Discovery of Small Molecule CXCR4 Antagonists

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• 作者：Weiqiang Zhan ; Zhongxing Liang ; Aizhi Zhu ; Serdar Kurtkaya ; Hyunsuk Shim ; James P. Snyder ; Dennis C. Liotta
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：November 15, 2007
• 年：2007
• 卷：50
• 期：23
• 页码：5655 - 5664
• 全文大小：313K
• 年卷期：v.50,no.23(November 15, 2007)
• ISSN：1520-4804

文摘

In light of a proposed molecular mechanism for the C-X-C chemokine receptor type 4 (CXCR4) antagonist1 (AMD3100), a template with the general structure 2 was designed, and 15 was identified as a lead bymeans of an affinity binding assay against the ligand-mimicking CXCR4 antagonist 3 (TN14003). Followinga structure-activity profile around 15, the design and synthesis of a series of novel small molecular CXCR4antagonists led to the discovery of 32 (WZ811). The compound shows subnanomolar potency (EC₅₀ = 0.3nM) in an affinity binding assay. In addition, when subjected to in vitro functional evaluation, 32 efficientlyinhibits CXCR4/stromal cell-derived factor-1 (SDF-1)-mediated modulation of cyclic adenosine monophophate(cAMP) levels (EC₅₀ = 1.2 nM) and SDF-1 induced Matrigel invasion (EC₅₀ = 5.2 nM). Molecular fieldtopology analysis (MFTA), a 2D quantitative structure-activity relationship (QSAR) approach based onlocal molecular properties (Van der Waals radii (VdW), atomic charges, and local lipophilicity), applied tothe 32 series suggests structural modifications to improve potency.