Hepatitis C is a viral infection of the liver that affects 130-150 million people worldwide including 4 million in the United States. Chronic infections occur in the majority of cases and may lead to fibrosis, cirrhosis liver failure, and liver cancer.
Experts agree that the future of the hepatitis C market belongs to direct acting antiviral drugs (DAAs) that are effective against all or multiple hepatitis C genotypes, have a high barrier to resistance and are effective in the absence of interferon and ribavirin, two drugs which were until recently part of the standard of care for hepatitis C and are poorly tolerated. Initial efforts towards the discovery of antiviral agents were focused on the NS3/4A serine protease1 and the NS5B RNA dependent polymerase2 but the non-structural NS5A protein emerged as an attractive target with discovery of picomolar inhibitors. These highly potent compounds paved the way for the design of fixed dose combinations with a better resistance profile.3,4,5,6,7,8 In fact, in October 2014,9 a combination of an NS5A inhibitor and a nucleoside NS5B inhibitor was approved by the US FDA for treatment of chronic genotype 1 hepatitis C infection in adults. In December 2014, a four direct-acting antiviral agent (DAA) regimen that includes an NS5A inhibitor, received approval when used with or without ribavirin.10 These advances give hope to patients infected with chronic hepatitis C, and we are confident that our DAA’s will join these efforts.
We are developing a series of compounds that are potent non-nucleoside and nucleoside inhibitors of hepatitis C NS5B RNA dependent RNA polymerase, a replication enzyme that is essential to viral replication and is highly conserved between all hepatitis C genotypes. Therefore, inhibitors of this enzyme are likely to have multi- or pan-genotypic activity.
We are also developing compounds that inhibit hepatitis C NS5A and NS5B, two enzymes that are essential for viral replication.
Cocrystal Pharma has identified a picomolar inhibitor of NS5A, another essential viral replication protein. Inhibitors of NS5A, in combination with nucleosides, have demonstrated excellent efficacy in treatment for hepatitis C in comparison with standard care.
Our compounds that target NS5B hepatitis C polymerase, NS5A and will be developed as a combination treatment. Such a combination treatment might have higher antiviral activity or a higher barrier to viral resistance than either treatment alone.
To learn more about Hepatitis C, please visit the information page at the Center for Disease Control and Prevention (CDC).
- Halfon, P.; Locarnini, S. J. Hepatol. 2011, 55,192.
- Coats, S. J.; Garnier-Amblard, E. C.; Amblard, F.; Ehteshami, M.; Amiralaei, S.; Zhang, H.; Zhou, L.; Boucle, S. R.; Lu, X.; Bondada, L.; Shelton, J. R.; Li, H.; Liu, P.; Li, C.; Cho, J. H.; Chavre, S. N.; Zhou, S.; Mathew, J.; Schinazi, R. F. Antiviral res. 2014, 102, 119.
- Zhang, H.; Zhou, L.; Amblard, F.; Shi, J.; Bobeck, D. R.; Tao, S.; McBrayer, T. R.; Tharnish, P. M.; Whitaker, T.; Coats, S. J.; Schinazi, R. F. Bioorg. Med. Chem. Lett. 2012, 22, 4864.
- Shi, J.; Zhou, L.; Amblard, F.; Bobeck, D. R.; Zhang, H.; Liu, P.; Bondada, L.; McBrayer, T. R.; Tharnish, P. M.; Whitaker, T.; Coats, S. J.; Schinazi, R. F. Bioorg. Med. Chem. Lett. 2012, 22, 3488.
- Belema, M.; Lopez, O. D.; Bender, J. A.; Romine, J. L.; St Laurent, D. R.; Langley, D. R.; Lemm, J. A.; O'Boyle, D. R.; Sun, J. H.; Wang, C.; Fridell, R. A.; Meanwell, N. A. J. Med. Chem. 2014, 57, 1643.
- 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. Y.; Yang, C.; Matles, M.; Wang, Y.; Wang, K.; Cheng, G.; Tian, Y.; Mogalian, E.; Mondou, E.; Cornpropst, M.; Perry, J.; Desai, M. C. J. Med. Chem. 2014, 57, 2033.
- 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. W.; Maring, C. J.; Molla, A.; Dumas, E.; Campbell, A.; Williams, L.; Collins, C.; Wagner, R.; Kati, W. M. J. Med. Chem. 2014, 57, 2047.
- Kazmierski, W. M.; Maynard, A.; Duan, M.; Baskaran, S.; Botyanszki, J.; Crosby, R.; Dickerson, S.; Tallant, M.; Grimes, R.; Hamatake, R.; Leivers, M.; Roberts, C. D.; Walker, J. J. Med. Chem. 2014, 57, 2058.