Literature DB >> 24900812

Discovery of SCH 900188: A Potent Hepatitis C Virus NS5B Polymerase Inhibitor Prodrug As a Development Candidate.

Kevin X Chen1, Srikanth Venkatraman1, Gopinadhan N Anilkumar1, Qingbei Zeng1, Charles A Lesburg1, Bancha Vibulbhan1, Francisco Velazquez1, Tin-Yau Chan1, Frank Bennet1, Yueheng Jiang1, Patrick Pinto1, Yuhua Huang1, Oleg Selyutin1, Sony Agrawal1, Hsueh-Cheng Huang1, Cheng Li1, Kuo-Chi Cheng1, Neng-Yang Shih1, Joseph A Kozlowski1, Stuart B Rosenblum1, F George Njoroge1.   

Abstract

Starting from indole-based hepatitis C virus (HCV) NS5B polymerase inhibitor lead compound 1, structure modifications were performed at multiple indole substituents to improve potency and pharmacokinetic (PK) properties. Bicyclic quinazolinone was found to be the best substituent at indole nitrogen, while 4,5-furanylindole was identified as the best core. Compound 11 demonstrated excellent potency. Its C2 N,N-dimethylaminoethyl ester prodrug 12 (SCH 900188) demonstrated significant improvement in PK and was selected as the development candidate.

Entities:  

Keywords:  HCV; NS5B polymerase; hepatitis C virus; polymerase inhibitor; prodrug

Year:  2013        PMID： 24900812      PMCID： PMC4027611          DOI： 10.1021/ml400192w

Source DB:  PubMed          Journal:  ACS Med Chem Lett        ISSN： 1948-5875            Impact factor:   4.345


  16 in total

1.  The scientific challenge of hepatitis C.

Authors:  J Cohen
Journal:  Science       Date:  1999-07-02       Impact factor: 47.728

2.  Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome.

Authors:  Q L Choo; G Kuo; A J Weiner; L R Overby; D W Bradley; M Houghton
Journal:  Science       Date:  1989-04-21       Impact factor: 47.728

Review 3.  A review of HCV protease inhibitors.

Authors:  Kevin X Chen; F George Njoroge
Journal:  Curr Opin Investig Drugs       Date:  2009-08

Review 4.  Global epidemiology of hepatitis C virus infection.

Authors:  Colin W Shepard; Lyn Finelli; Miriam J Alter
Journal:  Lancet Infect Dis       Date:  2005-09       Impact factor: 25.071

Review 5.  Challenges in modern drug discovery: a case study of boceprevir, an HCV protease inhibitor for the treatment of hepatitis C virus infection.

Authors:  F George Njoroge; Kevin X Chen; Neng-Yang Shih; John J Piwinski
Journal:  Acc Chem Res       Date:  2008-01       Impact factor: 22.384

Review 6.  HCV NS5B polymerase inhibitors.

Authors:  William J Watkins; Adrian S Ray; Lee S Chong
Journal:  Curr Opin Drug Discov Devel       Date:  2010-07

7.  Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line.

Authors:  V Lohmann; F Körner; J Koch; U Herian; L Theilmann; R Bartenschlager
Journal:  Science       Date:  1999-07-02       Impact factor: 47.728

8.  Crystal structure of the RNA-dependent RNA polymerase from hepatitis C virus reveals a fully encircled active site.

Authors:  C A Lesburg; M B Cable; E Ferrari; Z Hong; A F Mannarino; P C Weber
Journal:  Nat Struct Biol       Date:  1999-10

9.  Structure-activity relationship (SAR) development and discovery of potent indole-based inhibitors of the hepatitis C virus (HCV) NS5B polymerase.

Authors:  Kevin X Chen; Bancha Vibulbhan; Weiying Yang; Mousumi Sannigrahi; Francisco Velazquez; Tin-Yau Chan; Srikanth Venkatraman; Gopinadhan N Anilkumar; Qingbei Zeng; Frank Bennet; Yueheng Jiang; Charles A Lesburg; Jose Duca; Patrick Pinto; Stephen Gavalas; Yuhua Huang; Wanli Wu; Oleg Selyutin; Sony Agrawal; Boris Feld; Hsueh-Cheng Huang; Cheng Li; Kuo-Chi Cheng; Neng-Yang Shih; Joseph A Kozlowski; Stuart B Rosenblum; F George Njoroge
Journal:  J Med Chem       Date:  2012-01-06       Impact factor: 7.446

10.  Identification and properties of the RNA-dependent RNA polymerase of hepatitis C virus.

Authors:  S E Behrens; L Tomei; R De Francesco
Journal:  EMBO J       Date:  1996-01-02       Impact factor: 11.598
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