Abstract
The pyrrolidine-5,5-trans-lactam template was used to design small, neutral, mechanism-based inhibitors of hepatitis C NS3/4A protease displaying potent activity in the replicon cell-based assay. The activity of this series is not dependent upon its chemical reactivity and molecules have been synthesised which combine enhanced biochemical potency with improved plasma stability. Promising initial pharmacokinetic data indicating the potential for further optimisation of this series into low molecular weight, drug-like inhibitors is presented.
MeSH terms
-
Animals
-
Crystallography, X-Ray
-
Dogs
-
Drug Design*
-
Drug Stability
-
Hepacivirus / drug effects
-
Hepacivirus / enzymology*
-
Humans
-
Injections, Intravenous
-
Lactams / chemical synthesis
-
Lactams / pharmacokinetics
-
Lactams / pharmacology
-
Models, Biological
-
Molecular Structure
-
Protease Inhibitors / chemical synthesis*
-
Protease Inhibitors / pharmacokinetics
-
Protease Inhibitors / pharmacology*
-
Pyrrolidines / chemical synthesis
-
Pyrrolidines / pharmacokinetics
-
Pyrrolidines / pharmacology
-
Rats
-
Viral Nonstructural Proteins / antagonists & inhibitors*
-
Viral Nonstructural Proteins / metabolism
Substances
-
Lactams
-
NS3 protein, hepatitis C virus
-
Protease Inhibitors
-
Pyrrolidines
-
Viral Nonstructural Proteins