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.
| Original language | English |
|---|---|
| Pages (from-to) | 4774-4778 |
| Number of pages | 5 |
| Journal | Bioorganic and Medicinal Chemistry Letters |
| Volume | 23 |
| Issue number | 17 |
| DOIs | |
| Publication status | Published - Sep 1 2013 |
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Keywords
- Biphenyl-4-carboxylic acid
- HCV RNA replication
- PPAR delta
- PPAR delta antagonist
ASJC Scopus subject areas
- Pharmaceutical Science
- Drug Discovery
- Organic Chemistry
- Molecular Medicine
- Molecular Biology
- Clinical Biochemistry
- Biochemistry
Cite this
Peroxisome proliferator-activated receptor delta antagonists inhibit hepatitis C virus RNA replication. / Ban, Shintaro; Ueda, Youki; Ohashi, Masao; Matsuno, Kenji; Ikeda, Masanori; Kato, Nobuyuki; Miyachi, Hiroyuki.
In: Bioorganic and Medicinal Chemistry Letters, Vol. 23, No. 17, 01.09.2013, p. 4774-4778.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Peroxisome proliferator-activated receptor delta antagonists inhibit hepatitis C virus RNA replication
AU - Ban, Shintaro
AU - Ueda, Youki
AU - Ohashi, Masao
AU - Matsuno, Kenji
AU - Ikeda, Masanori
AU - Kato, Nobuyuki
AU - Miyachi, Hiroyuki
PY - 2013/9/1
Y1 - 2013/9/1
N2 - 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.
AB - 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.
KW - Biphenyl-4-carboxylic acid
KW - HCV RNA replication
KW - PPAR delta
KW - PPAR delta antagonist
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UR - http://www.scopus.com/inward/citedby.url?scp=84881372652&partnerID=8YFLogxK
U2 - 10.1016/j.bmcl.2013.07.005
DO - 10.1016/j.bmcl.2013.07.005
M3 - Article
C2 - 23891183
AN - SCOPUS:84881372652
VL - 23
SP - 4774
EP - 4778
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
SN - 0960-894X
IS - 17
ER -