Structure-activity relationship study on a novel series of cyclopentane-containing macrocyclic inhibitors of the hepatitis C virus NS3/4A protease leading to the discovery of TMC435350

被引：118

作者：

Raboisson, Pierre ^{[1
,2
]}

de Kock, Herman ^{[1
,2
]}

Rosenquist, Asa ^{[3
]}

Nilsson, Magnus ^{[3
]}

Salvador-Oden, Lourdes ^{[3
]}

Lin, Tse-I ^{[1
,2
]}

Roue, Natalie ^{[3
]}

Ivanov, Vladimir ^{[3
]}

Wahling, Horst ^{[3
]}

Wickstrom, Kristina ^{[3
]}

Hamelink, Elizabeth ^{[3
]}

Edlund, Michael ^{[3
]}

Vrang, Lotta ^{[3
]}

Vendeville, Sandrine ^{[1
,2
]}

Van de Vreken, Wim ^{[1
,2
]}

McGowan, David ^{[1
,2
]}

Tahri, Abdellah ^{[1
,2
]}

Hu, Lili ^{[1
,2
]}

Boutton, Carlo ^{[1
,2
]}

Lenz, Oliver ^{[1
,2
]}

Delouvroy, Frederic ^{[1
,2
]}

Pille, Geert ^{[1
,2
]}

Surleraux, Dominique ^{[1
,2
]}

Wigerinck, Piet ^{[1
,2
]}

Samuelsson, Bertil ^{[3
]}

Simmen, Kenneth ^{[1
,2
]}

机构：

[1] Tibotec BVBA, B-2800 Mechelen, Belgium

[2] Tibotec Pharmaceut Ltd, Little Isl, Cork, Ireland

[3] Medivir AB, SE-14122 Huddinge, Sweden

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2008年 / 18卷 / 17期

关键词：

hepatitis C; macrocycle; protease; NS3;

D O I：

10.1016/j.bmcl.2008.07.088

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

SAR analysis performed with a limited set of cyclopentane-containing macrocycles led to the identification of N-[17-[2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methylquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo [13.3.0.0(4,6)]octadec-7-ene-4-carbonyl](cyclopropyl) sulfonamide (TMC435350, 32c) as a potent inhibitor of HCV NS3/4A protease (K-i = 0.36 nM) and viral replication (replicon EC50 = 7.8 nM). TMC435350 also displayed low in vitro clearance and high permeability, which were confirmed by in vivo pharmacokinetic studies. TMC435350 is currently being evaluated in the clinics. (C) 2008 Elsevier Ltd. All rights reserved.

引用

页码：4853 / 4858

页数：6

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