title: Discovery of N-(4'-(indol-2-yl)phenyl)sulfonamides as novel inhibitors of HCV replication.
abstract: A series of novel 2-phenylindole analogs were synthesized and evaluated for activity in subgenomic HCV replicon inhibition assays. Several compounds containing small alkyl sulfonamides on the phenyl ring exhibiting submicromolar EC50 values against the genotype 1b replicon were identified. Among these, compound 25d potently inhibited the 1b replicon (EC50=0.17 μM) with 147-fold selectivity with respect to cytotoxicity. Compound 25d was stable in the presence of human liver microsomes and had a good pharmacokinetic profile in rats with an IV half-life of 4.3h and oral bioavailability (F) of 58%.
authors.affiliation: PTC Therapeutics, 100 Corporate Court, South Plainfield, NJ 07080, USA. gchen@ptcbio.com
authors.forename: Guangming
authors.initials: G
authors.lastname: Chen
authors.forename: Hongyu
authors.initials: H
authors.lastname: Ren
authors.forename: Anthony
authors.initials: A
authors.lastname: Turpoff
authors.forename: Alexander
authors.initials: A
authors.lastname: Arefolov
authors.forename: Richard
authors.initials: R
authors.lastname: Wilde
authors.forename: James
authors.initials: J
authors.lastname: Takasugi
authors.forename: Atiyya
authors.initials: A
authors.lastname: Khan
authors.forename: Neil
authors.initials: N
authors.lastname: Almstead
authors.forename: Zhengxian
authors.initials: Z
authors.lastname: Gu
authors.forename: Takashi
authors.initials: T
authors.lastname: Komatsu
authors.forename: Connie
authors.initials: C
authors.lastname: Freund
authors.forename: Jamie
authors.initials: J
authors.lastname: Breslin
authors.forename: Joseph
authors.initials: J
authors.lastname: Colacino
authors.forename: Jean
authors.initials: J
authors.lastname: Hedrick
authors.forename: Marla
authors.initials: M
authors.lastname: Weetall
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*; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D008862:Microsomes, Liver / Q000187:drug effects*; D015394:Molecular Structure; D051381:Rats; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D007211:Indoles; D013449:Sulfonamides