Novel macrocyclic HCV NS3 protease inhibitors derived from alpha-amino cyclic boronates

Pennicott, Lewis (2010) Novel macrocyclic HCV NS3 protease inhibitors derived from alpha-amino cyclic boronates. Bioorganic & Medicinal Chemistry Letters, 20 (19). pp. 5695-5700. ISSN 0960894X

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A novel series of P2P4 macrocyclic HCV NS3/4A protease inhibitors with -amino cyclic boronates as warheads at the P1 site was designed and synthesized. When compared to their linear analogs, these macrocyclic inhibitors exhibited a remarkable improvement in cell-based replicon activities, with compounds 9a and 9e reaching sub-micromolar potency in replicon assay. The SAR around -amino cyclic boronates clearly established the influence of ring size, chirality and of the substitution pattern. Furthermore, X-ray structure of the co-crystal of inhibitor 9a and NS3 protease revealed that Ser-139 in the enzyme active site traps boron in the warhead region of 9a, thus establishing its mode of action.

Item Type: Article
Additional Information: (with Xianfeng Lia, Yong-Kang Zhang, Yang Liu, Charles Z. Ding, Yasheen Zhou, Qun Li, Jacob J. Plattner, Stephen J. Baker, Suoming Zhang, Wieslaw M. Kazmierski, Lois L. Wright, Gary K. Smith, Richard M. Grimes, Renae M. Crosby, Katrina L. Creech, Luz H. Carballo, Martin J. Slater, Richard L. Jarvest, Pia Thommes, Julia A. Hubbard, Maire A. Convery, Pamela M. Nassau, William McDowell, Tadeusz J. Skarzynski, Xuelei Qian, Dazhong Fan, Liang Liao, Zhi-Jie Ni, Wuxin Zouf and Jon Wright)
Schools and Departments: School of Life Sciences > Chemistry
Depositing User: Lewis Pennicott
Date Deposited: 06 Feb 2012 19:08
Last Modified: 31 May 2012 14:53
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