Des-A-ring benzothiadiazines: Inhibitors of HCV genotype 1 NS5B RNA-dependent RNA polymerase

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• 作者：Pamela L. Donner ; Qinghua Xie ; John K. Pratt ; Clarence J. Maring ; Warren Kati ; Wen Jiang ; Yaya Liu ; Gennadiy Koev ; Sherie Masse ; Debra Montgomery ; Akhter Molla ; Dale J. Kempf
• 关键词：HCV polymerase ; Benzothiadiazines ; HCV genotype 1 ; Antivirals
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2008
• 出版时间：15 April 2008
• 年：2008
• 卷：18
• 期：8
• 页码：2735-2738
• 全文大小：185 K

文摘

In our program to discover non-nucleoside, small molecule inhibitors of genotype 1 HCV polymerase, we investigated a series of promising analogs based on a benzothiadiazine screening hit that contains an ABCD ring system. After demonstrating that a methylsulfonylamino D-ring substituent increased the enzyme potency into the low nanomolar range, we explored a minimum core required for activity by truncating to a three-ring system. Described herein are the syntheses and structure–activity relationship of a set of inhibitors lacking the A-ring of an ABCD ring system. We observed that small aromatic rings and alkenyl groups appended to the 5-position of the B-ring were optimal, resulting in inhibitors with low nanomolar potencies.