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

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.

SUBMITTER: Chen KX

PROVIDER: S-EPMC4027611 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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

Chen Kevin X KX Venkatraman Srikanth S Anilkumar Gopinadhan N GN Zeng Qingbei Q Lesburg Charles A CA Vibulbhan Bancha B Velazquez Francisco F Chan Tin-Yau TY Bennet Frank F Jiang Yueheng Y Pinto Patrick P Huang Yuhua Y Selyutin Oleg O Agrawal Sony S Huang Hsueh-Cheng HC Li Cheng C Cheng Kuo-Chi KC Shih Neng-Yang NY Kozlowski Joseph A JA Rosenblum Stuart B SB Njoroge F George FG

ACS medicinal chemistry letters 20130812 3

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 i ...[more]

PMID: 24900812

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