I. Novel HCV NS5B polymerase inhibitors: Discovery of indole 2-carboxylic acids with C3-heterocycles

被引:46
作者
Anilkumar, Gopinadhan N. [1 ]
Lesburg, Charles A. [1 ]
Selyutin, Oleg [1 ]
Rosenblum, Stuart B. [1 ]
Zeng, Qingbei [1 ]
Jiang, Yueheng [1 ]
Chan, Tin-Yau [1 ]
Pu, Haiyan [1 ]
Vaccaro, Henry [1 ]
Wang, Li [1 ]
Bennett, Frank [1 ]
Chen, Kevin X. [1 ]
Duca, Jose [1 ]
Gavalas, Stephen [1 ]
Huang, Yuhua [1 ]
Pinto, Patrick [1 ]
Sannigrahi, Mousumi [1 ]
Velazquez, Francisco [1 ]
Venkatraman, Srikanth [1 ]
Vibulbhan, Bancha [1 ]
Agrawal, Sony [1 ]
Butkiewicz, Nancy [1 ]
Feld, Boris [1 ]
Ferrari, Eric [1 ]
He, Zhiqing [1 ]
Jiang, Chuan-kui [1 ]
Palermo, Robert E. [1 ]
Mcmonagle, Patricia [1 ]
Huang, H. -C. [1 ]
Shih, Neng-Yang [1 ]
Njoroge, George [1 ]
Kozlowski, Joseph A. [1 ]
机构
[1] Merck Res Labs, Kenilworth, NJ 07033 USA
关键词
HCV; NS5B polymerase; HEPATITIS-C VIRUS; DEPENDENT RNA-POLYMERASE; CRYSTAL-STRUCTURE; INFECTION;
D O I
10.1016/j.bmcl.2011.07.021
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
SAR development of indole-based palm site inhibitors of HCV NS5B polymerase exemplified by initial indole lead 1 (NS5B IC(50) = 0.9 mu M, replicon EC(50) > 100 mu M) is described. Structure-based drug design led to the incorporation of novel heterocyclic moieties at the indole C3-position which formed a bidentate interaction with the protein backbone. SAR development resulted in leads 7q (NS5B IC(50) = 0.032 mu M, replicon EC(50) = 1.4 mu M) and 7r (NS5B IC(50) = 0.017 mu M, replicon EC(50) = 0.3 mu M) with improved enzyme and replicon activity. (C) 2011 Elsevier Ltd. All rights reserved.
引用
收藏
页码:5336 / 5341
页数:6
相关论文
共 13 条
[1]   The prevalence of hepatitis C virus infection in the United States, 1988 through 1994 [J].
Alter, MJ ;
Kruszon-Moran, D ;
Nainan, OV ;
McQuillan, GM ;
Gao, FX ;
Moyer, LA ;
Kaslow, RA ;
Margolis, HS .
NEW ENGLAND JOURNAL OF MEDICINE, 1999, 341 (08) :556-562
[2]   Recent advances in the development of NS5B polymerase inhibitors for the treatment of hepatitis C virus infection [J].
Beaulieu, Pierre L. .
EXPERT OPINION ON THERAPEUTIC PATENTS, 2009, 19 (02) :145-164
[3]   Crystal structure of the RNA-dependent RNA polymerase of hepatitis C virus [J].
Bressanelli, S ;
Tomei, L ;
Roussel, A ;
Incitti, I ;
Vitale, RL ;
Mathieu, M ;
De Francesco, R ;
Rey, FA .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (23) :13034-13039
[4]   Inhibitors of hepatitis C virus polymerase: Synthesis and characterization of novel 2-oxy-6-fluoro-N-((S)-1-hydroxy-3-phenylpropan-2-yl)-benzamides [J].
Cheng, Cliff C. ;
Shipps, Gerald W., Jr. ;
Yang, Zhiwei ;
Kawahata, Noriyuki ;
Lesburg, Charles A. ;
Duca, Jose S. ;
Bandouveres, Jamie ;
Bracken, Jack D. ;
Jiang, Chuan-kui ;
Agrawal, Sony ;
Ferrari, Eric ;
Huang, H. -C. .
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2010, 20 (07) :2119-2124
[5]   The scientific challenge of hepatitis C [J].
Cohen, J .
SCIENCE, 1999, 285 (5424) :26-30
[6]   HEPATITIS-C - PROGRESS AND PROBLEMS [J].
CUTHBERT, JA .
CLINICAL MICROBIOLOGY REVIEWS, 1994, 7 (04) :505-&
[7]   New therapeutic strategies for hepatitis C [J].
Di Bisceglie, AM ;
McHutchinson, J ;
Rice, CM .
HEPATOLOGY, 2002, 35 (01) :224-231
[8]   Hepatitis C Virus NS5B Polymerase Exhibits Distinct Nucleotide Requirements for Initiation and Elongation [J].
Ferrari, Eric ;
He, Zhiqing ;
Palermo, Robert E. ;
Huang, H. -C. .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2008, 283 (49) :33893-33901
[9]  
Lesburg CA, 1999, NAT STRUCT BIOL, V6, P937
[10]   The epidemiology and prevention of hepatocellular carcinoma [J].
Monto, A ;
Wright, TL .
SEMINARS IN ONCOLOGY, 2001, 28 (05) :441-449