丙型肝炎病毒NS3/NS4A丝氨酸蛋白酶的高效非肽类抑制剂。
Highly potent non-peptidic inhibitors of the HCV NS3/NS4A serine protease.
作者信息
Sperandio David, Gangloff Anthony R, Litvak Joane, Goldsmith Richard, Hataye Jason M, Wang Vivian R, Shelton Emma J, Elrod Kyle, Janc James W, Clark James M, Rice Ken, Weinheimer Steve, Yeung Kap-Sun, Meanwell Nicholas A, Hernandez Dennis, Staab Andrew J, Venables Brian L, Spencer Jeffrey R
机构信息
Celera, 180 Kimball Way, South San Francisco, CA 94080, USA.
出版信息
Bioorg Med Chem Lett. 2002 Nov 4;12(21):3129-33. doi: 10.1016/s0960-894x(02)00680-7.
Screening of a diverse set of bisbenzimidazoles for inhibition of the hepatitis C virus (HCV) serine protease NS3/NS4A led to the identification of a potent Zn(2+)-dependent inhibitor (1). Optimization of this screening hit afforded a 10-fold more potent inhibitor (46) under Zn(2+) conditions (K(i)=27nM). This compound (46) binds also to NS3/NS4A in a Zn(2+) independent fashion (K(i)=1microM). The SAR of this class of compounds under Zn(2+) conditions is highly divergent compared to the SAR in the absence of Zn(2+), suggesting two distinct binding modes.
对多种双苯并咪唑进行筛选以抑制丙型肝炎病毒（HCV）丝氨酸蛋白酶NS3/NS4A，从而鉴定出一种有效的锌离子依赖性抑制剂（1）。对该筛选命中物进行优化，在锌离子条件下得到了一种活性增强10倍的抑制剂（46）（K(i)=27nM）。该化合物（46）也以锌离子非依赖性方式与NS3/NS4A结合（K(i)=1μM）。与无锌离子条件下的构效关系相比，这类化合物在锌离子条件下的构效关系差异很大，表明存在两种不同的结合模式。
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