title: Substituted benzothiadizine inhibitors of Hepatitis C virus polymerase.
abstract: The synthesis and optimisation of HCV NS5B polymerase inhibitors with improved potency versus the existing compound 1 is described. Substitution in the benzothiadiazine portion of the molecule, furnishing improvement in potency in the high protein Replicon assay, is highlighted, culminating in the discovery of 12h, a highly potent oxyacetamide derivative.
authors.affiliation: Department of Medicinal Chemistry, GlaxoSmithKline, Collegeville, PA 19426, USA.
authors.forename: Antony N
authors.initials: AN
authors.lastname: Shaw
authors.forename: Rosanna
authors.initials: R
authors.lastname: Tedesco
authors.forename: Ramesh
authors.initials: R
authors.lastname: Bambal
authors.forename: Deping
authors.initials: D
authors.lastname: Chai
authors.forename: Nestor O
authors.initials: NO
authors.lastname: Concha
authors.forename: Michael G
authors.initials: MG
authors.lastname: Darcy
authors.forename: Dashyant
authors.initials: D
authors.lastname: Dhanak
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Duffy
authors.forename: Duke M
authors.initials: DM
authors.lastname: Fitch
authors.forename: Adam
authors.initials: A
authors.lastname: Gates
authors.forename: Victor K
authors.initials: VK
authors.lastname: Johnston
authors.forename: Richard M
authors.initials: RM
authors.lastname: Keenan
authors.forename: Juili
authors.initials: J
authors.lastname: Lin-Goerke
authors.forename: Nannan
authors.initials: N
authors.lastname: Liu
authors.forename: Robert T
authors.initials: RT
authors.lastname: Sarisky
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Wiggall
authors.forename: Michael N
authors.initials: MN
authors.lastname: Zimmerman
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001581:Benzothiadiazines / Q000737:chemistry* / Q000494:pharmacology; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D016174:Hepacivirus / Q000201:enzymology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D008968:Molecular Conformation; D015394:Molecular Structure; D051381:Rats; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D001581:Benzothiadiazines; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase