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Title: Discovery of (1R,5S)-N-[3-Amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]- 3-[2(S)-[[[(1,1-dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2(S)-carboxamide (SCH 503034), a Selective, Potent, Orally Bioavailable Hepatitis C Virus NS3 Protease Inhibitor: A Potential Therapeutic Agent for the Treatment of Hepatitis C Infection

Abstract

Hepatitis C virus (HCV) infection is the major cause of chronic liver disease, leading to cirrhosis and hepatocellular carcinoma, which affects more than 170 million people worldwide. Currently the only therapeutic regimens are subcutaneous interferon-{alpha} or polyethylene glycol (PEG)-interferon-{alpha} alone or in combination with oral ribavirin. Although combination therapy is reasonably successful with the majority of genotypes, its efficacy against the predominant genotype (genotype 1) is moderate at best, with only about 40% of the patients showing sustained virological response. Herein, the SAR leading to the discovery of 70 (SCH 503034), a novel, potent, selective, orally bioavailable NS3 protease inhibitor that has been advanced to clinical trials in human beings for the treatment of hepatitis C viral infections is described. X-ray structure of inhibitor 70 complexed with the NS3 protease and biological data are also discussed.

Authors:
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  1. (SPRI)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE
OSTI Identifier:
1007779
Resource Type:
Journal Article
Journal Name:
J. Med. Chem.
Additional Journal Information:
Journal Volume: 49; Journal Issue: (20) ; 10, 2006; Journal ID: ISSN 0022-2623
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 99 GENERAL AND MISCELLANEOUS//MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE; CLINICAL TRIALS; DRUGS; GENOTYPE; HEPATITIS; LIVER; PATIENTS; POLYETHYLENE GLYCOLS; THERAPY

Citation Formats

Venkatraman, Srikanth, Bogen, Stephane L., Arasappan, Ashok, Bennett, Frank, Chen, Kevin, Jao, Edwin, Liu, Yi-Tsung, Lovey, Raymond, Hendrata, Siska, Huang, Yuhua, Pan, Weidong, Parekh, Tejal, Pinto, Patrick, Popov, Veljko, Pike, Russel, Ruan, Sumei, Santhanam, Bama, Vibulbhan, Bancha, Wu, Wanli, Yang, Weiying, Kong, Jianshe, Liang, Xiang, Wong, Jesse, Liu, Rong, Butkiewicz, Nancy, Chase, Robert, Hart, Andrea, Agrawal, Sony, Ingravallo, Paul, Pichardo, John, Kong, Rong, Baroudy, Bahige, Malcolm, Bruce, Guo, Zhuyan, Prongay, Andrew, Madison, Vincent, Broske, Lisa, Cui, Xiaoming, Cheng, Kuo-Chi, Hsieh, Yunsheng, Brisson, Jean-Marc, Prelusky, Danial, Korfmacher, Walter, White, Ronald, Bogdanowich-Knipp, Susan, Pavlovsky, Anastasia, Bradley, Prudence, Saksena, Anil K., Ganguly, Ashit, Piwinski, John, Girijavallabhan, Viyyoor, and Njoroge, F. George. Discovery of (1R,5S)-N-[3-Amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]- 3-[2(S)-[[[(1,1-dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2(S)-carboxamide (SCH 503034), a Selective, Potent, Orally Bioavailable Hepatitis C Virus NS3 Protease Inhibitor: A Potential Therapeutic Agent for the Treatment of Hepatitis C Infection. United States: N. p., 2008. Web. doi:10.1021/jm060325b.
Venkatraman, Srikanth, Bogen, Stephane L., Arasappan, Ashok, Bennett, Frank, Chen, Kevin, Jao, Edwin, Liu, Yi-Tsung, Lovey, Raymond, Hendrata, Siska, Huang, Yuhua, Pan, Weidong, Parekh, Tejal, Pinto, Patrick, Popov, Veljko, Pike, Russel, Ruan, Sumei, Santhanam, Bama, Vibulbhan, Bancha, Wu, Wanli, Yang, Weiying, Kong, Jianshe, Liang, Xiang, Wong, Jesse, Liu, Rong, Butkiewicz, Nancy, Chase, Robert, Hart, Andrea, Agrawal, Sony, Ingravallo, Paul, Pichardo, John, Kong, Rong, Baroudy, Bahige, Malcolm, Bruce, Guo, Zhuyan, Prongay, Andrew, Madison, Vincent, Broske, Lisa, Cui, Xiaoming, Cheng, Kuo-Chi, Hsieh, Yunsheng, Brisson, Jean-Marc, Prelusky, Danial, Korfmacher, Walter, White, Ronald, Bogdanowich-Knipp, Susan, Pavlovsky, Anastasia, Bradley, Prudence, Saksena, Anil K., Ganguly, Ashit, Piwinski, John, Girijavallabhan, Viyyoor, & Njoroge, F. George. Discovery of (1R,5S)-N-[3-Amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]- 3-[2(S)-[[[(1,1-dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2(S)-carboxamide (SCH 503034), a Selective, Potent, Orally Bioavailable Hepatitis C Virus NS3 Protease Inhibitor: A Potential Therapeutic Agent for the Treatment of Hepatitis C Infection. United States. doi:10.1021/jm060325b.
Venkatraman, Srikanth, Bogen, Stephane L., Arasappan, Ashok, Bennett, Frank, Chen, Kevin, Jao, Edwin, Liu, Yi-Tsung, Lovey, Raymond, Hendrata, Siska, Huang, Yuhua, Pan, Weidong, Parekh, Tejal, Pinto, Patrick, Popov, Veljko, Pike, Russel, Ruan, Sumei, Santhanam, Bama, Vibulbhan, Bancha, Wu, Wanli, Yang, Weiying, Kong, Jianshe, Liang, Xiang, Wong, Jesse, Liu, Rong, Butkiewicz, Nancy, Chase, Robert, Hart, Andrea, Agrawal, Sony, Ingravallo, Paul, Pichardo, John, Kong, Rong, Baroudy, Bahige, Malcolm, Bruce, Guo, Zhuyan, Prongay, Andrew, Madison, Vincent, Broske, Lisa, Cui, Xiaoming, Cheng, Kuo-Chi, Hsieh, Yunsheng, Brisson, Jean-Marc, Prelusky, Danial, Korfmacher, Walter, White, Ronald, Bogdanowich-Knipp, Susan, Pavlovsky, Anastasia, Bradley, Prudence, Saksena, Anil K., Ganguly, Ashit, Piwinski, John, Girijavallabhan, Viyyoor, and Njoroge, F. George. Mon . "Discovery of (1R,5S)-N-[3-Amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]- 3-[2(S)-[[[(1,1-dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2(S)-carboxamide (SCH 503034), a Selective, Potent, Orally Bioavailable Hepatitis C Virus NS3 Protease Inhibitor: A Potential Therapeutic Agent for the Treatment of Hepatitis C Infection". United States. doi:10.1021/jm060325b.
@article{osti_1007779,
title = {Discovery of (1R,5S)-N-[3-Amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]- 3-[2(S)-[[[(1,1-dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2(S)-carboxamide (SCH 503034), a Selective, Potent, Orally Bioavailable Hepatitis C Virus NS3 Protease Inhibitor: A Potential Therapeutic Agent for the Treatment of Hepatitis C Infection},
author = {Venkatraman, Srikanth and Bogen, Stephane L. and Arasappan, Ashok and Bennett, Frank and Chen, Kevin and Jao, Edwin and Liu, Yi-Tsung and Lovey, Raymond and Hendrata, Siska and Huang, Yuhua and Pan, Weidong and Parekh, Tejal and Pinto, Patrick and Popov, Veljko and Pike, Russel and Ruan, Sumei and Santhanam, Bama and Vibulbhan, Bancha and Wu, Wanli and Yang, Weiying and Kong, Jianshe and Liang, Xiang and Wong, Jesse and Liu, Rong and Butkiewicz, Nancy and Chase, Robert and Hart, Andrea and Agrawal, Sony and Ingravallo, Paul and Pichardo, John and Kong, Rong and Baroudy, Bahige and Malcolm, Bruce and Guo, Zhuyan and Prongay, Andrew and Madison, Vincent and Broske, Lisa and Cui, Xiaoming and Cheng, Kuo-Chi and Hsieh, Yunsheng and Brisson, Jean-Marc and Prelusky, Danial and Korfmacher, Walter and White, Ronald and Bogdanowich-Knipp, Susan and Pavlovsky, Anastasia and Bradley, Prudence and Saksena, Anil K. and Ganguly, Ashit and Piwinski, John and Girijavallabhan, Viyyoor and Njoroge, F. George},
abstractNote = {Hepatitis C virus (HCV) infection is the major cause of chronic liver disease, leading to cirrhosis and hepatocellular carcinoma, which affects more than 170 million people worldwide. Currently the only therapeutic regimens are subcutaneous interferon-{alpha} or polyethylene glycol (PEG)-interferon-{alpha} alone or in combination with oral ribavirin. Although combination therapy is reasonably successful with the majority of genotypes, its efficacy against the predominant genotype (genotype 1) is moderate at best, with only about 40% of the patients showing sustained virological response. Herein, the SAR leading to the discovery of 70 (SCH 503034), a novel, potent, selective, orally bioavailable NS3 protease inhibitor that has been advanced to clinical trials in human beings for the treatment of hepatitis C viral infections is described. X-ray structure of inhibitor 70 complexed with the NS3 protease and biological data are also discussed.},
doi = {10.1021/jm060325b},
journal = {J. Med. Chem.},
issn = {0022-2623},
number = (20) ; 10, 2006,
volume = 49,
place = {United States},
year = {2008},
month = {6}
}