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Bioorg Med Chem Lett. 2013 Sep 1;23(17):4774-8. doi: 10.1016/j.bmcl.2013.07.005. Epub 2013 Jul 13.

Peroxisome proliferator-activated receptor delta antagonists inhibit hepatitis C virus RNA replication.

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Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-Naka, Kita-ku, Okayama 700-8530, Japan.


It has been reported that ligand-mediated transcription factor peroxisome proliferator-activated receptor alpha (hPPARα) is involved in hepatitis C virus (HCV) RNA replication, whereas hPPARγ is not, and the effect of hPPARδ is unknown. Here, we show that hPPARδ-selective antagonists effectively inhibit HCV RNA replication. We describe the design, synthesis and pharmacological evaluation of a series of biphenyl-4-carboxylic acid-type hPPARδ antagonists, including previously reported compounds, as candidate anti-HCV agents. A representative compound (4c) dose-dependently inhibited HCV RNA replication (EC50 0.22 μM), while exhibiting relatively weak cytotoxicity to the host cells (CC50 2.5 μM). It also showed an additive and dose-dependent effect on the inhibition of HCV RNA replication by pegylated interferon alpha (Peg-IFNα) alone and by both Peg-IFNα and ribavirin (currently the clinical treatment of choice for HCV infection). Thus, combination of a hPPARδ antagonist with current therapy may improve the efficacy of treatment for HCV infection.


Biphenyl-4-carboxylic acid; HCV RNA replication; PPAR delta; PPAR delta antagonist

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