title: Structure-activity relationship (SAR) optimization of 6-(indol-2-yl)pyridine-3-sulfonamides: identification of potent, selective, and orally bioavailable small molecules targeting hepatitis C (HCV) NS4B.
abstract: A novel, potent, and orally bioavailable inhibitor of hepatitis C RNA replication targeting NS4B, compound 4t (PTC725), has been identified through chemical optimization of the 6-(indol-2-yl)pyridine-3-sulfonamide 2 to improve DMPK and safety properties. The focus of the SAR investigations has been to identify the optimal combination of substituents at the indole N-1, C-5, and C-6 positions and the sulfonamide group to limit the potential for in vivo oxidative metabolism and to achieve an acceptable pharmacokinetic profile. Compound 4t has excellent potency against the HCV 1b replicon, with an EC50 = 2 nM and a selectivity index of >5000 with respect to cellular GAPDH. Compound 4t has an overall favorable pharmacokinetic profile with oral bioavailability values of 62%, 78%, and 18% in rats, dogs, and monkeys, respectively, as well as favorable tissue distribution properties with a liver to plasma exposure ratio of 25 in rats.
authors.affiliation: PTC Therapeutics, Inc. , 100 Corporate Court, South Plainfield, New Jersey 07080, United States.
authors.forename: Nanjing
authors.initials: N
authors.lastname: Zhang
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Zhang
authors.forename: Jin
authors.initials: J
authors.lastname: Zhu
authors.forename: Anthony
authors.initials: A
authors.lastname: Turpoff
authors.forename: Guangming
authors.initials: G
authors.lastname: Chen
authors.forename: Christie
authors.initials: C
authors.lastname: Morrill
authors.forename: Song
authors.initials: S
authors.lastname: Huang
authors.forename: William
authors.initials: W
authors.lastname: Lennox
authors.forename: Ramesh
authors.initials: R
authors.lastname: Kakarla
authors.forename: Ronggang
authors.initials: R
authors.lastname: Liu
authors.forename: Chunshi
authors.initials: C
authors.lastname: Li
authors.forename: Hongyu
authors.initials: H
authors.lastname: Ren
authors.forename: Neil
authors.initials: N
authors.lastname: Almstead
authors.forename: Srikanth
authors.initials: S
authors.lastname: Venkatraman
authors.forename: F George
authors.initials: FG
authors.lastname: Njoroge
authors.forename: Zhengxian
authors.initials: Z
authors.lastname: Gu
authors.forename: Valerie
authors.initials: V
authors.lastname: Clausen
authors.forename: Jason
authors.initials: J
authors.lastname: Graci
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Jung
authors.forename: Yingcong
authors.initials: Y
authors.lastname: Zheng
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Colacino
authors.forename: Fred
authors.initials: F
authors.lastname: Lahser
authors.forename: Josephine
authors.initials: J
authors.lastname: Sheedy
authors.forename: Anna
authors.initials: A
authors.lastname: Mollin
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: D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D001682:Biological Availability; D004285:Dogs; D000882:Haplorhini; D016174:Hepacivirus / Q000187:drug effects*; D006801:Humans; D051381:Rats; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000998:Antiviral Agents; D013449:Sulfonamides