Raboisson Pierre, de Kock Herman, Rosenquist Asa, Nilsson Magnus, Salvador-Oden Lourdes, Lin Tse-I, Roue Natalie, Ivanov Vladimir, Wähling Horst, Wickström Kristina, Hamelink Elizabeth, Edlund Michael, Vrang Lotta, Vendeville Sandrine, Van de Vreken Wim, McGowan David, Tahri Abdellah, Hu Lili, Boutton Carlo, Lenz Oliver, Delouvroy Frederic, Pille Geert, Surleraux Dominique, Wigerinck Piet, Samuelsson Bertil, Simmen Kenneth
Tibotec BVBA, Gen. De Wittelaan L11 B3, B-2800 Mechelen, Belgium.
Bioorg Med Chem Lett. 2008 Sep 1;18(17):4853-8. doi: 10.1016/j.bmcl.2008.07.088. Epub 2008 Jul 24.
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-carbonylsulfonamide (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.
使用一组有限的含环戊烷大环化合物进行的构效关系分析，确定了N-17-[2-(4-异丙基噻唑-2-基)-7-甲氧基-8-甲基喹啉-4-氧基]-13-甲基-2,14-二氧代-3,13-二氮杂三环[13.3.0.0(4,6)]十八碳-7-烯-4-羰基磺酰胺（TMC435350，32c）是丙型肝炎病毒NS3/4A蛋白酶的强效抑制剂（K(i)=0.36 nM），对病毒复制也有抑制作用（复制子EC(50)=7.8 nM）。TMC435350在体外还表现出低清除率和高渗透性，体内药代动力学研究证实了这一点。TMC435350目前正在进行临床评估。
