Naphthalene-linked P2-P4 macrocycles within a tri-peptide-based acyl sulfonamide chemotype have been synthesized and found to inhibit HCV NS3 proteases representing genotypes 1a and 1b with single digit nanomolar potency. The pharmacokinetic profile of compounds in this series was optimized through structural modifications along the macrocycle tether as well as the P1 subsite. Ultimately a compound with oral bioavailability of 100% in rat, and a long half-life in plasma was obtained. However, compounds in this macrocyclic series exhibited cardiac effects in an isolated rabbit heart model and for this reason further optimization efforts were discontinued.

合成了基于三肽的酰基磺酰胺化学型中的萘连结的P2-P4大环化合物，发现该化合物以一位数的纳摩尔浓度抑制代表基因型1a和1b的HCV NS3蛋白酶。通过沿大环系链以及P1亚位点进行结构修饰，优化了该系列化合物的药代动力学特性。最终获得在大鼠中口服生物利用度为100％，在血浆中具有长半衰期的化合物。但是，此大环化合物系列的化合物在孤立的兔心脏模型中显示出心脏效应，因此，中止了进一步的优化工作。