[摘要]:HCV infection is considered a silent epidemic because most people infected do not develop acute symptoms. Instead, the disease progresses to a chronic state leading to cirrhosis and hepatocarcinoma. Novel therapies are needed to combat this major health threat. The HCV NS3 serine protease has been the target of continuous investigation because of its pivotal role in viral replication. Herein, the authors present the P1-P3 macrocyclization approach followed for identification of HCV NS3 inhibitors as potential backup candidates to their first generation drug candidate, Sch 503034. Different P1-P3 linkers were investigated to identify novel macrocyclic scaffolds. SAR exploration of P3-caps in the macrocyclic cores allowed the identification of L-serine-derived macrocycle I (Ki* = 3 nM, EC90 = 30 nM) and allo-threonine-derived macrocycle II (Ki* = 3 nM, EC90 = 30 nM) as potent HCV NS3 protease inhibitors.