title: An efficient, asymmetric solid-phase synthesis of benzothiadiazine-substituted tetramic acids: potent inhibitors of the hepatitis C virus RNA-dependent RNA polymerase.
abstract: An efficient, asymmetric solid-phase synthesis of benzothiadiazine-substituted tetramic acids is reported. Starting from commercially available chiral Fmoc-protected alpha-amino acids loaded onto Wang resin, Fmoc removal, reductive amination followed by amide bond formation, and base-catalyzed cyclization with simultaneous cleavage from the resin provided the desired products. Compounds described are potent inhibitors of the hepatitis C virus RNA-dependent RNA polymerase.
authors.affiliation: Department of Discovery Research, GlaxoSmithKline Pharmaceuticals, Collegeville, PA 19426-0989, USA. karen.a.evans@gsk.com
authors.forename: Karen A
authors.initials: KA
authors.lastname: Evans
authors.forename: Deping
authors.initials: D
authors.lastname: Chai
authors.forename: Todd L
authors.initials: TL
authors.lastname: Graybill
authors.forename: George
authors.initials: G
authors.lastname: Burton
authors.forename: Robert T
authors.initials: RT
authors.lastname: Sarisky
authors.forename: Juili
authors.initials: J
authors.lastname: Lin-Goerke
authors.forename: Victor K
authors.initials: VK
authors.lastname: Johnston
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Rivero
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001581:Benzothiadiazines / Q000138:chemical synthesis* / Q000494:pharmacology; D002384:Catalysis; D003500:Cyclization; D024882:Drug Resistance, Viral; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology; D006526:Hepatitis C / Q000188:drug therapy; D006801:Humans; D020128:Inhibitory Concentration 50; D011760:Pyrrolidinones / Q000138:chemical synthesis* / Q000494:pharmacology; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors*
chemical_list: D000998:Antiviral Agents; D001581:Benzothiadiazines; D011760:Pyrrolidinones; C009435:tetramic acid; D012324:RNA-Dependent RNA Polymerase