Mitigating hERG Inhibition: Design of Orally Bioavailable CCR5 Antagonists as Potent Inhibitors of R5 HIV-1 Replication
Mitigating hERG Inhibition: Design of Orally Bioavailable CCR5 Antagonists as Potent Inhibitors of R5 HIV-1 Replication
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DOI：
10.1021/ml2002604
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发表时间：
2012-03-01
影响因子：
4.2
通讯作者：
Schols, Dominique
中科院分区：
文献类型：
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作者：
Skerlj, Renato;Bridger, Gary;Schols, Dominique
设计了一系列代表噻吩-3-基-甲基脲的CCR 5拮抗剂，其满足HIV-1抑制的药理学标准并减轻人ether-a-go-go相关基因（hERG）抑制倾向。降低亲脂性是用于鉴定不抑制hERG通道的化合物的主要设计标准，但细微的结构修饰也很重要。有趣的是，在该系列中，具有低hERG抑制的化合物延长了犬浦肯野纤维中的动作电位时程（APD），表明对心脏离子通道的混合效应。
A series of CCR5 antagonists representing the thiophene-3-yl-methyl ureas were designed that met the pharmacological criteria for HIV-1 inhibition and mitigated a human ether-a-go-go related gene (hERG) inhibition liability. Reducing lipophilicity was the main design criteria used to identify compounds that did not inhibit the hERG channel, but subtle structural modifications were also important. Interestingly, within this series, compounds with low hERG inhibition prolonged the action potential duration (APD) in dog Purkinje fibers, suggesting a mixed effect on cardiac ion channels.