Anacor Pharmaceuticals, Inc., 1020 E. Meadow Circle, Palo Alto, CA 94303, USA.
Bioorg Med Chem Lett. 2010 Oct 1;20(19):5695-700. doi: 10.1016/j.bmcl.2010.08.022. Epub 2010 Aug 10.
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.
设计并合成了一系列新型的 P2-P4 环化 HCV NS3/4A 蛋白酶抑制剂，其 P1 位以α-氨基环硼酸酯作为弹头。与线性类似物相比，这些环化抑制剂在基于细胞的复制子活性方面表现出显著改善，化合物 9a 和 9e 在复制子测定中达到亚微摩尔效力。α-氨基环硼酸酯周围的 SAR 清楚地确定了环大小、手性和取代模式的影响。此外，抑制剂 9a 和 NS3 蛋白酶的共晶 X 射线结构表明，酶活性位点的 Ser-139 将硼捕获在 9a 的弹头区域，从而确定了其作用模式。
