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.
Bioorg Med Chem Lett
; 16(14): 3784-8, 2006 Jul 15.
Article
in English
| MEDLINE
| ID: mdl-16697194
ABSTRACT
A series of novel, non-basic 3-(6-chloronaphth-2-ylsulfonyl)aminopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating an alanylamide P4 group, was designed and synthesised. Within this series, the N-2-(morpholin-4-yl)-2-oxoethyl derivative 24 was shown to be a potent, selective fXa inhibitor with good anticoagulant activity. Moreover, 24 possessed highly encouraging rat and dog pharmacokinetic profiles with excellent oral bioavailabilities in both species.
