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Bioorg Med Chem Lett ; 18(17): 4853-8, 2008 Sep 01.
Article in English | MEDLINE | ID: mdl-18678486

ABSTRACT

SAR analysis performed with a limited set of cyclopentane-containing macrocycles led to the identification of N-[17-[2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methylquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo [13.3.0.0(4,6)]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamide (TMC435350, 32c) as a potent inhibitor of HCV NS3/4A protease (K(i)=0.36nM) and viral replication (replicon EC(50)=7.8nM). TMC435350 also displayed low in vitro clearance and high permeability, which were confirmed by in vivo pharmacokinetic studies. TMC435350 is currently being evaluated in the clinics.


Subject(s)
Carrier Proteins/antagonists & inhibitors , Cyclopentanes/pharmacology , Hepacivirus/drug effects , Hepacivirus/enzymology , Heterocyclic Compounds, 3-Ring/pharmacology , Macrocyclic Compounds/pharmacology , Protease Inhibitors/pharmacology , Sulfonamides/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Proteins/antagonists & inhibitors , Animals , Caco-2 Cells , Cell Line , Cyclopentanes/chemistry , Dogs , Hepatitis C/drug therapy , Heterocyclic Compounds, 3-Ring/chemistry , Humans , Intracellular Signaling Peptides and Proteins , Macrocyclic Compounds/chemistry , Male , Protease Inhibitors/chemistry , Rats , Rats, Sprague-Dawley , Simeprevir , Structure-Activity Relationship , Sulfonamides/chemistry
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