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

被引：156

作者：

Hirashima, Shintaro ^{[1
]}

Suzuki, Takayoshi ^{[1
]}

Ishida, Tomio ^{[1
]}

Noji, Satoru ^{[1
]}

Yata, Shinji ^{[1
]}

Ando, Izuru ^{[1
]}

Komatsu, Masakazu ^{[1
]}

Ikeda, Satoru ^{[1
]}

Hashimoto, Hiromasa ^{[1
]}

机构：

[1] Japan Tobacco Inc, Cent Pharmaceut Res Inst, Takatsuki, Osaka 5691125, Japan

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2006年 / 49卷 / 15期

关键词：

D O I：

10.1021/jm060269e

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：4721 / 4736

页数：16

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