An efficient, asymmetric solid-phase synthesis of benzothiadiazine-substituted tetramic acids: potent inhibitors of the hepatitis C virus RNA-dependent RNA polymerase.
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.
Evans
Karen A
KA
Department of Discovery Research, GlaxoSmithKline Pharmaceuticals, Collegeville, PA 19426-0989, USA. karen.a.evans@gsk.com
Chai
Deping
D
Graybill
Todd L
TL
Burton
George
G
Sarisky
Robert T
RT
Lin-Goerke
Juili
J
Johnston
Victor K
VK
Rivero
Ralph A
RA
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*
D000998:Antiviral Agents; D001581:Benzothiadiazines; D011760:Pyrrolidinones; C009435:tetramic acid; D012324:RNA-Dependent RNA Polymerase