Send to

Choose Destination
J Med Chem. 2010 Dec 23;53(24):8556-68. doi: 10.1021/jm100786g. Epub 2010 Nov 24.

Dipyrimidine amines: a novel class of chemokine receptor type 4 antagonists with high specificity.

Author information

Department of Radiology, Emory University, Atlanta, Georgia 30322, USA.


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.

[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Supplementary concept, Grant support

Supplemental Content

Full text links

Icon for American Chemical Society Icon for PubMed Central
Loading ...
Support Center