An efficient, asymmetric solid-phase synthesis of benzothiadiazine-substituted tetramic acids: potent inhibitors of the hepatitis C virus RNA-dependent RNA polymerase

Karen A Evans; Deping Chai; Todd L Graybill; George Burton; Robert T Sarisky; Juili Lin-Goerke; Victor K Johnston; Ralph A Rivero

doi:10.1016/j.bmcl.2006.01.034

An efficient, asymmetric solid-phase synthesis of benzothiadiazine-substituted tetramic acids: potent inhibitors of the hepatitis C virus RNA-dependent RNA polymerase

Bioorg Med Chem Lett. 2006 Apr 15;16(8):2205-8. doi: 10.1016/j.bmcl.2006.01.034. Epub 2006 Feb 7.

Authors

Karen A Evans¹, Deping Chai, Todd L Graybill, George Burton, Robert T Sarisky, Juili Lin-Goerke, Victor K Johnston, Ralph A Rivero

Affiliation

¹ Department of Discovery Research, GlaxoSmithKline Pharmaceuticals, Collegeville, PA 19426-0989, USA. karen.a.evans@gsk.com

PMID: 16455253
DOI: 10.1016/j.bmcl.2006.01.034

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.

MeSH terms

Animals
Antiviral Agents / pharmacology*
Antiviral Agents / therapeutic use
Benzothiadiazines / chemical synthesis*
Benzothiadiazines / pharmacology
Catalysis
Cyclization
Drug Resistance, Viral
Hepacivirus / drug effects*
Hepacivirus / enzymology
Hepatitis C / drug therapy
Humans
Inhibitory Concentration 50
Pyrrolidinones / chemical synthesis*
Pyrrolidinones / pharmacology
RNA-Dependent RNA Polymerase / antagonists & inhibitors*

Substances

Antiviral Agents
Benzothiadiazines
Pyrrolidinones
tetramic acid
RNA-Dependent RNA Polymerase