title: Discovery of 2-(4-sulfonamidophenyl)-indole 3-carboxamides as potent and selective inhibitors with broad hepatitis C virus genotype activity targeting HCV NS4B.
abstract: A novel series of 2-(4-sulfonamidophenyl)-indole 3-carboxamides was identified and optimized for activity against the HCV genotype 1b replicon resulting in compounds with potent and selective activity. Further evaluation of this series demonstrated potent activity across HCV genotypes 1a, 2a and 3a. Compound 4z had reduced activity against HCV genotype 1b replicons containing single mutations in the NS4B coding sequence (F98C and V105M) indicating that NS4B is the target. This novel series of 2-(4-sulfonamidophenyl)-indole 3-carboxamides serves as a promising starting point for a pan-genotype HCV discovery program.
authors.affiliation: PTC Therapeutics, Inc., 100 Corporate Court, South Plainfield, NJ 07080, USA.
authors.forename: Nanjing
authors.initials: N
authors.lastname: Zhang
authors.affiliation: PTC Therapeutics, Inc., 100 Corporate Court, South Plainfield, NJ 07080, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Turpoff
authors.affiliation: PTC Therapeutics, Inc., 100 Corporate Court, South Plainfield, NJ 07080, USA.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: PTC Therapeutics, Inc., 100 Corporate Court, South Plainfield, NJ 07080, USA.
authors.forename: Song
authors.initials: S
authors.lastname: Huang
authors.affiliation: PTC Therapeutics, Inc., 100 Corporate Court, South Plainfield, NJ 07080, USA.
authors.forename: Yalei
authors.initials: Y
authors.lastname: Liu
authors.affiliation: PTC Therapeutics, Inc., 100 Corporate Court, South Plainfield, NJ 07080, USA.
authors.forename: Neil
authors.initials: N
authors.lastname: Almstead
authors.affiliation: Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: F George
authors.initials: FG
authors.lastname: Njoroge
authors.affiliation: PTC Therapeutics, Inc., 100 Corporate Court, South Plainfield, NJ 07080, USA.
authors.forename: Zhengxian
authors.initials: Z
authors.lastname: Gu
authors.affiliation: PTC Therapeutics, Inc., 100 Corporate Court, South Plainfield, NJ 07080, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Graci
authors.affiliation: PTC Therapeutics, Inc., 100 Corporate Court, South Plainfield, NJ 07080, USA.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Jung
authors.affiliation: PTC Therapeutics, Inc., 100 Corporate Court, South Plainfield, NJ 07080, USA.
authors.forename: John
authors.initials: J
authors.lastname: Pichardo
authors.affiliation: PTC Therapeutics, Inc., 100 Corporate Court, South Plainfield, NJ 07080, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Colacino
authors.affiliation: Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Fred
authors.initials: F
authors.lastname: Lahser
authors.affiliation: Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Ingravallo
authors.affiliation: PTC Therapeutics, Inc., 100 Corporate Court, South Plainfield, NJ 07080, USA.
authors.forename: Marla
authors.initials: M
authors.lastname: Weetall
authors.affiliation: Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Amin
authors.initials: A
authors.lastname: Nomeir
authors.affiliation: PTC Therapeutics, Inc., 100 Corporate Court, South Plainfield, NJ 07080, USA.
authors.forename: Gary M
authors.initials: GM
authors.lastname: Karp
mesh_terms: D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology*; D016174:Hepacivirus / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D006526:Hepatitis C / Q000188:drug therapy; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology*; D008969:Molecular Sequence Data; D009154:Mutation; D012093:Replicon / Q000187:drug effects; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D000998:Antiviral Agents; D007211:Indoles; C080107:NS4B protein, flavivirus; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins
keywords: 2-(4-Sulfonamidophenyl)-indole 3-carboxamides; HCV inhibitor; NS4B; Replicon