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

被引：25

作者：

Cummings, Maxwell D. ^{[1
]}

Lin, Tse-I ^{[1
]}

Hu, Lili ^{[1
]}

Tahri, Abdellah ^{[1
]}

McGowan, David ^{[1
]}

Amssoms, Katie ^{[1
]}

Last, Stefaan ^{[1
]}

Devogelaere, Benoit ^{[1
]}

Rouan, Marie-Claude ^{[1
]}

Vijgen, Leen ^{[1
]}

Berke, Jan Martin ^{[1
]}

Dehertogh, Pascale ^{[1
]}

Fransen, Els ^{[1
]}

Cleiren, Erna ^{[1
]}

van der Helm, Liesbet ^{[1
]}

Fanning, Gregory ^{[1
]}

Nyanguile, Origene ^{[1
]}

Simmen, Kenny ^{[1
]}

Van Remoortere, Pieter ^{[1
]}

Raboisson, Pierre ^{[1
]}

Vendeville, Sandrine ^{[1
]}

机构：

[1] Janssen Infect Dis BVBA, B-2340 Beerse, Belgium

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2014年 / 57卷 / 05期

关键词：

DEPENDENT RNA-POLYMERASE; FINGER-LOOP INHIBITORS; GENOTYPE; INFECTION; PROTEASE INHIBITOR; IN-VITRO; MACROCYCLIC INHIBITORS; ALLOSTERIC INHIBITORS; HCVNS5B POLYMERASE; ANTIVIRAL ACTIVITY; HCV;

D O I：

10.1021/jm401396p

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 0) 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.

引用

页码：1880 / 1892

页数：13

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