Discovery and Early Development of TMC647055, a Non-Nucleoside Inhibitor of the Hepatitis C Virus NS5B Polymerase

详细信息    查看全文

• 作者：Maxwell D. Cummings ; Tse-I Lin ; Lili Hu ; Abdellah Tahri ; David McGowan ; Katie Amssoms ; Stefaan Last ; Benoit Devogelaere ; Marie-Claude Rouan ; Leen Vijgen ; Jan Martin Berke ; Pascale Dehertogh ; Els Fransen ; Erna Cleiren ; Liesbet van der Helm ; Gregory Fanning ; Orig猫ne Nyanguile ; Kenny Simmen ; Pieter Van Remoortere ; Pierre Raboisson ; Sandrine Vendeville
• 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：1880-1892
• 全文大小：569K
• 年卷期：v.57,no.5(March 13, 2014)
• ISSN：1520-4804

文摘

Structure-based macrocyclization of a 6-carboxylic acid indole chemotype has yielded potent and selective finger-loop inhibitors of the hepatitis C virus (HCV) NS5B polymerase. Lead optimization in conjunction with in vivo evaluation in rats identified several compounds showing (i) nanomolar potency in HCV replicon cells, (ii) limited toxicity and off-target activities, and (iii) encouraging preclinical pharmacokinetic profiles characterized by high liver distribution. This effort culminated in the identification of TMC647055 (10a), a nonzwitterionic 17-membered-ring macrocycle characterized by high affinity, long polymerase residence time, and broad genotypic coverage. In vitro results of the combination of 10a with the HCV protease inhibitor TMC435 (simeprevir) supported an evaluation of this combination in patients with regard to virus suppression and resistance emergence. In a phase 1b trial with HCV genotype 1-infected patients, 10a was considered to be safe and well-tolerated and demonstrated potent antiviral activity, which was further enhanced in a combination study with TMC435.