title: Discovery of novel HCV inhibitors: synthesis and biological activity of 6-(indol-2-yl)pyridine-3-sulfonamides targeting hepatitis C virus NS4B.
abstract: A novel series of 6-(indol-2-yl)pyridine-3-sulfonamides was prepared and evaluated for their ability to inhibit HCV RNA replication in the HCV replicon cell culture assay. Preliminary optimization of this series furnished compounds with low nanomolar potency against the HCV genotype 1b replicon. Among these, compound 8c has identified as a potent HCV replicon inhibitor (EC50=4 nM) with a selectivity index with respect to cellular GAPDH of more than 2500. Further, compound 8c had a good pharmacokinetic profile in rats with an IV half-life of 6h and oral bioavailability (F) of 62%. Selection of HCV replicon resistance identified an amino acid substitution in HCV NS4B that confers resistance to these compounds. These compounds hold promise as a new chemotype with anti-HCV activity mediated through an underexploited viral target.
authors.affiliation: PTC Therapeutics, 100 Corporate Court, South Plainfield, NJ 07080, USA. szhang@ptcbio.com
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Zhang
authors.forename: Nanjing
authors.initials: N
authors.lastname: Zhang
authors.forename: Guangming
authors.initials: G
authors.lastname: Chen
authors.forename: Anthony
authors.initials: A
authors.lastname: Turpoff
authors.forename: Hongyu
authors.initials: H
authors.lastname: Ren
authors.forename: James
authors.initials: J
authors.lastname: Takasugi
authors.forename: Christie
authors.initials: C
authors.lastname: Morrill
authors.forename: Jin
authors.initials: J
authors.lastname: Zhu
authors.forename: Chunshi
authors.initials: C
authors.lastname: Li
authors.forename: William
authors.initials: W
authors.lastname: Lennox
authors.forename: Steven
authors.initials: S
authors.lastname: Paget
authors.forename: Yalei
authors.initials: Y
authors.lastname: Liu
authors.forename: Neil
authors.initials: N
authors.lastname: Almstead
authors.forename: F George
authors.initials: FG
authors.lastname: Njoroge
authors.forename: Zhengxian
authors.initials: Z
authors.lastname: Gu
authors.forename: Takashi
authors.initials: T
authors.lastname: Komatsu
authors.forename: Valerie
authors.initials: V
authors.lastname: Clausen
authors.forename: Christine
authors.initials: C
authors.lastname: Espiritu
authors.forename: Jason
authors.initials: J
authors.lastname: Graci
authors.forename: Joseph
authors.initials: J
authors.lastname: Colacino
authors.forename: Fred
authors.initials: F
authors.lastname: Lahser
authors.forename: Nicole
authors.initials: N
authors.lastname: Risher
authors.forename: Marla
authors.initials: M
authors.lastname: Weetall
authors.forename: Amin
authors.initials: A
authors.lastname: Nomeir
authors.forename: Gary M
authors.initials: GM
authors.lastname: Karp
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D008862:Microsomes, Liver / Q000378:metabolism; D015394:Molecular Structure; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects* / Q000235:genetics
chemical_list: D000998:Antiviral Agents; D007211:Indoles; C080107:NS4B protein, flavivirus; D011725:Pyridines; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins