title: 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.
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Kevin X
authors.initials: KX
authors.lastname: Chen
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Srikanth
authors.initials: S
authors.lastname: Venkatraman
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Gopinadhan N
authors.initials: GN
authors.lastname: Anilkumar
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Qingbei
authors.initials: Q
authors.lastname: Zeng
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Lesburg
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Bancha
authors.initials: B
authors.lastname: Vibulbhan
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Francisco
authors.initials: F
authors.lastname: Velazquez
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Tin-Yau
authors.initials: TY
authors.lastname: Chan
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Frank
authors.initials: F
authors.lastname: Bennet
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Yueheng
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Patrick
authors.initials: P
authors.lastname: Pinto
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Oleg
authors.initials: O
authors.lastname: Selyutin
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Sony
authors.initials: S
authors.lastname: Agrawal
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Hsueh-Cheng
authors.initials: HC
authors.lastname: Huang
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Cheng
authors.initials: C
authors.lastname: Li
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Kuo-Chi
authors.initials: KC
authors.lastname: Cheng
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Neng-Yang
authors.initials: NY
authors.lastname: Shih
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Kozlowski
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Stuart B
authors.initials: SB
authors.lastname: Rosenblum
authors.affiliation: Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: F George
authors.initials: FG
authors.lastname: Njoroge
keywords: HCV; NS5B polymerase; hepatitis C virus; polymerase inhibitor; prodrug