Hepatitis C Virus NS5A Replication Complex Inhibitors. Part 6: Discovery of a Novel and Highly Potent Biarylimidazole Chemotype with Inhibitory Activity Toward Genotypes 1a and 1b Replicons

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• 作者：Makonen Belema ; Van N. Nguyen ; Jeffrey L. Romine ; Denis R. St. Laurent ; Omar D. Lopez ; Jason T. Goodrich ; Peter T. Nower ; Donald R. O鈥橞oyle ; II ; Julie A. Lemm ; Robert A. Fridell ; Min Gao ; Hua Fang ; Rudolph G. Krause ; Ying-Kai Wang ; A. Jayne Oliver ; Andrew C. Good ; Jay O. Knipe ; Nicholas A. Meanwell ; Lawrence B. Snyder
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：March 13, 2014
• 年：2014
• 卷：57
• 期：5
• 页码：1995-2012
• 全文大小：625K
• 年卷期：v.57,no.5(March 13, 2014)
• ISSN：1520-4804

文摘

A medicinal chemistry campaign that was conducted to address a potential genotoxic liability associated with an aniline-derived scaffold in a series of HCV NS5A inhibitors with dual GT-1a/-1b inhibitory activity is described. Anilides 3b and 3c were used as vehicles to explore structural modifications that retained antiviral potency while removing the potential for metabolism-based unmasking of the embedded aniline. This effort resulted in the discovery of a highly potent biarylimidazole chemotype that established a potency benchmark in replicon assays, particularly toward HCV GT-1a, a strain with significant clinical importance. Securing potent GT-1a activity in a chemotype class lacking overt structural liabilities was a critical milestone in the effort to realize the full clinical potential of targeting the HCV NS5A protein.