Bogen Stéphane L, Arasappan Ashok, Bennett Frank, Chen Kevin, Jao Edwin, Liu Yi-Tsung, Lovey Raymond G, Venkatraman Srikanth, Pan Weidong, Parekh Tajel, Pike Russel E, Ruan Sumei, Liu Rong, Baroudy Bahige, Agrawal Sony, Chase Robert, Ingravallo Paul, Pichardo John, Prongay Andrew, Brisson Jean-Marc, Hsieh Tony Y, Cheng Kuo-Chi, Kemp Scott J, Levy Odile E, Lim-Wilby Marguerita, Tamura Susan Y, Saksena Anil K, Girijavallabhan Viyyoor, Njoroge F George
Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, USA.
J Med Chem. 2006 May 4;49(9):2750-7. doi: 10.1021/jm060077j.
Introduction of various modified prolines at P(2) and optimization of the P(1) side chain led to the discovery of SCH6 (24, Table 2), a potent ketoamide inhibitor of the HCV NS3 serine protease. In addition to excellent enzyme potency (K(i)*= 3.8 nM), 24 was also found to be a potent inhibitor of HCV subgenomic RNA replication with IC(50) and IC(90) of 40 and 100 nM, respectively. Recently, antiviral activity of 24 was demonstrated with inhibition of the full-length genotype 2a HCV genome. In addition, 24 was found to restore the responsiveness of the interferon regulatory factor 3 (IRF-3) in cells containing HCV RNA replicons.
在P(2)位点引入各种修饰脯氨酸并优化P(1)侧链，从而发现了SCH6（24，表2），一种有效的丙型肝炎病毒NS3丝氨酸蛋白酶酮酰胺抑制剂。除了具有出色的酶活性（K(i)* = 3.8 nM）外，24还被发现是丙型肝炎病毒亚基因组RNA复制的有效抑制剂，其IC(50)和IC(90)分别为40和100 nM。最近，通过抑制全长2a基因型丙型肝炎病毒基因组证明了24的抗病毒活性。此外，发现24可恢复含有丙型肝炎病毒RNA复制子的细胞中干扰素调节因子3（IRF-3）的反应性。
