Finger loop inhibitors of the HCV NS5b polymerase. Part II. Optimization of tetracyclic indole-based macrocycle leading to the discovery of TMC647055

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• 作者：Sandrine Vendeville ; ^{svendev1@its.jnj.com} ; Tse-I. Lin ; Lili Hu ; Abdellah Tahri ; David McGowan ; Maxwell D. Cummings ; Katie Amssoms ; Maxime Canard ; Stefaan Last ; Iris Van den Steen ; Benoit Devogelaere ; Marie-Claude Rouan ; Leen Vijgen ; Jan Martin Berke ; Pascale Dehertogh ; Els Fransen ; Erna Cleiren ; Liesbet van der Helm ; Gregory Fanning ; Kristof Van Emelen ; Origè ; ne Nyanguile ; Kenny Simmen ; Pierre Raboisson
• 关键词：Hepatitis C virus ; NS5b polymerase ; Allosteric inhibitor ; Macrocycle
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：1 July, 2012
• 卷：22
• 期：13
• 页码：4437-4443
• 文件大小：1663 K

摘要

Optimization of a novel series of macrocyclic indole-based inhibitors of the HCV NS5b polymerase targeting the finger loop domain led to the discovery of lead compounds exhibiting improved potency in cellular assays and superior pharmacokinetic profile. Further lead optimization performed on the most promising unsaturated-bridged subseries provided the clinical candidate 27-cyclohexyl-12,13,16,17-tetrahydro-22-methoxy-11,17-dimethyl-10,10-dioxide-2,19-methano-3,7:4,1-dimetheno-1m>Hm>,11m>Hm>-14,10,2,9,11,17-benzoxathiatetraazacyclo docosine-8,18(9m>Hm>,15m>Hm>)-dione, TMC647055 (compound 18a). This non-zwitterionic 17-membered ring macrocycle combines nanomolar cellular potency (EC₅₀ of 82 nM) with minimal associated cell toxicity (CC₅₀ >20 渭M) and promising pharmacokinetic profiles in rats and dogs. TMC647055 is currently being evaluated in the clinic.