Discovery and preclinical evaluation of potent, orally bioavailable, metabolically stable cyclopropylindolobenzazepine acylsulfonamides as thumb site 1 inhibitors of the hepatitis c virus NS5B RNA-dependent, RNA polymerase

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• 作者：Piyasena Hewawasam^a ; ^{hewawasp@gmail.com" class="auth_mail" title="E-mail the corresponding author} ; Yong Tu^a ; Min Gao^c ; Umesh Hanumegowda^b ; Jay Knipe^b ; Julie A. Lemm^c ; Dawn D. Parker^b ; Karen L. Rigat^c ; Susan B. Roberts^c ; Nicholas A. Meanwell^a ; John F. Kadow^a
• 关键词：HCV ; NS5B ; Replicase ; Inhibitors ; Cyclopropylindolobenzazepine ; Direct-acting ; Antiviral agent
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：1 February 2016
• 年：2016
• 卷：26
• 期：3
• 页码：936-940
• 全文大小：540 K

文摘

Herein, we describe the synthesis, antiviral structure–activity relationships (SAR), metabolic stability, and pharmacokinetic (PK) properties for a series of cyclopropylindolobenzazepine acylsulfonamide HCV NS5B polymerase inhibitors. Optimization of SAR, metabolic stability and PK led to the identification of compound 19 which was advanced into pre-IND enabling toxicology studies.