTRATION, ORAL; AMIDES; ANIMALS; ANTIVIRAL AGENTS; BINDING SITES; CELL LINE; COMPUTER SIMULATION; HUMANS; INDOLES; PROTEASE INHIBITORS; RATS; RATS, WISTAR; VIRAL NONSTRUCTURAL PROTEINS;

HEPATITIS C VIRUS; RATTUS;

EID: 72049130800     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.11.005     Document Type: Article

References (46)

1. De Francesco R., and Migliaccio G. Nature 436 (2005) 953
2. Chen S.L., and Morgan T.R. Int. J. Med. Sci. 3 (2006) 47
3. Perz J.F., Armstrong G.L., Farrington L.A., Hutin Y.J., and Bell B.P. J. Hepatol. 45 (2006) 529
4. Alter M.J. World. J. Gastroenterol. 13 (2007) 2436
5. National Institutes of Health. Hepatology 2002, 36, S3-S20.
6. Chen S.H., and Tan S.L. Curr. Med. Chem. 12 (2005) 2317
7. Manns M.P., Foster G.R., Rockstroh J.K., Zeuzem S., Zoulim F., and Houghton M. Nat. Rev. Drug Disc. 6 (2007) 991
8. Lamarre D., Anderson P.C., Bailey M., Beaulieu P., Bolger G., Bonneau P., Boes M., Cameron D.R., Tsantrizos Y.S., Weldon S.M., Yong C.-L., and Llinas-Brunet M. Nature 426 (2003) 186
9. Hinrichsen H., Benhamou Y., and Wedemeyer H. Gastroenterology 127 (2004) 1347
10. Kwong A.D., McNair L., Jacobson I., and George S. Curr. Opin. Pharmacol. 8 (2008) 522
11. Melkinova I. Nat. Rev. Drug Disc. 7 (2008) 799
12. Rajagopalan R., Misialek S., Stevens S.K., Myszka D.G., Brandhuber B.J., Ballard J.A., and Kossen K. Biochemistry 48 (2009) 2559
13. Liverton N.J., Holloway K., McCauley J., and Butcher J. J. Am. Chem. Soc. 130 (2008) 4607
14. McCauley J.A., Rudd M.T., Nguyen K.T., McIntyre C.J., Romano J.J., Bush K.J., Varga S.L., Ross C.W., Carroll S.S., DiMuzio J., Stahlhut M.W., Olsen D.B., Lyle T.A., Vacca J.P., and Liverton N.J. Angew. Chem., Int. Ed. 47 (2008) 9104
15. Pompei M., Di Francesco M.E., Koch U., Liverton N.J., and Summa V. Bioorg. Med. Chem. Lett. 19 (2009) 2574
16. Avolio S., Robertson K., Hernando J.M.I., Di Muzio J., and Summa V. Bioorg. Med. Chem. Lett. 19 (2009) 2295
17. McCauley, J. A. Abstract of Papers, 235th ACS National Meeting, New Orleans, LA, USA, April 6-10, 2008.
18. Protease inhibitors show promise against HCV. Nat. Rev. Drug Disc. 2009, 8, 11.
19. Harper S., Ferrara M., Crescenzi B., Pompei M., Palumbi M.C., DiMuzio J.M., Donghi M., Fiore F., Koch U., Liverton N.J., Pesci S., Petrocchi A., Rowley M., Summa V., and Gardelli C. J. Med. Chem. 52 (2009) 4820
20. Di Francesco, M. E.; Dessole, G.; Nizi, E.; Pace, P.; Koch, U.; Fiore, F.; Pesci, S.; DiMuzio, J. M.; Monteagudo, E.; Rowley, M.; Summa, V. J. Med. Chem., 2009. doi:10.1021/jm9005246.
21. Barlaam B., Bird T.G., Lambert-van der Brempt C., Campbell D., Foster S.J., and Maciewicz R. J. Med. Chem. 42 (1999) 4890
22. Xue C.B., He X., Corbett R.L., Roderick J., Wasserman Z.R., Liu R.Q., Jaffe B.D., Covington M.B., Quian M., Trzaskos J.M., Newton R.C., Magoda R.L., Wexler R.R., and Decicco C.P. J. Med. Chem. 44 (2001) 3351
23. Kottirsch G., Kock G., Feifel R., and Neumann U. J. Med. Chem. 45 (2002) 2289
24. Curtin M.L., Garland R.B., Heyman H.R., Frey R.R., Michaelides M.R., Li J., Pease L.J., Glaser K.B., Marcotte P.A., and Davidsen S.K. Bioorg. Med. Chem. Lett. 12 (2002) 2919
25. Bailey, M. D.; Llinas-Brunet, M. U.S. Patent 0224900, 2004.
26. Chatterjee A.K., Liu H., Tully D.C., Guo J., Epple R., Russo R., and Williams J. Bioorg. Med. Chem. Lett. 17 (2007) 2899
27. Love R.A., Parge H.E., Wickersham J.A., Hostomsky Z., Habuka N., and Moomaw E.W. Cell 87 (1996) 331
28. Yan Y., Li Y., Sardana V., Cole J.L., Sardana M., Steinkueler C., Tomei L., and De Francesco R. Protein Sci. 7 (1998) 837
29. Thomson J.A., Murcko M.A., Lin C., and Caron P.R. Structure 6 (1998) 89
30. Lindebach B.D., and Rice C.M. Nature 436 (2005) 933
31. Venkatraman S., and Njoroge F.G. Curr. Top. Med. Chem. 7 (2007) 1290
32. Colarusso S., Gerlach B., Koch U., Muraglia E., Conte I., Stansfield I., Matassa V.G., and Narjes F. Bioorg. Med. Chem. Lett. 12 (2002) 705
33. Perni R.B., Chandorkar G., Cottrell K.M., Gates C.A., Kai Lin C.L., Rao G., Schairer W.C., Van Drie J., and Wei Y. Bioorg. Med. Chem. Lett. 17 (2007) 3406
34. Holloway, M. K.; Liverton, N. J.; Ludmerer, S. W.; McCauley, J. A.; Olsen, D. B.; Rudd, M. T.; Vacca, J. P.; McIntyre, C. J. U.S. Patent 027071, 2007.
35. Liverton, N. J.; Summa, V.; Vacca, J. P.; Di Francesco, M. E.; Pompei, M. WO Patent 051477, 2008.
36. Wang, X. A.; Sun, L.-Q.; Sit, S. Y.; Sin, Y.; Scola, P. M.; Hewawasam, P.; Good, A. C.; Chen, Y.; Campbell, J. A. U.S. Patent 6995174, 2006.
37. + found 738.2.
38. Bender C.F., and Widenhoefer R.A. Org. Lett. 8 (2006) 5303
39. Catrell, K. M. WO Patent 025307, 2007.
40. Farner, L.; Bethiel, R. S.; Jacobs, D.; Perni, R.B.; WO Patent 106058, 2008.
41. Greene T.W., and Wuts P.G.M. Greene's Protective Groups in Organic Synthesis. 4th ed. (2007), John Wiley & Sons
42. 3, T = 300 K) δ 7.22 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.4 Hz, 2H), 5.87-5.73 (m, 1H), 5.03 (br s, 1H), 4.97-4.92 (m, 1H), 3.78 (s, 3H), 3.59 (s, 2H), 2.62 (t, J = 6.9 Hz, 2H), 2.08 (q, J = 7.2 Hz, 2H), 1.65-1.55 (m, 2H)
43. 13C HMBC experiment. The two carbonyl carbons of the amide and the acid moieties (detected at 171.1 ppm and 175.3 ppm, respectively) were unambiguously distinguished by the pattern of proton-carbon connectivities observed for the C11-C9 fragment (H8 correlate to both C9 and C11, while H14 and H20 only correlate to C9); the analysis of the proton-carbon connectivities from the c-Hex moiety showed the key correlation H1-C11 (175.3 ppm). The structure of 22a was assigned in analogous manner.{A figure is presented}
44. Poliakov A., Hubatsch I., Shuman C., and Stenberg G. Protein Expr. Purif. 25 (2002) 363
45. Lohmann V., Korner F., and Herian U. Science 285 (1999) 110
46. 50 (10% FCS) = 12 nM. The complete characterization of 2 will be the subject of a separate publication by our organization.