An unprecedented series of organometallic HCV (hepatitis C virus) NS5A (nonstructural 5A protein) replication complex inhibitors that incorporates a 1,1′-ferrocenediyl scaffold was explored. This scaffold introduces the elements of linear flexibility and non-planar topology that are unconventional for this class of inhibitors. Data from 2-D NMR spectroscopic analyses of these complexes in solution support an anti (unstacked) arrangement of the pharmacophoric groups. Several complexes demonstrate single-digit picomolar in vitro activity in an HCV genotype-1b replicon system. One complex to arise from this investigation (10a) exhibits exceptional picomolar activity against HCV genotype 1a and 1b replicons, low hepatocellular cytotoxicity, and good pharmacokinetic properties in rat.

探索了一系列史无前例的有机金属 HCV（丙型肝炎病毒）NS5A（非结构性 5A 蛋白）复制复合物抑制剂，其中包含 1,1'-二茂铁支架。该支架引入了对于此类抑制剂来说非常规的线性柔韧性和非平面拓扑结构。来自溶液中这些配合物的 2-D NMR 光谱分析的数据支持药效团的反（未堆叠）排列。几种复合物在 HCV 基因型 1b 复制子系统中表现出单位数皮摩尔的体外活性。该研究产生的一种复合物 ( 10a ) 对 HCV 基因型 1a 和 1b 复制子表现出卓越的皮摩尔活性、低肝细胞毒性和在大鼠中的良好药代动力学特性。