- Dipyrimidine amines: A novel class of chemokine receptor type 4 antagonists with high specificity
-
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 Gαi 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.
- Zhu, Aizhi,Zhan, Weiqiang,Liang, Zhongxing,Yoon, Younghyoun,Yang, Hua,Grossniklaus, Hans E.,Xu, Jianguo,Rojas, Mauricio,Lockwood, Mark,Snyder, James P.,Liotta, Dennis C.,Shim, Hyunsuk
-
p. 8556 - 8568
(2011/02/28)
-
- CXER4 ANTAGONISTS INCLUDING DIAZINE AND TRIAZINE STRUCTURES FOR THE TREATMENT OF MEDICAL DISORDERS
-
The invention provides compounds, pharmaceutical compositions and methods of use of certain compounds that are antagonists of the chemokine CXCR4 receptor for the treatment of proliferative conditions mediated by CXCR4 receptors or for the treatment of viral infections. The compounds provided interfere with the binding of SDFl to the receptor. These compounds are particularly useful for treating or reducing the severity of hyperproliferative diseases by inhibiting metastasis, or for reducing entry of HIV in to a cell while not reducing the capacity of the stem cells to proliferate. The compounds may be useful for long term treatment regimes.
- -
-
Page/Page column 41
(2008/06/13)
-