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

被引：27

作者：

Vendeville, Sandrine ^{[1
]}

Lin, Tse-I ^{[1
]}

Hu, Lili ^{[1
]}

Tahri, Abdellah ^{[1
]}

McGowan, David ^{[1
]}

Cummings, Maxwell D. ^{[1
]}

Amssoms, Katie ^{[1
]}

Canard, Maxime ^{[1
]}

Last, Stefaan ^{[1
]}

Van den Steen, Iris ^{[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
]}

Van Emelen, Kristof ^{[1
]}

Nyanguile, Origene ^{[1
]}

Simmen, Kenny ^{[1
]}

Raboisson, Pierre ^{[1
]}

机构：

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

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2012年 / 22卷 / 13期

关键词：

Hepatitis C virus; NS5b polymerase; Allosteric inhibitor; Macrocycle; DEPENDENT RNA-POLYMERASE; N-ACETAMIDE INHIBITORS; HEPATITIS-C; ALLOSTERIC INHIBITORS; HCVNS5B POLYMERASE; POTENT INHIBITORS; RECENT PROGRESS; IDENTIFICATION; PROTEASE;

D O I：

10.1016/j.bmcl.2012.04.113

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

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-1H, 11H-14,10,2,9,11,17-benzoxathiatetraazacyclo docosine-8,18(9H, 15H)-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 mu M) and promising pharmacokinetic profiles in rats and dogs. TMC647055 is currently being evaluated in the clinic. (C) 2012 Elsevier Ltd. All rights reserved.

引用

页码：4437 / 4443

页数：7

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