Synthesis and Structure-Activity Relationships of Azamacrocyclic C-X-C Chemokine Receptor 4 Antagonists: Analogues Containing a Single Azamacrocyclic Ring are Potent Inhibitors of T-Cell Tropic (X4) HIV-1 Replication
Synthesis and Structure-Activity Relationships of Azamacrocyclic C-X-C Chemokine Receptor 4 Antagonists: Analogues Containing a Single Azamacrocyclic Ring are Potent Inhibitors of T-Cell Tropic (X4) HIV-1 Replication
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DOI：
10.1021/jm901530b
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发表时间：
2010-02-11
影响因子：
7.3
通讯作者：
Schols, Dominique
中科院分区：
文献类型：
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作者：
Bridger, Gary J.;Skerlj, Renato T.;Schols, Dominique
双四氮杂大环化合物，如双环AMD 3100（1），是一类有效的选择性抗HIV-1药物，通过与趋化因子受体CXCR 4（X4病毒进入的辅助受体）结合来抑制病毒复制。通过顺序替换和/或删除的氨基内的氮杂大环系统，我们已经确定了在这类化合物的有效的抗病毒活性所需的最低结构特征。活性不需要所有八个氨基，每个环上的关键氨基是不相同的，并且在生理pH下的总电荷可以降低而不影响效力。该方法鉴定出几种单环氮杂大环类似物，如AMD 3465（3d）、36和40，其抗HIV-1细胞病变效应的EC 50分别为9.0、1.0和4.0 nM，抗病毒效力与1相当（抗HIV-1的EC 50为4.0 nM）。然而，更重要的是，I的抗病毒活性所需的关键结构元素可能有助于设计适合于通过口服给药治疗HIV的非大环CXCR 4拮抗剂。
Bis-tetraazamacrocycles such as the bicyclam AMD3100 (1) are a class of potent and selective anti-HIV-1 agents that inhibit virus replication by binding to the chemokine receptor CXCR4, the coreceptor for entry of X4 viruses. By sequential replacement and/or deletion of the amino groups within the azamacrocyclic ring systems, we have determined the minimum structural features required for potent antiviral activity in this class of compounds. All eight amino groups are not required for activity, the critical amino groups on a per ring basis are nonidentical, and the overall charge at physiological pH can be reduced without compromising potency. This approach led to the identification of several single ring azamacrocyclic analogues such as AMD3465 (3d), 36, and 40, which exhibit EC50's against the cytopathic effects of HIV-1 of 9.0, 1.0, and 4.0 nM, respectively, antiviral potencies that are comparable to 1 (EC50 against HIV-1 of 4.0 nM). More importantly, however, the key structural elements of I required for antiviral activity may facilitate the design of nonmacrocyclic CXCR4 antagonists suitable for HIV treatment via oral administration.