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.
From: Central Pharmaceutical Research Institute, Japan Tobacco Inc., Takatsuki, Osaka 569-1125, Japan.
Journal of medicinal chemistry
- Publish Date: Jul 2006
- ISSN: 0022-2623
- Volume: 49
- Issue: 15
- Pages: 4721-36
- Medium: Print
- Language: English
- Citation (JAMA): Hirashima Shintaro, Suzuki Takayoshi, Ishida Tomio, et al. 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.. J. Med. Chem. Jul 2006;49:4721-36
Abstract
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.
Mesh Headings (Keywords): Animals, Antiviral Agents, Benzimidazoles, Biphenyl Compounds, Cell Line, Cell Survival, Hepacivirus, Humans, Liver, RNA Replicase, Rats, Replicon, Structure-Activity Relationship, Viral Nonstructural Proteins
Check for Full Text / PubMed Unique Identifier (PMID): 16854079
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