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

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• 作者：Kevin X. Chen ; Charles A. Lesburg ; Bancha Vibulbhan ; Weiying Yang ; Tin-Yau Chan ; Srikanth Venkatraman ; Francisco Velazquez ; Qingbei Zeng ; Frank Bennett ; Gopinadhan N. Anilkumar ; Jose Duca ; Yueheng Jiang ; Patrick Pinto ; Li Wang ; Yuhua Huang ; Oleg Selyutin ; Stephen Gavalas ; Haiyan Pu ; Sony Agrawal ; Boris Feld ; Hsueh-Cheng Huang ; Cheng Li ; Kuo-Chi Cheng ; Neng-Yang Shih ; Joseph A. Kozlowski ; Stuart B. Rosenblum ; F. George Njoroge
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：March 8, 2012
• 年：2012
• 卷：55
• 期：5
• 页码：2089-2101
• 全文大小：467K
• 年卷期：v.55,no.5(March 8, 2012)
• ISSN：1520-4804

文摘

Starting from indole-based C-3 pyridone HCV NS5B polymerase inhibitor 2, structure鈥揳ctivity 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 渭M路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.