Substituted benzothiadizine inhibitors of Hepatitis C virus polymerase.
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.
Shaw
Antony N
AN
Department of Medicinal Chemistry, GlaxoSmithKline, Collegeville, PA 19426, USA.
Tedesco
Rosanna
R
Bambal
Ramesh
R
Chai
Deping
D
Concha
Nestor O
NO
Darcy
Michael G
MG
Dhanak
Dashyant
D
Duffy
Kevin J
KJ
Fitch
Duke M
DM
Gates
Adam
A
Johnston
Victor K
VK
Keenan
Richard M
RM
Lin-Goerke
Juili
J
Liu
Nannan
N
Sarisky
Robert T
RT
Wiggall
Kenneth J
KJ
Zimmerman
Michael N
MN
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
D000998:Antiviral Agents; D001581:Benzothiadiazines; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase