Optimization of novel acyl pyrrolidine inhibitors of hepatitis C virus RNA-dependent RNA polymerase leading to a development candidate

Martin J Slater; Elizabeth M Amphlett; David M Andrews; Gianpaolo Bravi; George Burton; Anne G Cheasty; John A Corfield; Malcolm R Ellis; Rebecca H Fenwick; Stephanie Fernandes; Rossella Guidetti; David Haigh; C David Hartley; Peter D Howes; Deborah L Jackson; Richard L Jarvest; Victoria L H Lovegrove; Katrina J Medhurst; Nigel R Parry; Helen Price; Pritom Shah; Onkar M P Singh; Richard Stocker; Pia Thommes; Claire Wilkinson; Alan Wonacott

doi:10.1021/jm061207r

Optimization of novel acyl pyrrolidine inhibitors of hepatitis C virus RNA-dependent RNA polymerase leading to a development candidate

J Med Chem. 2007 Mar 8;50(5):897-900. doi: 10.1021/jm061207r. Epub 2007 Feb 2.

Affiliation

¹ Infectious Diseases CEDD and Medicinal Discovery Research, GlaxoSmithKline, GSK Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, United Kingdom. [email protected]

PMID: 17269759
DOI: 10.1021/jm061207r

Abstract

Optimization of a pyrrolidine-based template using structure-based design and physicochemical considerations has provided a development candidate 20b (3082) with submicromolar potency in the HCV replicon and good pharmacokinetic properties.

MeSH terms

Animals
Antiviral Agents / chemical synthesis*
Antiviral Agents / chemistry
Antiviral Agents / pharmacology
Binding Sites
Biological Availability
Chlorocebus aethiops
Hepacivirus / drug effects*
Hepacivirus / enzymology
Models, Molecular
Pyrrolidines / chemical synthesis*
Pyrrolidines / chemistry
Pyrrolidines / pharmacology
RNA-Dependent RNA Polymerase / antagonists & inhibitors*
RNA-Dependent RNA Polymerase / chemistry
Rats
Stereoisomerism
Structure-Activity Relationship
Vero Cells

Substances

Antiviral Agents
Pyrrolidines
RNA-Dependent RNA Polymerase