Substituted benzothiadizine inhibitors of Hepatitis C virus polymerase

Antony N Shaw; Rosanna Tedesco; Ramesh Bambal; Deping Chai; Nestor O Concha; Michael G Darcy; Dashyant Dhanak; Kevin J Duffy; Duke M Fitch; Adam Gates; Victor K Johnston; Richard M Keenan; Juili Lin-Goerke; Nannan Liu; Robert T Sarisky; Kenneth J Wiggall; Michael N Zimmerman

doi:10.1016/j.bmcl.2009.05.091

Substituted benzothiadizine inhibitors of Hepatitis C virus polymerase

Bioorg Med Chem Lett. 2009 Aug 1;19(15):4350-3. doi: 10.1016/j.bmcl.2009.05.091. Epub 2009 May 28.

Authors

Antony N Shaw¹, Rosanna Tedesco, Ramesh Bambal, Deping Chai, Nestor O Concha, Michael G Darcy, Dashyant Dhanak, Kevin J Duffy, Duke M Fitch, Adam Gates, Victor K Johnston, Richard M Keenan, Juili Lin-Goerke, Nannan Liu, Robert T Sarisky, Kenneth J Wiggall, Michael N Zimmerman

Affiliation

¹ Department of Medicinal Chemistry, GlaxoSmithKline, Collegeville, PA 19426, USA.

PMID: 19515564
DOI: 10.1016/j.bmcl.2009.05.091

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.

MeSH terms

Administration, Oral
Animals
Antiviral Agents / chemical synthesis*
Antiviral Agents / pharmacology
Benzothiadiazines / chemistry*
Benzothiadiazines / pharmacology
Chemistry, Pharmaceutical / methods*
Drug Design
Hepacivirus / enzymology*
Humans
Inhibitory Concentration 50
Models, Chemical
Molecular Conformation
Molecular Structure
Rats
Structure-Activity Relationship
Viral Nonstructural Proteins / antagonists & inhibitors*

Substances

Antiviral Agents
Benzothiadiazines
Viral Nonstructural Proteins
NS-5 protein, hepatitis C virus