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 Hi
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- 作者：Shintaro Hirashima ; Takayoshi Suzuki ; Tomio Ishida ; Satoru Noji ; Shinji Yata ; Izuru Ando ; Masakazu Komatsu ; Satoru Ikeda ; Hiromasa Hashimoto
- 刊名：Journal of Medicinal Chemistry
- 出版年：2006
- 出版时间：July 27, 2006
- 年：2006
- 卷：49
- 期：15
- 页码：4721 - 4736
- 全文大小：222K
- 年卷期：v.49,no.15(July 27, 2006)
- ISSN：1520-4804
文摘
Following the discovery of a new series of benzimidazole derivatives bearing a diarylmethyl group asinhibitors of hepatitis C virus NS5B RNA-dependent RNA polymerase (HCV NS5B RdRp),1,2 we extendedthe structure-activity relationship (SAR) study to analogues bearing a substituted biphenyl group andsucceeded 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. Thecompounds, which have a substituent with a carbonyl function at the 4-position of the B-ring, efficientlyblocked 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, highselectivity for NS5B, and good safety profiles, suggesting the potential for a clinical candidate in the treatmentof hepatitis C.