Benzimidazole derivatives bearing substituted biphenyls as hepatitis C virus NS5B RNA-dependent RNA polymerase inhibitors: structure-activity relationship studies and identification of a potent and highly selective inhibitor JTK-109.
Following the discovery of a new series of benzimidazole derivatives bearing a diarylmethyl group as inhibitors of hepatitis C virus NS5B RNA-dependent RNA polymerase (HCV NS5B RdRp),1,2 we extended the structure-activity relationship (SAR) study to analogues bearing a substituted biphenyl group and succeeded in a significant advancement of activity. Starting from compound 1, optimization of the A, B, and C rings afforded potent inhibitors with low nanomolar potency against genotype 1b NS5B. The compounds, which have a substituent with a carbonyl function at the 4-position of the B-ring, efficiently blocked subgenomic viral RNA replication in the replicon cell assay at low submicromolar concentrations. Among the new compounds, compound 10n (JTK-109) exhibited favorable pharmacokinetic profiles, high selectivity for NS5B, and good safety profiles, suggesting the potential for a clinical candidate in the treatment of hepatitis C.
Hirashima
Shintaro
S
Central Pharmaceutical Research Institute, Japan Tobacco Inc., Takatsuki, Osaka 569-1125, Japan.
Suzuki
Takayoshi
T
Ishida
Tomio
T
Noji
Satoru
S
Yata
Shinji
S
Ando
Izuru
I
Komatsu
Masakazu
M
Ikeda
Satoru
S
Hashimoto
Hiromasa
H
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D016174:Hepacivirus / Q000235:genetics; D006801:Humans; D008099:Liver / Q000378:metabolism; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors*; D051381:Rats; D012093:Replicon; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry
C513006:2-(4-(4'-chloro-4-(2-oxopyrrolidin-1-yl)biphenyl-2-ylmethoxy)-2-fluorophenyl)-1-cyclohexyl-1H-benzimidazole-5-carboxylic acid; D000998:Antiviral Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase