Discovery of Chromane Containing Hepatitis C Virus (HCV) NS5A Inhibitors with Improved Potency against Resistance-Associated Variants

Journal of Medicinal Chemistry

Volumn 59, Issue 22, 2016, Pages 10228-10243

  Yu, Wensheng ^a   Tong, Ling ^a   Hu, Bin ^b   Zhong, Bin ^b   Hao, Jinglai ^b   Ji, Tao ^b   Zan, Shuai ^b   Coburn, Craig A ^a   Selyutin, Oleg ^a   Chen, Lei ^a   Rokosz, Laura ^a   Agrawal, Sony ^a   Liu, Rong ^a   Curry, Stephanie ^a   McMonagle, Patricia ^a   Ingravallo, Paul ^a   Asante Appiah, Ernest ^a   Chen, Shiying ^a   Kozlowski, Joseph A ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

^b WUXI APPTEC   (China)

Author keywords

[No Author keywords available]

Indexed keywords

CHROMAN DERIVATIVE; DIHYDROBENZOFURAN DERIVATIVE; ELBASVIR; INDOLE; NONSTRUCTURAL PROTEIN 5A INHIBITOR; PHENYL GROUP; ANTIVIRUS AGENT; NS-5 PROTEIN, HEPATITIS C VIRUS; VIRAL PROTEIN;

ANIMAL EXPERIMENT; ANTIVIRAL RESISTANCE; AREA UNDER THE CURVE; ARTICLE; CONTROLLED STUDY; DOG; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG CYTOTOXICITY; DRUG POTENCY; DRUG SCREENING; DRUG STRUCTURE; DRUG SYNTHESIS; ELIMINATION HALF-LIFE; GENOTYPE; HEPATITIS C VIRUS; IN VITRO STUDY; MALE; MAXIMUM PLASMA CONCENTRATION; MEAN RESIDENCE TIME; NONHUMAN; RAT; TIME TO MAXIMUM PLASMA CONCENTRATION; ANIMAL; ANTAGONISTS AND INHIBITORS; CHEMICAL STRUCTURE; CHEMISTRY; DOSE RESPONSE; DRUG DEVELOPMENT; DRUG EFFECTS; HEPACIVIRUS; MICROBIAL SENSITIVITY TEST; STRUCTURE ACTIVITY RELATION; SYNTHESIS; WISTAR RAT;

ANIMALS; ANTIVIRAL AGENTS; CHROMANS; DOGS; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG DISCOVERY; DRUG RESISTANCE, VIRAL; HEPACIVIRUS; MALE; MICROBIAL SENSITIVITY TESTS; MOLECULAR STRUCTURE; RATS; RATS, WISTAR; STRUCTURE-ACTIVITY RELATIONSHIP; VIRAL NONSTRUCTURAL PROTEINS;

EID: 84999672440     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/acs.jmedchem.6b01234     Document Type: Article

References (34)

1. Guidelines for Screening, Care and Treatment of Persons with Hepatitis C Infection; WHO: Geneva, Switzerland, September 3, 2015; http://www.who.int/hiv/pub/hepatitis/hepatitic-c-guidelines/en/.
2. Hajarizadeh, B.; Grebely, J.; Dore, J. G. Epidemiology and natural history of HCV infection Nat. Rev. Gastroenterol. Hepatol. 2013, 10, 553-562 10.1038/nrgastro.2013.107
3. Mohd Hanafiah, K.; Groeger, J.; Flaxman, A. D.; Wiersma, S. T. Global epidemiologyof hepatitis C virus infection: new estimates of age-specific antibody to HCV seroprevalence Hepatology 2013, 57, 1333-1342 10.1002/hep.26141
4. Gonzalez, S. A. Management of recurrent hepatitis C following liver transplantation Gastroenterol. Hepatol. 2010, 6 (10) 637-645
5. Sheridan, C. New Merck and Vertex drugs raise standard of care in hepatitis C Nat. Biotechnol. 2011, 29, 553-554 10.1038/nbt0711-553
6. Gentile, I.; Scotto, R.; Zappulo, E.; Buonomo, A. R.; Pinchera, B.; Borgia, G. Investigational direct-acting antivirals in hepatitis C treatment: the latest drugs in clinical development Expert Opin. Invest. Drugs 2016, 25, 557-572 10.1517/13543784.2016.1161023
7. Holmes, J.; Thompson, A. Interferon-free combination therapies for the treatment of hepatitis C: current insights Hepatic Med. 2015, 51-70 10.2147/HMER.S55864
8. Poordad, F.; Dieterich, D. Treating hepatitis C: current standard of care and emerging direct-acting antiviral agents J. Viral Hepatitis 2012, 19, 449-464 10.1111/j.1365-2893.2012.01617.x
9. McGivern, D. R.; Masaki, T.; Williford, S.; Ingravallo, P.; Feng, Z.; Lahser, F.; Asante-Appiah, E.; Neddermann, P.; De Francesco, R.; Howe, A. Y.; Lemon, S. M. Kinetic analyses reveal potent and early blockade of hepatitis C virus assembly by NS5A inhibitors Gastroenterology 2014, 147, 453-462 10.1053/j.gastro.2014.04.021
10. Gao, M.; Nettles, R. E.; Belema, M.; Snyder, L. B.; Nguyen, V. N.; Fridell, R. A.; Serrano-Wu, M. H.; Langley, D. R.; Sun, J.-H.; O'Boyle, D. R., II; Lemm, J. A.; Wang, C.; Knipe, J. O.; Chien, C.; Colonno, R. J.; Grasela, D. M.; Meanwell, N. A.; Hamann, L. G. Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect Nature 2010, 465, 96-100 10.1038/nature08960
11. Scheel, T. K.; Rice, C. M. Understanding the hepatitis C virus life cycle paves the way for highly effective therapies Nat. Med. 2013, 19, 837-849 10.1038/nm.3248
12. Belema, M.; Meanwell, N. A. Discovery of daclatasvir, a pan-genotypic hepatitis C virus NS5A replication complex inhibitor with potent clinical effect J. Med. Chem. 2014, 57, 5057-5071 10.1021/jm500335h
13. Link, J. O.; Taylor, J. G.; Xu, L.; Mitchell, M.; Guo, H.; Liu, H.; Kato, D.; Kirschberg, T.; Sun, J.; Squires, N.; Parrish, J.; Keller, T.; Yang, Z.; Yang, C.; Matles, M.; Wang, Y.; Wang, K.; Cheng, G.; Tian, Y.; Mogalian, E.; Mondou, E.; Cornpropst, M.; Perry, J.; Desai, M. C. Discovery of ledipasvir (GS-5885): a potent, once-daily oral NS5A inhibitor for the treatment of hepatitis C virus infection J. Med. Chem. 2014, 57, 2033-2046 10.1021/jm401499g
14. DeGoey, D. A.; Randolph, J. T.; Liu, D.; Pratt, J.; Hutchins, C.; Donner, P.; Krueger, A. C.; Matulenko, M.; Patel, S.; Motter, C. E.; Nelson, L.; Keddy, R.; Tufano, M.; Caspi, D. D.; Krishnan, P.; Mistry, N.; Koev, G.; Reisch, T. J.; Mondal, R.; Pilot-Matias, T.; Gao, Y.; Beno, D. A.; Maring, C. J.; Molla, A.; Dumas, E.; Campbell, A.; Williams, L.; Collins, C.; Wagner, R.; Kati, W. M. Discovery of ABT-267, a pan-genotypic inhibitor of HCV NS5A J. Med. Chem. 2014, 57, 2047-2057 10.1021/jm401398x
15. Coburn, C. A.; Meinke, P. T.; Chang, W.; Fandozzi, C. A.; Graham, D. J.; Hu, B.; Huang, Q.; Kargman, S.; Kozlowski, J.; Liu, R.; McCauley, J. A.; Nomeir, A. A.; Soll, R. M.; Vacca, J. P.; Wang, D.; Wu, H.; Zhong, B.; Olsen, D. B.; Ludmerer, S. W. Discovery of MK-8742: an HCV NS5A inhibitor with broad genotype activity ChemMedChem 2013, 8, 1930-1940 10.1002/cmdc.201300343
16. Kozlowski, J. A.; Rosenblum, S. B.; Coburn, C. A.; Shankar, B. B.; Anilkumar, G. N.; Chen, L.; Dwyer, M. P.; Jiang, Y.; Keertikar, K. M.; Lavey, B. J.; Seluytin, O. B.; Tong, L.; Wong, M.; Yang, D.-Y.; Yu, W.; Zhao, G.; Wu, H.; Hu, B.; Zhong, B.; Sun, F.; Ji, T.; Shen, C.; Rizvi, R.; Zeng, Q. Tetracyclic indole derivatives for treating hepatitis C virus infection. WO 2012041014, 2012.
17. Younossi, Z. M.; Stepanova, M.; Feld, J.; Zeuzem, S.; Jacobson, I.; Agarwal, K.; Hezode, C.; Nader, F.; Henry, L.; Hunt, S. Sofosbuvir/velpatasvir improves patient-reported outcomes in HCV patients: results from ASTRAL-1 placebo-controlled trial J. Hepatol. 2016, 65, 33-39 10.1016/j.jhep.2016.02.042
18. Messina, J.; Humphreys, I.; Flaxman, A.; Brown, A.; Cooke, G.; Pybus, O.; Barnes, E. Global distribution and prevalence of hepatitis C virus genotypes Hepatology 2015, 61, 77-87 10.1002/hep.27259
19. Smith, D. B.; Bukh, J.; Kuiken, C.; Muerhoff, A. S.; Rice, C. M.; Stapleton, J. T.; Simmonds, P. Expanded classification of hepatitis C virus into 7 genotypes and 67 subtypes: updated criteria and genotype assignment web resource Hepatology 2014, 59, 318-327 10.1002/hep.26744
20. Lavanchy, D. Evolving epidemiology of hepatitis C virus Clin. Microbiol. Infect. 2011, 17, 107-115 10.1111/j.1469-0691.2010.03432.x
21. Nair, A. G.; Zeng, Q.; Selyutin, O.; Rosenblum, S. B.; Jiang, Y.; Yang, D.-Y.; Keertikar, K.; Zhou, G.; Dwyer, M.; Kim, S. H.; Shankar, B.; Yu, W.; Tong, L.; Chen, L.; Mazzola, R.; Caldwell, J.; Tang, H.; Allard, M.; Buckle, R. N.; Gauuan, P. J. F.; Holst, C. L.; Martin, G. S.; Naicker, K. P.; Vellekoop, S.; Agrawal, S.; Liu, R.; Kong, R.; Ingravallo, P.; Xia, E.; Zhai, Y.; Nomeir, A.; Kozlowski, J. A. Discovery of silyl proline containing HCV NS5A inhibitors with pan-genotype activity: SAR development Bioorg. Med. Chem. Lett. 2016, 26, 1475-1479 10.1016/j.bmcl.2016.01.050
22. Yu, W.; Coburn, C. A.; Yang, D.-Y.; Meinke, P. T.; Wong, M.; Rosenblum, S. B.; Chen, K. X.; Njoroge, G. F.; Chen, L.; Dwyer, M. P.; Jiang, Y.; Nair, A. G.; Selyutin, O.; Tong, L.; Zeng, Q.; Zhong, B.; Ji, T.; Hu, B.; Agrawal, S.; Xia, E.; Zhai, Y.; Liu, R.; Kong, R.; Ingravallo, P.; Asante-Appiah, E.; Nomeir, A.; Fells, J.; Kozlowski, J. A. Discovery of fused tricyclic core containing HCV NS5A inhibitors with pan-genotype activity Bioorg. Med. Chem. Lett. 2016, 26, 3158-3162 10.1016/j.bmcl.2016.04.084
23. Yu, W.; Vibulbhan, B.; Rosenblum, S. B.; Martin, G. S.; Vellekoop, A. S.; Holst, C. L.; Coburn, C. A.; Wong, M.; Selyutin, O.; Ji, T.; Zhong, B.; Hu, B.; Chen, L.; Dwyer, M. P.; Jiang, Y.; Nair, A. G.; Tong, L.; Zeng, Q.; Agrawal, S.; Carr, D.; Rokosz, L.; Liu, R.; Curry, S.; McMonagle, P.; Ingravallo, P.; Lahser, F.; Asante-Appiah, E.; Fells, J.; Kozlowski, J. A. Discovery of potent macrocyclic HCV NS5A inhibitors Bioorg. Med. Chem. Lett. 2016, 26, 3793-3799 10.1016/j.bmcl.2016.05.042
24. Tong, L.; Yu, W.; Coburn, C. A.; Meinke, P. T.; Nair, A. G.; Dwyer, M. P.; Chen, L.; Selyutin, O.; Rosenblum, S. B.; Jiang, Y.; Fells, J.; Hu, B.; Zhong, B.; Soll, R. M.; Liu, R.; Agrawal, S.; Xia, E.; Zhai, Y.; Kong, R.; Ingravallo, P.; Nomeir, A.; Asante-Appiah, E.; Kozlowski, J. A. Alternative core development around the tetracyclic indole class of HCV NS5A inhibitors Bioorg. Med. Chem. Lett. 2016, 26, 5132-5137 10.1016/j.bmcl.2016.07.057
25. Yu, W.; Coburn, C. A.; Nair, G. N.; Wong, M.; Tong, L.; Dwyer, M. P.; Hu, B.; Zhong, B.; Hao, J.; Yang, D.-Y.; Selyutin, O.; Jiang, Y.; Rosenblum, S. B.; Kim, S. H.; Lavey, B. J.; Zhou, G.; Rizvi, R.; Shankar, B. B.; Zeng, Q.; Chen, L.; Agrawal, S.; Carr, D.; Rokosz, L.; Liu, R.; Curry, S.; McMonagle, P.; Ingravallo, P.; Lahser, F.; Asante-Appiah, E.; Nomeir, A.; Kozlowski, J. A. Alkyl substituted aminal derivatives of HCV NS5A inhibitor MK-8742 Bioorg. Med. Chem. Lett. 2016, 26, 3800-3805 10.1016/j.bmcl.2016.05.041
26. Yu, W.; Coburn, C. A.; Nair, A. G.; Wong, M.; Rosenblum, S. B.; Zhou, G.; Dwyer, M. P.; Tong, L.; Hu, B.; Zhong, B.; Hao, J.; Ji, T.; Zan, S.; Kim, S. H.; Zeng, Q.; Selyutin, O.; Chen, L.; Masse, F.; Agrawal, S.; Liu, R.; Xia, E.; Zhai, Y.; Curry, S.; McMonagle, P.; Ingravallo, P.; Asante-Appiah, E.; Lin, X.; Kozlowski, J. A. Aryl or heteroaryl substituted aminal derivatives of HCV NS5A inhibitor MK-8742 Bioorg. Med. Chem. Lett. 2016, 26, 3414-3420 10.1016/j.bmcl.2016.06.056
27. Dwyer, M. P.; Keertikar, K. M.; Chen, L.; Tong, L.; Selyutin, O.; Nair, A. G.; Yu, W.; Zhou, G.; Lavey, B. J.; Yang, D.-Y.; Wong, M.; Kim, S. H.; Coburn, C. A.; Rosenblum, S. B.; Zeng, Q.; Jiang, Y.; Shankar, B. B.; Rizvi, R.; Nomeir, A. A.; Liu, R.; Agrawal, S.; Xia, E.; Kong, R.; Zhai, Y.; Ingravallo, P.; Asante-Appiah, E.; Kozlowski, J. A. Matched and mixed cap derivatives of the HCV NS5A inhibitor MK-8742 Bioorg. Med. Chem. Lett. 2016, 26, 4106-4111 10.1016/j.bmcl.2016.06.063
28. Tong, L.; Yu, W.; Coburn, C. A.; Chen, L.; Selyutin, O.; Zeng, Q.; Dwyer, M. P.; Nair, A. G.; Shankar, B. B.; Kim, S. H.; Yang, D.-Y.; Rosenblum, S. B.; Ruck, R. T.; Davies, I. W.; Hu, B.; Zhong, B.; Hao, J.; Ji, T.; Zan, S.; Liu, R.; Agrawal, S.; Carr, D.; Curry, S.; McMonagle, P.; Bystol, K.; Lahser, F.; Ingravallo, P.; Asante-Appiah, E.; Chen, S.; Kozlowski, J. A. Structure-activity relationships of proline modifications around the tetracyclic-indole class of NS5A inhibitors Bioorg. Med. Chem. Lett. 2016, 26, 5354-5360 10.1016/j.bmcl.2016.08.097
29. Yu, W.; Zhou, G.; Coburn, C. A.; Zeng, Q.; Tong, L.; Dwyer, M. P.; Hu, B.; Zhong, B.; Hao, J.; Ji, T.; Zan, S.; Chen, L.; Mazzola, R.; Kim, J.-H.; Sha, D.; Selyutin, O.; Rosenblum, S. B.; Lavey, B.; Nair, A. G.; Kim, S. H.; Keertikar, K. M.; Rokosz, L.; Agrawal, S.; Liu, R.; Xia, E.; Zhai, Y.; Curry, S.; McMonagle, P.; Ingravallo, P.; Asante-Appiah, E.; Chen, S.; Kozlowski, J. A. Substituted tetracyclic indole core derivatives of HCV NS5A inhibitor MK-8742 Bioorg. Med. Chem. Lett. 2016, 26, 4851-4856 10.1016/j.bmcl.2016.08.002
30. Barakat, K. H.; Anwar-Mohamed, A.; Tuszynski, J. A.; Robins, M. J.; Tyrrell, D. L.; Houghton, M. A refined model of the HCV NS5A protein bound to daclatasvir explains drug-resistant mutations and activity against divergent genotypes J. Chem. Inf. Model. 2015, 55, 362-373 10.1021/ci400631n
31. Nettles, J. H.; Stanton, R. A.; Broyde, J.; Amblard, F.; Zhang, H.; Zhou, L.; Shi, J.; McBrayer, T. R.; Whitaker, T.; Coats, S. J.; Kohler, J. J.; Schinazi, R. F. Asymmetric binding to NS5A by daclatasvir (BMS-790052) and analogs suggests two novel modes of HCV inhibition J. Med. Chem. 2014, 57, 10031-10043 10.1021/jm501291c
32. Tong, X.; Bogen, S.; Chase, R.; Girijavallabhan, V.; Guo, Z.; Njoroge, F. G.; Prongay, A.; Saksena, A.; Skelton, A.; Xia, E.; Ralston, R. Characterization of resistance mutations against HCV ketoamide protease inhibitors Antiviral Res. 2008, 77, 177-185 10.1016/j.antiviral.2007.11.010
33. Carroll, S. S.; Ludmerer, S. W.; Handt, L.; Koeplinger, K.; Zhang, N. R.; Graham, D.; Davies, M. E.; MacCoss, M.; Hazuda, D. J.; Olsen, D. B. Robust antiviral efficacy upon administration of a nucleoside analog to hepatitis C virus-infected chimpanzees Antimicrob. Agents Chemother. 2009, 53, 926-934 10.1128/AAC.01032-08
34. Lohmann, V.; Körner, F.; Koch, J.; Herian, U.; Theilmann, L.; Bartenschlager, R. Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line Science 1999, 285 (5424) 110-113 10.1126/science.285.5424.110