The discovery of lead compound 2e was described. Its covalent binding to HCV NS5B polymerase enzyme was investigated by X-ray analysis. The results of distribution, metabolism and pharmacokinetics were reported. Compound 2e was demonstrated to be potent (replicon GT-1b EC50 = 0.003 mu M), highly selective, and safe in in vitro and in vivo assays. (C) 2013 Elsevier Ltd. All rights reserved.
Discovery of an irreversible HCV NS5B polymerase inhibitor
Zeng, Q., Nair, A. G., Rosenblum, S. B., Huang, H-C., Lesburg, C. A., Jiang, Y., Selyutin, O., Chan, T-Y., Bennett, F., Chen, K. X., Venkatraman, S., Sannigrahi, M., Velazquez, F., Duca, J. S., Gavalas, S., Huang, Y., Pu, H., Wang, L., Pinto, P., ... Kozlowski, J. A. (2013). Discovery of an irreversible HCV NS5B polymerase inhibitor. Bioorganic and Medicinal Chemistry Letters, 23(24), 6585-6587. https://doi.org/10.1016/j.bmcl.2013.10.060