publications

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

Huang P, Goff DA, Huang Q, Martinez A, Xu X, Crowder S, Issakani SD, Anderson E, Sheng N, Achacoso P, Yen A, Kinsella T, Darwish IS, Kolluri R, Hong H, Qu K, Stauffer E, Goldstein E, Singh R, Payan DG, Lu HH.

Antimicrob Agents Chemother. 2008 Apr;52(4):1419-29. Epub 2008 Jan 28.

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-alpha in blocking HCV RNA replicon in the replicon model. In combination studies, R803 showed weak synergistic effect with IFN-alpha/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.

PMID: 18227176 [PubMed - as supplied by publisher]