Discovery of MK-5172, a Macrocyclic Hepatitis C Virus NS3/4a Protease Inhibitor
Discovery of MK-5172, a Macrocyclic Hepatitis C Virus NS3/4a Protease Inhibitor
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DOI：
10.1021/ml300017p
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发表时间：
2012-04-01
影响因子：
4.2
通讯作者：
Liverton, Nigel J.
中科院分区：
文献类型：
--
作者：
Harper, Steven;McCauley, John A.;Liverton, Nigel J.
采用一种源自分子建模的策略，设计了一类含有从P2到P4大环约束的新型丙型肝炎病毒（HCV）NS3/4a蛋白酶抑制剂。基于先前临床化合物的特性，并对该系列的P2和连接区域进行探索，能够优化对多种基因型和突变酶的效力、细胞活性以及口服给药后的大鼠肝脏暴露情况。这些研究确定了临床候选药物15（MK - 5172），它对基因型1 - 3的NS3/4a以及临床相关的突变酶具有活性，并且在多个物种中具有良好的血浆暴露和优异的肝脏暴露。
A new class of HCV NS3/4a protease inhibitors containing a P2 to P4 macrocyclic constraint was designed using a molecular modeling-derived strategy. Building on the profile of previous clinical compounds and exploring the P2 and linker regions of the series allowed for optimization of broad genotype and mutant enzyme potency, cellular activity, and rat liver exposure following oral dosing. These studies led to the identification of clinical candidate 15 (MK-5172), which is active against genotype 1-3 NS3/4a and clinically relevant mutant enzymes and has good plasma exposure and excellent liver exposure in multiple species.