Design, synthesis, and biological evaluation of the combinatorial library with a new spirodiketopiperazine scaffold. Discovery of novel potent and selective low-molecular-weight CCR5 antagonists
Design, synthesis, and biological evaluation of the combinatorial library with a new spirodiketopiperazine scaffold. Discovery of novel potent and selective low-molecular-weight CCR5 antagonists
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DOI：
10.1021/jm060051s
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发表时间：
2006-07-13
影响因子：
7.3
通讯作者：
Mitsuya, Hiroaki
中科院分区：
文献类型：
--
作者：
Habashita, Hiromu;Kokubo, Masaya;Mitsuya, Hiroaki
我们先前报道了几个螺二酮哌嗪衍生物作为有效的CCR5拮抗剂具有抗HIV活性。在这里，我们详细描述了使用组合化学方法来鉴定这些先导化合物。基于G蛋白偶联受体(GPCRs)特权结构的概念，设计了一种新型的螺二酮哌嗪支架。这种新的骨架是由容易制备的异腈树脂通过乌吉反应、顺序转化和循环裂解以可接受的产率和高纯度获得的。通过测量初始文库中每个化合物对MIP-1α刺激的细胞内钙动员的抑制活性，发现几个化合物显示出适度但选择性的CCR5拮抗活性。在对这些命中化合物进行快速评估后，已经确定了几种个位数的纳米分子、低分子CCR5拮抗剂，它们可以有效地阻断艾滋病毒实验室和临床毒株的传染性和复制，以及那些细胞毒性最小的高度耐药的艾滋病毒变种。
We previously reported the discovery of several spirodiketopiperazine derivatives as potent CCR5 antagonists with anti-HIV activity. Herein, we describe in detail the identification of these lead compounds using a combinatorial chemistry approach. A novel spirodiketopiperazine scaffold was designed on the basis of the concept of the privileged structure of G-protein-coupled receptors (GPCRs). This new framework was obtained in acceptable yield with high purity from the readily prepared isonitrile resin through the Ugi reaction, sequential transformations, and cyclative cleavage. By measuring the inhibitory activity of each compound in the initial library against the intracellular calcium mobilization stimulated by MIP-1 alpha, several compounds were found to show modest but selective CCR5 antagonistic activity. After the rapid evaluation of these hit compounds, several single-digit nanomolar, low-molecular-weight CCR5 antagonists that can potently block the infectivity and replication of laboratory and clinical strains of HIV as well as those of highly drug-resistant HIV variants with minimal cytotoxicity have been identified.