title: Hepatitis C replication inhibitors that target the viral NS4B protein.
abstract: We describe the preclinical development and in vivo efficacy of a novel chemical series that inhibits hepatitis C virus replication via direct interaction with the viral nonstructural protein 4B (NS4B). Significant potency improvements were realized through isosteric modifications to our initial lead 1a. The temptation to improve antiviral activity while compromising physicochemical properties was tempered by the judicial use of ligand efficiency indices during lead optimization. In this manner, compound 1a was transformed into (+)-28a which possessed an improved antiviral profile with no increase in molecular weight and only a modest elevation in lipophilicity. Additionally, we employed a chimeric "humanized" mouse model of HCV infection to demonstrate for the first time that a small molecule with high in vitro affinity for NS4B can inhibit viral replication in vivo. This successful proof-of-concept study suggests that drugs targeting NS4B may represent a viable treatment option for curing HCV infection.
authors.affiliation: GlaxoSmithKline Research and Development , 5 Moore Drive, Research Triangle Park, North Carolina 27709, United States.
authors.forename: John F
authors.initials: JF
authors.lastname: Miller
authors.forename: Pek Y
authors.initials: PY
authors.lastname: Chong
authors.forename: J Brad
authors.initials: JB
authors.lastname: Shotwell
authors.forename: John G
authors.initials: JG
authors.lastname: Catalano
authors.forename: Vincent W-F
authors.initials: VW
authors.lastname: Tai
authors.forename: Jing
authors.initials: J
authors.lastname: Fang
authors.forename: Anna L
authors.initials: AL
authors.lastname: Banka
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Roberts
authors.forename: Michael
authors.initials: M
authors.lastname: Youngman
authors.forename: Huichang
authors.initials: H
authors.lastname: Zhang
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Xiong
authors.forename: Amanda
authors.initials: A
authors.lastname: Mathis
authors.forename: Jeffery J
authors.initials: JJ
authors.lastname: Pouliot
authors.forename: Robert K
authors.initials: RK
authors.lastname: Hamatake
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Price
authors.forename: John W
authors.initials: JW
authors.lastname: Seal
authors.forename: Lisa L
authors.initials: LL
authors.lastname: Stroup
authors.forename: Katrina L
authors.initials: KL
authors.lastname: Creech
authors.forename: Luz H
authors.initials: LH
authors.lastname: Carballo
authors.forename: Dan
authors.initials: D
authors.lastname: Todd
authors.forename: Andrew
authors.initials: A
authors.lastname: Spaltenstein
authors.forename: Sylvia
authors.initials: S
authors.lastname: Furst
authors.forename: Zhi
authors.initials: Z
authors.lastname: Hong
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Peat
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D004195:Disease Models, Animal; D016174:Hepacivirus / Q000187:drug effects* / Q000502:physiology; D006526:Hepatitis C / Q000821:virology; D051379:Mice; D011355:Prodrugs / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; C080107:NS4B protein, flavivirus; D011355:Prodrugs; D017361:Viral Nonstructural Proteins