Hepatitis C virus (HCV) infection is a major health problem that leads to chronic liver disease, such as cirrhosis and hepatocellular carcinoma. HCV infects a substantial number of individuals, estimated to be 2-15% of the world's population. The approved Standard of Care (SOC) involves the combination of a protease inhibitor with pegylated-interferon (PEG-IFN) and the oral nucleoside ribavirin (RBV) but it is limited clinical benefit for HCV Genotype 2, 3, 4, 5 and 6 infected patients. The sustained virologic response (SVR or undetectable HCV RNA in serum at the end of treatment) rate for most�difficult-to-treat genotype-1 HCV patients with approved drugs boceprevir and telaprevir is about 70% with the protease inhibitor, RBV, and PEG-IFN combination and produces undesired side effects. Moreover, there is no established vaccine for HCV. Consequently, there is an urgent need for improved therapeutic agents that effectively combat chronic HCV infection in all genotypes.A number of potential HCV molecular targets for which anti-HCV therapeutics have now been in clinical trials include, but are not limited to, NS3/4A protease, NS5A replication factor and the NS5B polymerase. Another HCV auxiliary protein is NS4B. NS4B is relatively poorly characterized and believed to be associates with a number of additional non-structural proteins that permit formation of the so-called 'membranous web' structure that facilitates HCV replication. In an effort to improve treatment of HCV, it remains of vital interest to identify compounds capable of inhibiting the action of the NS4B protein of HCV. Herein, we report the identification and SAR development studies of potent piperazinone derivatives as a novel class of HCV NS4B inhibitors.

Discovery of a novel class of potent HCV NS4B inhibitors: Identification and optimization of piperazinone derivatives

245th National Meeting (2013)

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