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

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  = 0.36 nM) and viral replication (replicon EC 50  = 7.8 nM). 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.