Dipyrimidine Amines: A Novel Class of Chemokine Receptor Type 4 Antagonists with High Specificity

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• 作者：Aizhi Zhu ; Weiqiang Zhan ; Zhongxing Liang ; Younghyoun Yoon ; Hua Yang ; Hans E. Grossniklaus ; Jianguo Xu ; Mauricio Rojas ; Mark Lockwood ; James P. Snyder ; Dennis C. Liotta ; Hyunsuk Shim
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：December 23, 2010
• 年：2010
• 卷：53
• 期：24
• 页码：8556-8568
• 全文大小：1130K
• 年卷期：v.53,no.24(December 23, 2010)
• ISSN：1520-4804

文摘

The C-X-C chemokine receptor type 4 (CXCR4)/stromal cell derived factor-1 (SDF-1 or CXCL12) interaction and the resulting cell signaling cascade play a key role in metastasis and inflammation. On the basis of the previously published CXCR4 antagonist 5 (WZ811), a series of novel nonpeptidic anti-CXCR4 small molecules have been designed and synthesized to improve potency. Following a structure−activity profile around 5, more advanced compounds in the N,N′-(1, 4-phenylenebis(methylene)) dipyrimidin-2-amines series were discovered and shown to possess higher CXCR4 binding potential and specificity than 5. Compound 26 (508MCl) is the lead compound and exhibits subnanomolar potency in three in vitro assays including competitive binding, Matrigel invasion and Gα_i cyclic adenosine monophosphate (cAMP) modulation signaling. Furthermore, compound 26 displays promising effects by interfering with CXCR4 function in three mouse models: paw inflammation, Matrigel plug angiogenesis, and uveal melanoma micrometastasis. These data demonstrate that dipyrimidine amines are unique CXCR4 antagonists with high potency and specificity.