title: Discovery and characterization of substituted diphenyl heterocyclic compounds as potent and selective inhibitors of hepatitis C virus replication.
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 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-alpha) at blocking HCV RNA replication in the replicon model. In combination studies, R803 showed a weak synergistic effect with IFN-alpha/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.
authors.affiliation: Department of Virology, Rigel Pharmaceuticals, Inc., 1180 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Peiyong
authors.initials: P
authors.lastname: Huang
authors.forename: Dane A
authors.initials: DA
authors.lastname: Goff
authors.forename: Qi
authors.initials: Q
authors.lastname: Huang
authors.forename: Anthony
authors.initials: A
authors.lastname: Martinez
authors.forename: Xiang
authors.initials: X
authors.lastname: Xu
authors.forename: Scott
authors.initials: S
authors.lastname: Crowder
authors.forename: Sarkiz D
authors.initials: SD
authors.lastname: Issakani
authors.forename: Emily
authors.initials: E
authors.lastname: Anderson
authors.forename: Ning
authors.initials: N
authors.lastname: Sheng
authors.forename: Philip
authors.initials: P
authors.lastname: Achacoso
authors.forename: Ann
authors.initials: A
authors.lastname: Yen
authors.forename: Todd
authors.initials: T
authors.lastname: Kinsella
authors.forename: Ihab S
authors.initials: IS
authors.lastname: Darwish
authors.forename: Rao
authors.initials: R
authors.lastname: Kolluri
authors.forename: Hui
authors.initials: H
authors.lastname: Hong
authors.forename: Kunbin
authors.initials: K
authors.lastname: Qu
authors.forename: Emily
authors.initials: E
authors.lastname: Stauffer
authors.forename: Eileen
authors.initials: E
authors.lastname: Goldstein
authors.forename: Rajinder
authors.initials: R
authors.lastname: Singh
authors.forename: Donald G
authors.initials: DG
authors.lastname: Payan
authors.forename: H Henry
authors.initials: HH
authors.lastname: Lu
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology*; D001572:Benzofurans / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004347:Drug Interactions; D024882:Drug Resistance, Viral; D005838:Genotype; D016174:Hepacivirus / Q000145:classification / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006571:Heterocyclic Compounds / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology; D008826:Microbial Sensitivity Tests / Q000379:methods*; D012367:RNA, Viral / Q000096:biosynthesis; D012093:Replicon / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D001572:Benzofurans; D006571:Heterocyclic Compounds; D016898:Interferon-alpha; D012367:RNA, Viral; C010258:enprofen