title: Inhibitors of HCV NS5B polymerase: synthesis and structure-activity relationships of N-1-heteroalkyl-4-hydroxyquinolon-3-yl-benzothiadiazines.
abstract: N-1-Alkylamino and N-1-alkyloxy-4-hydroxyquinolon-3-yl benzothiadiazines were synthesized and evaluated as inhibitors of genotype 1 HCV polymerase. The N-1-alkyloxy derivatives were not potent inhibitors, however N-1-alkylamino derivatives displayed comparable potency to carbon analogs. Analogs with aliphatic substituents were significantly more potent than those with benzylic substituents against genotype 1a polymerase. The most potent inhibitors contained small alkyl or carbocyclic substituents and exhibited IC50's of 50-100 and 200-400 nM against genotype 1b and 1a HCV polymerase, respectively.
authors.affiliation: Infectious Disease Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA. john.k.pratt@abbott.com
authors.forename: John K
authors.initials: JK
authors.lastname: Pratt
authors.forename: Pamela
authors.initials: P
authors.lastname: Donner
authors.forename: Keith F
authors.initials: KF
authors.lastname: McDaniel
authors.forename: Clarence J
authors.initials: CJ
authors.lastname: Maring
authors.forename: Warren M
authors.initials: WM
authors.lastname: Kati
authors.forename: Hongmei
authors.initials: H
authors.lastname: Mo
authors.forename: Tim
authors.initials: T
authors.lastname: Middleton
authors.forename: Yaya
authors.initials: Y
authors.lastname: Liu
authors.forename: Teresa
authors.initials: T
authors.lastname: Ng
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Xie
authors.forename: Rong
authors.initials: R
authors.lastname: Zhang
authors.forename: Debra
authors.initials: D
authors.lastname: Montgomery
authors.forename: Akhteruzzaman
authors.initials: A
authors.lastname: Molla
authors.forename: Dale J
authors.initials: DJ
authors.lastname: Kempf
authors.forename: William
authors.initials: W
authors.lastname: Kohlbrenner
mesh_terms: D001581:Benzothiadiazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D016174:Hepacivirus / Q000201:enzymology*; D008956:Models, Chemical; D015394:Molecular Structure; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*
chemical_list: D001581:Benzothiadiazines; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase