Bioorganic & Medicinal Chemistry Letters 2012-12-15

Synthesis and antiviral activity of novel HCV NS3 protease inhibitors with P4 capping groups

Xianfeng Li, Yang Liu, Yong-Kang Zhang, Jacob J. Plattner, Stephen J. Baker, Wei Bu, Liang Liu, Yasheen Zhou, Charles Z. Ding, Suoming Zhang, Wieslaw M. Kazmierski, Robert Hamatake, Maosheng Duan, Lois L. Wright, Gary K. Smith, Richard L. Jarvest, Jing-Jing Ji, Joel P. Cooper, Matthew D. Tallant, Renae M. Crosby, Katrina Creech, Amy Wang

Index: Bioorg. Med. Chem. Lett. 22(24) , 7351-6, (2012)

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Abstract

We have synthesized and evaluated a series of novel HCV NS3 protease inhibitors with various P4 capping groups, which include urea, carbamate, methoxy-carboxamide, cyclic carbamate and amide, pyruvic amide, oxamate, oxalamide and cyanoguanidine. Most of these compounds are remarkably potent, exhibiting single-digit to sub-nanomolar activity in the enzyme assay and cell-based replicon assay. Selected compounds were also evaluated in the protease-inhibitor-resistant mutant transient replicon assay, and they were found to show quite different potency profiles against a panel of HCV protease-inhibitor-resistant mutants.Copyright © 2012 Elsevier Ltd. All rights reserved.