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Antimicrobial Agents and Chemotherapy, April 2008, p. 1419-1429, Vol. 52, No. 4
0066-4804/08/$08.00+0     doi:10.1128/AAC.00525-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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

Peiyong Huang,¹ Dane A. Goff,² Qi Huang,¹ Anthony Martinez,¹ Xiang Xu,³ Scott Crowder,¹ Sarkiz D. Issakani,³ Emily Anderson,¹ Ning Sheng,¹ Philip Achacoso,¹ Ann Yen,¹ Todd Kinsella,¹ Ihab S. Darwish,² Rao Kolluri,² Hui Hong,² Kunbin Qu,² Emily Stauffer,² Eileen Goldstein,² Rajinder Singh,² Donald G. Payan,^1,2,3 and H. Henry Lu^1*

Departments of Virology,¹ Chemistry,² High-Throughput Screening, Rigel Pharmaceuticals, Inc., 1180 Veterans Boulevard, South San Francisco, California 94080³

Received 20 April 2007/ Returned for modification 1 June 2007/ Accepted 14 December 2007

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 reverse transcription-PCR and Western blotting of R706-treated replicon cells. Structure-activity iterations of the R706 series yielded a lead compound, R803, that 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 by a panel of biochemical and cell-based assays for on-target and off-target activities, and the data suggested that the compound had a therapeutic window close to 100-fold, while its exact mechanism of action remained elusive. We found that R803 was more effective than alpha interferon (IFN-) at blocking HCV RNA replication in the replicon model. In combination studies, R803 showed a weak synergistic effect with IFN-/ribavirin but only additive effects with a protease inhibitor and an allosteric inhibitor of RNA-dependent RNA polymerase (20). We conclude that R803 and related heterocyclic compounds constitute a new class of HCV-specific inhibitors that could potentially be developed as a treatment for HCV infection.

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* Corresponding author. Mailing adddress: Department of Virology, Rigel Pharmaceuticals, Inc., 1180 Veterans Boulevard, South San Francisco, CA 94080. Phone: (650) 624-1331. Fax: (650) 624-1101. E-mail: hlu{at}rigel.com

Published ahead of print on 28 January 2008.

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Antimicrobial Agents and Chemotherapy, April 2008, p. 1419-1429, Vol. 52, No. 4
0066-4804/08/$08.00+0     doi:10.1128/AAC.00525-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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