1.
J Med Chem
; 50(5): 897-900, 2007 Mar 08.
Article
in English
| MEDLINE
| ID: mdl-17269759
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.
Subject(s)
Antiviral Agents/chemical synthesis , Hepacivirus/drug effects , Pyrrolidines/chemical synthesis , RNA-Dependent RNA Polymerase/antagonists & inhibitors , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Binding Sites , Biological Availability , Chlorocebus aethiops , Hepacivirus/enzymology , Models, Molecular , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , RNA-Dependent RNA Polymerase/chemistry , Rats , Stereoisomerism , Structure-Activity Relationship , Vero Cells
2.
Org Lett
; 5(24): 4627-30, 2003 Nov 27.
Article
in English
| MEDLINE
| ID: mdl-14627400
ABSTRACT
[reaction: see text] In this, the first of two Letters, we describe how a P3/P4 urea linking unit was used to greatly enhance the biochemical and replicon potency of inhibitors based upon the pyrrolidine-5,5-trans-lactam template. Compound 7b demonstrated a 100 nM IC(50) in the replicon cell-based surrogate HCV assay.