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

Li, Xianfeng, Zhang, Yong-Kang, Liu, Yang, Ding, Charles Z, Zhou, Yasheen, Li, Qun, Plattner, Jacob J, Baker, Stephen J, Zhang, Suoming, Kazmierski, Wieslaw M, Wright, Lois L, Smith, Gary K, Grimes, Richard M, Crosby, Renae M, Creech, Katrina L, Carballo, Luz H, Slater, Martin J, Jarvest, Richard L, Thommes, Pia, Hubbard, Julia A, Convery, Maire A, Nassau, Pamela M, McDowell, William, Skarzynski, Tadeusz J, Qian, Xuelei, Fan, Dazhong, Liao, Liang, Ni, Zhi-Jie, Pennicott, Lewis E, Zou, Wuxin and Wright, Jon (2010) Novel macrocyclic HCV NS3 protease inhibitors derived from α-amino cyclic boronates. Bioorganic and Medicinal Chemistry Letters, 20 (19). pp. 5695-5700. ISSN 0960-894X

[img] PDF - Published Version
Restricted to SRO admin only

Download (1MB)


A novel series of P2-P4 macrocyclic HCV NS3/4A protease inhibitors with α-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 α-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
Schools and Departments: School of Life Sciences > Chemistry
Subjects: Q Science > QD Chemistry > QD0241 Organic chemistry
Depositing User: Lewis Pennicott
Date Deposited: 21 Jul 2015 06:50
Last Modified: 08 Mar 2017 06:39

View download statistics for this item

📧 Request an update