Structure鈥揂ctivity Relationship (SAR) Development and Discovery of Potent Indole-Based Inhibitors of the Hepatitis C Virus (HCV) NS5B Polymerase

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• 作者：Kevin X. Chen ; Bancha Vibulbhan ; Weiying Yang ; Mousumi Sannigrahi ; Francisco Velazquez ; Tin-Yau Chan ; Srikanth Venkatraman ; Gopinadhan N. Anilkumar ; Qingbei Zeng ; Frank Bennet ; Yueheng Jiang ; Charles A. Lesburg ; Jose Duca ; Patrick Pinto ; Stephen Gavalas ; Yuhua Huang ; Wanli Wu ; Oleg Selyutin ; 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：January 26, 2012
• 年：2012
• 卷：55
• 期：2
• 页码：754-765
• 全文大小：433K
• 年卷期：v.55,no.2(January 26, 2012)
• ISSN：1520-4804

文摘

Starting with the indole-based C-3 pyridone lead HCV polymerase inhibitor 2, extensive SAR studies were performed at different positions of the indole core. The best C-5 groups were found to be compact and nonpolar moieties and that the C-6 attachments were not affecting potency. Limited N-1 benzyl-type substituent studies indicated that the best substitutions were fluoro or methyl groups at 2鈥?or 5鈥?positions of the benzyl group. To improve pharmacokinetic (PK) properties, acylsulfonamides were incorporated as acid isosteres at the C-2 position. Further optimization of the combination at N-1, C-2, C-5, and C-6 resulted in the identification of compound 56, which had an excellent potency in both NS5B enzyme (IC₅₀ = 0.008 渭M) and cell-based replicon (EC₅₀ = 0.02 渭M) assays and a good oral PK profile with area-under-the curve (AUC) of 14 and 8 渭M路h in rats and dogs, respectively. X-ray structure of inhibitor 56 bound to the enzyme was also reported.