title: 6-(Azaindol-2-yl)pyridine-3-sulfonamides as potent and selective inhibitors targeting hepatitis C virus NS4B.
abstract: A structure-activity relationship investigation of various 6-(azaindol-2-yl)pyridine-3-sulfonamides using the HCV replicon cell culture assay led to the identification of a potent series of 7-azaindoles that target the hepatitis C virus NS4B. Compound 2ac, identified via further optimization of the series, has excellent potency against the HCV 1b replicon with an EC50 of 2nM and a selectivity index of >5000 with respect to cellular GAPDH RNA. Compound 2ac also has excellent oral plasma exposure levels in rats, dogs and monkeys and has a favorable liver to plasma distribution profile in rats.
authors.affiliation: PTC Therapeutics, Inc., 100 Corporate Court, South Plainfield, NJ 07080, USA.
authors.forename: Guangming
authors.initials: G
authors.lastname: Chen
authors.affiliation: PTC Therapeutics, Inc., 100 Corporate Court, South Plainfield, NJ 07080, USA.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Ren
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: William
authors.initials: W
authors.lastname: Lennox
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: Steven
authors.initials: S
authors.lastname: Paget
authors.affiliation: PTC Therapeutics, Inc., 100 Corporate Court, South Plainfield, NJ 07080, USA.
authors.forename: Chunshi
authors.initials: C
authors.lastname: Li
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: 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: PTC Therapeutics, Inc., 100 Corporate Court, South Plainfield, NJ 07080, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhao
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: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology; D004285:Dogs; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D008252:Macaca fascicularis; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000494:pharmacology*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*
chemical_list: D000998:Antiviral Agents; C080107:NS4B protein, flavivirus; D011725:Pyridines; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins
keywords: 6-(Azaindol-2-yl)pyridine-3-sulfonamides; HCV inhibitors; NS4B; Replicon; Structure–activity relationship