title: Peroxisome proliferator-activated receptor delta antagonists inhibit hepatitis C virus RNA replication.
abstract: 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.
authors.affiliation: Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-Naka, Kita-ku, Okayama 700-8530, Japan.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Ban
authors.forename: Youki
authors.initials: Y
authors.lastname: Ueda
authors.forename: Masao
authors.initials: M
authors.lastname: Ohashi
authors.forename: Kenji
authors.initials: K
authors.lastname: Matsuno
authors.forename: Masanori
authors.initials: M
authors.lastname: Ikeda
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Kato
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Miyachi
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000737:chemistry / Q000494:pharmacology*; D002264:Carboxylic Acids / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics*; D006526:Hepatitis C / Q000188:drug therapy / Q000821:virology*; D006801:Humans; D047494:PPAR delta / Q000037:antagonists & inhibitors*; D012367:RNA, Viral / Q000235:genetics*
chemical_list: D000998:Antiviral Agents; D001713:Biphenyl Compounds; D002264:Carboxylic Acids; D047494:PPAR delta; D012367:RNA, Viral
keywords: Biphenyl-4-carboxylic acid; HCV RNA replication; PPAR delta; PPAR delta antagonist