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Antimicrob. Agents Chemother. doi:10.1128/AAC.00525-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Discovery and Characterization of Substituted Diphenyl Heterocyclic Compounds as Potent and Selective Inhibitors of Hepatitis C Virus Replication

Department of Virology, Chemistry, and High Throughput Screening, Rigel Pharmaceuticals, Inc., 1180 Veterans Boulevard, South San Francisco, CA 94080

^* To whom correspondence should be addressed. Email: hlu{at}rigel.com.

	Abstract

A novel small molecule inhibitor, referred to here as R706, was discovered in a high throughput screen of chemical libraries against Huh-7-derived replicon cells carrying autonomously replicating subgenomic RNA of hepatitis C virus (HCV). R706 was highly potent in blocking HCV RNA replication, as measured by real time RT-PCR and Western blot of R706-treated replicon cells. Structure activity iterations of the R706 series yielded a lead compound, R803, which was more potent and highly specific for HCV replication with no significant inhibitory activity against a panel of HCV-related positive stranded RNA viruses. Furthermore, HCV genotype 1 replicons displayed markedly higher sensitivity to R803 treatment than a genotype 2a-derived replicon. In addition, R803 was tested in a panel of biochemical and cell based assays for on target and off target activities, and the data suggested the compound had a close to 100-fold therapeutic window while its exact mechanism of action remained elusive. We found that R803 was more effective than IFN- in blocking HCV RNA replicon in the replicon model. In combination studies, R803 showed weak synergistic effect with IFN-/ribavirin, but showed only additive effect with a protease inhibitor and an allosteric RdRp (RNA-dependent RNA polymerase) inhibitor (20). We conclude that R803 and related heterocyclic compounds are a new class of HCV-specific inhibitors that could potentially be developed as a treatment for HCV infection.