New inhibitors of hepatitis C virus targeting cyclooxygenase-2

Hepatitis C virus (HCV) is a small (40–60 nM in diameter), enveloped, single-stranded (ss) RNA Hepacivirus in the Flaviviridae family. The current HCV therapy suffers from inadequate sustained viral response rate, rapid emergence of drug resistance, in particular for patients infected with genotype 1 HCV.1,2 We synthesized new pyrazolecarboxamide derivatives 3 as anti-HCV agents, and investigated the mechanism of inhibition. The most active compounds inhibited the subgenomic HCV replicon 1b in Huh 5-2 cells with EC50 of 6.7 μM and selectivity index of 23 against HCV 1b. Hit compound 1 did not target HCV NS5B or HCV IRES mediated translation; evaluation of the mechanism of anti-HCV activity of 1 revealed that it suppressed HCV-induced COX-2 mRNA and protein expression, exhibiting an IC50 of 3.2 μM in COX-2 promoter-linked luciferase reporter assay. Our data suggest that the pyrazolecarboxamide derivatives behave as anti-HCV agents by targeting COX-2 at both the transcriptional and translational levels. These results provide a strong basis for hit optimization of this new chemical class of HCV inhibitors. References (1) Tan, S. L.; Pause, A.; Sonenberg N. , Hepatitis C therapeutics: current status and emerging strategies. Nat. Rev. Drug. Disc. 2002, 1, 867-881. (2) Manvar, D.; Pelliccia, S.; La Regina, G. et al. New 1-phenyl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides inhibit hepatitis C virus replication via suppression of cyclooxygenase-2. Eur. J. Med. Chem. 2015, 90, 497-506.