A Novel Class of Highly Potent Irreversible Hepatitis C Virus NS5B Polymerase Inhibitors

被引：25

作者：

Chen, Kevin X. ^{[1
]}

Lesburg, Charles A. ^{[1
]}

Vibulbhan, Bancha ^{[1
]}

Yang, Weiying ^{[1
]}

Chan, Tin-Yau ^{[1
]}

Venkatraman, Srikanth ^{[1
]}

Velazquez, Francisco ^{[1
]}

Zeng, Qingbei ^{[1
]}

Bennett, Frank ^{[1
]}

Anilkumar, Gopinadhan N. ^{[1
]}

Duca, Jose ^{[1
]}

Jiang, Yueheng ^{[1
]}

Pinto, Patrick ^{[1
]}

Wang, Li ^{[1
]}

Huang, Yuhua ^{[1
]}

Selyutin, Oleg ^{[1
]}

Gavalas, Stephen ^{[1
]}

Pu, Haiyan ^{[1
]}

Agrawal, Sony ^{[1
]}

Feld, Boris ^{[1
]}

Huang, Hsueh-Cheng ^{[1
]}

Li, Cheng ^{[1
]}

Cheng, Kuo-Chi ^{[1
]}

Shih, Neng-Yang ^{[1
]}

Kozlowski, Joseph A. ^{[1
]}

Rosenblum, Stuart B. ^{[1
]}

Njoroge, F. George ^{[1
]}

机构：

[1] Merck Res Labs, Kenilworth, NJ 07033 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2012年 / 55卷 / 05期

关键词：

DEPENDENT RNA-POLYMERASE; ANTIVIRAL ACTIVITY; NONNUCLEOSIDE INHIBITORS; PROTEASE INHIBITOR; CRYSTAL-STRUCTURE; IN-VITRO; DISCOVERY; NUCLEOTIDE; DESIGN; IDENTIFICATION;

D O I：

10.1021/jm201322r

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Starting from indole-based C-3 pyridone HCV NS5B polymerase inhibitor 2, structure-activity relationship (SAR) investigations of the indole N-1 benzyl moiety were performed. This study led to the discovery of irreversible inhibitors with p-fluoro-sulfone- or p-fluoro-nitro-substituted N-1 benzyl groups which achieved breakthrough replicon assay potency (EC50 = 1 nM). The formation of a covalent bond with adjacent cysteine-366 thiol was was proved by mass spectroscopy and X-ray crystal structure studies. The C-5 ethyl C-2 carboxylic acid derivative 47 had an excellent oral area-under-the-curve (AUC) of 18 mu M.h (10 mg/kg). Its oral exposure in monkeys and dogs was also very good. The NMR ALARM assay, mass spectroscopy experiments, in vitro counter screening, and toxicology assays demonstrated that the covalent bond formation between compound 47 and the protein was highly selective and specific. The overall excellent profile of 47 made it an interesting candidate for further investigation.

引用

页码：2089 / 2101

页数：13

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