- Structure-activity relationship study on a novel series of cyclopentane-containing macrocyclic inhibitors of the hepatitis C virus NS3/4A protease leading to the discovery of TMC435350.
Structure-activity relationship study on a novel series of cyclopentane-containing macrocyclic inhibitors of the hepatitis C virus NS3/4A protease leading to the discovery of TMC435350.
Bioorganic & medicinal chemistry letters (2008-08-06)
Pierre Raboisson, Herman de Kock, Asa Rosenquist, Magnus Nilsson, Lourdes Salvador-Oden, Tse-I Lin, Natalie Roue, Vladimir Ivanov, Horst Wähling, Kristina Wickström, Elizabeth Hamelink, Michael Edlund, Lotta Vrang, Sandrine Vendeville, Wim Van de Vreken, David McGowan, Abdellah Tahri, Lili Hu, Carlo Boutton, Oliver Lenz, Frederic Delouvroy, Geert Pille, Dominique Surleraux, Piet Wigerinck, Bertil Samuelsson, Kenneth Simmen
PMID18678486
ABSTRAKT
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.
MATERIAŁY