Hepatitis C virus (HCV) is a blood-borne, positive-sense RNA virus, which belongs to the Hepacivirus genus in the Flaviviridae family. A majority of people infected with HCV develop chronic HCV infection, which leads to serious disorders such as liver cirrhosis, followed eventually by hepatocellular carcinoma. For treatment of HCV infection, a widely used combination includes pegylated interferon-? and ribavirin. A new treatment has also been introduced based on HCV protease inhibitors. However, the current treatment protocols are riddled with substantial adverse effects like fatigue, depression together with partial efficacy, and sustained virologic response (SVR) for genotype 1 is about 60~80%. Therefore it is necessary to develop new anti-HCV drug candidates exhibiting less side effects and more effective cure rate. Recently, novel treatments through the use of direct acting agents (DAA) are in the limelight of many pharmaceutical companies and research laboratories.
Herein we report the discovery of a series of extremely potent HCV NS5A inhibitors based on the benzidine prolinamide skeleton. Taking a simple synthetic route, we developed a novel inhibitor flatform, which allows easy modification, and through optimization of the benzidine core structure, we identified BMK-20313, BMK-20613, and BMK-20713 possessing highly potent anti-HCV activities. Especially, BMK-20313 is nontoxic and anticipated to be an effective HCV drug candidate.