Discovery of an irreversible HCV NS5B polymerase inhibitor

David Hesk; Qingbei Zeng; Anilkumar G. Nair; Stuart B. Rosenblum; Hsueh-Cheng Huang; Charles A. Lesburg; Yueheng Jiang; Oleg Selyutin; Tin-Yau Chan; Frank Bennett; Kevin X. Chen; Srikanth Venkatraman; Mousumi Sannigrahi; Francisco Velazquez; Jose S. Duca; Stephen Gavalas; Yuhua Huang; Haiyan Pu; LI Wang; Patrick Pinto; Bancha Vibulbhan; Sony Agrawal; Eric Ferrari; Chuan-kui Jiang; Cheng Li; David Hesk; Jennifer Gesell; Steve Sorota; Neng-Yang Shih; F. George Njoroge; Joseph A. Kozlowski

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

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Abstract

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.