Discovery of fused tricyclic core containing HCV NS5A inhibitors with pan-genotype activity

Bioorganic and Medicinal Chemistry Letters

Volumn 26, Issue 13, 2016, Pages 3158-3162

  Yu, Wensheng ^a   Coburn, Craig A ^a   Yang, De Yi ^a   Meinke, Peter T ^a   Wong, Michael ^a   Rosenblum, Stuart B ^a   Chen, Kevin X ^a   Njoroge, George F ^a   Chen, Lei ^a   Dwyer, Michael P ^a   Jiang, Yueheng ^a   Nair, Anilkumar G ^a   Selyutin, Oleg ^a   Tong, Ling ^a   Zeng, Qingbei ^a   Zhong, Bin ^b   Ji, Tao ^b   Hu, Bin ^b   Agrawal, Sony ^a   Xia, Ellen ^a   Zhai, Ying ^a   Liu, Rong ^a   Kong, Rong ^a   Ingravallo, Paul ^a   Asante Appiah, Ernest ^a   Nomeir, Amin ^a   Fells, James ^a   Kozlowski, Joseph A ^a   more..

^a MERCK RESEARCH LABORATORIES   (United States)

^b WUXI APPTEC   (China)

Author keywords

Direct acting antiviral agents (DAA); Elbasvir; HCV NS5A inhibitor; Hepatitis C; Pan genotype activity; Tricyclic

Indexed keywords

NONSTRUCTURAL PROTEIN 5A INHIBITOR; ANTIVIRUS AGENT; NS-5 PROTEIN, HEPATITIS C VIRUS; VIRAL PROTEIN;

ALKYLATION; ANIMAL EXPERIMENT; ARTICLE; DRUG BIOAVAILABILITY; DRUG CLEARANCE; EC50; GENOTYPE; HEPATITIS C; MOLECULAR MODEL; NONHUMAN; RAT; STRUCTURE ACTIVITY RELATION; SUZUKI REACTION; ANTAGONISTS AND INHIBITORS; CHEMICAL STRUCTURE; CHEMISTRY; DOSE RESPONSE; DRUG DEVELOPMENT; DRUG EFFECTS; GENETICS; HEPACIVIRUS; MICROBIAL SENSITIVITY TEST; SYNTHESIS; VIRUS REPLICATION;

ANTIVIRAL AGENTS; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG DISCOVERY; GENOTYPE; HEPACIVIRUS; HEPATITIS C; MICROBIAL SENSITIVITY TESTS; MOLECULAR STRUCTURE; STRUCTURE-ACTIVITY RELATIONSHIP; VIRAL NONSTRUCTURAL PROTEINS; VIRUS REPLICATION;

EID: 84970038690     PISSN: 0960894X     EISSN: 14643405     Source Type: Journal    
DOI: 10.1016/j.bmcl.2016.04.084     Document Type: Article

References (22)

1. J.T. Liang, J.H. Hoofnagle, and C. Hepatitis Biomedical Research Reports 2000 Academic Press London, UK 185
2. D.R. Bobeck, R.F. Schinazi, and S.J. Coats Antivir. Ther. 15 2010 935
3. Refer to the USPI (US product insert) for (a). US Prescribing Information, VICTRELIS™ (boceprevir) capsules, for oral use: 2011; (b). US Prescribing Information, INCIVEK (telaprevir), Film Coated tablets, for oral use: 2011.
4. F. Poordad, and D. Dieterich J. Viral Hepat 19 2012 449
5. T.K. Scheel, and C.M. Rice Nat. Med. 19 2013 837
6. C. Sheridan Nat. Biotechnol. 29 2011 553
7. R.F. Schinazi, L. Bassit, and C. Gavegnano J. Viral Hepat. 17 2010 77
8. M. Gao, R.E. Nettles, M. Belema, L.B. Snyder, V.N. Nguyen, R.A. Fridell, M.H. Serrano-Wu, D.R. Langley, J.-H. Sun, D.R. O'Boyle II, J.A. Lemm, C. Wang, J.O. Knipe, C. Chien, R.J. Colonno, D.M. Grasela, N.A. Meanwell, and L.G. Hamman Nature 465 2010 96
9. M. Belema, and N.A. Meanwell J. Med. Chem. 57 2014 5057
10. J.O. Link, J.G. Taylor, L. Xu, M. Mitchell, H. Guo, H. Liu, D. Kato, T. Kirschberg, J. Sun, N. Squires, J. Parrish, T. Keller, Z. Yang, C. Yang, M. Matles, Y. Wang, K. Wang, G. Cheng, Y. Tian, E. Mogalian, E. Mondou, M. Cornpropst, J. Perry, and M.C. Desai J. Med. Chem. 57 2014 2033
11. D.A. DeGoey, J.T. Randolph, D. Liu, J. Pratt, C. Hutchins, P. Donner, A.C. Krueger, M. Matulenko, S. Patel, C.E. Motter, L. Nelson, R. Keddy, M. Tufano, D.D. Caspi, P. Krishnan, N. Mistry, G. Koev, T.J. Reisch, R. Mondal, T. Pilot-Matias, Y. Gao, D.A. Beno, C.J. Maring, A. Molla, E. Dumas, A. Campbell, L. Williams, C. Collins, R. Wagner, and W.M. Kati J. Med. Chem 57 2014 2047
12. C.A. Coburn, P.T. Meinke, W. Chang, C.A. Fandozzi, D.J. Graham, B. Hu, Q. Huang, S. Kargman, J. Kozlowski, R. Liu, J.A. McCauley, A.A. Nomeir, R.M. Soll, J.P. Vacca, D. Wang, H. Wu, B. Zhong, D.B. Olsen, and S.W. Ludmerer ChemMedChem 8 2013 1930
13. A.G. Nair, Q. Zeng, O. Selyutin, S.B. Rosenblum, Y. Jiang, D.-Y. Yang, K. Keertikar, G. Zhou, M. Dwyer, S.H. Kim, B. Shankar, W. Yu, L. Tong, L. Chen, R. Mazzola, J. Caldwell, H. Tang, M. Allard, R.N. Buckle, P.J.F. Gauuan, C.L. Holst, G.S. Martin, K.P. Naicker, S. Vellekoop, S. Agrawal, R. Liu, R. Kong, P. Ingravallo, E. Xia, Y. Zhai, A. Nomeir, and J.A. Kozlowski Bioorg. Med. Chem. Lett. 26 2016 1475
14. Alignment was performed using Rapid Overlay of Chemical Structures (ROCS v. 3.2.0.4) software. A single low-energy conformation of MK-8742 was used as the query molecule to align the compounds. Omega software v. 2.5.1.4 (OpenEye Scientific Software, Inc., Santa Fe, NM, USA) was used to generate up to 500 conformations of each compound using default parameters. ROCS was then employed to superimpose MK-8742 and other compounds. Results were visualized using PYMOL (v. 1.7).
15. V.J. Schmutz, F. Kunzle, F. Hunziker, and A. Burki Helv. Chim. Acta 48 1965 336
16. H.J.M. Gijsen, D. Berthelot, M. Zaja, B.B. One, I. Geuens, and M. Mercken J. M. Chem. 53 2010 7011
17. Rosenblum, S. B.; Chen, K. X.; Kozlowski, J. A.; Njoroge, F. G.; Coburn, C. A. WO2010132538, 2010.
18. For the assay methods used for this publication, see example 15 in Ref. 15 and example 7 in Ref. 17. Assay variation is up to 3-fold. For additional references, see X. Tong, S. Bogen, R. Chase, V. Girijavallabhan, Z. Guo, F.G. Njoroge, A. Prongay, A. Saksena, A. Skelton, E. Xia, and R. Ralston Antiviral Res. 77 2008 177
19. S.S. Carroll, S.W. Ludmerer, L. Handt, K. Koeplinger, N.R. Zhang, D. Graham, M.E. Davies, M. MacCoss, D.J. Hazuda, and D.B. Olsen Antimicrob. Agents Chemother. 2009 926
20. Coburn, C. A.; Wu, H.; Hu, B.; Zhong, B. Wang, D.; Xu, Z.; Sun, F.; Ji, T.; Dan, Z. WO 2012003642, 2012.
21. J. Clayden, A. Lund, L. Vallverdu, and M. Helliwell Nature 431 2004 966
22. H. Gilman, and L.O. Moore J. Am. Chem. Soc. 79 1957 3485