Dipyrimidine amines: a novel class of chemokine receptor type 4 antagonists with high specificity.
Dipyrimidine amines: a novel class of chemokine receptor type 4 antagonists with high specificity.
复制标题
DOI：
10.1021/jm100786g
复制
发表时间：
2010-12-23
影响因子：
7.3
通讯作者：
Shim H
中科院分区：
文献类型：
--
作者：
Zhu A;Zhan W;Liang Z;Yoon Y;Yang H;Grossniklaus HE;Xu J;Rojas M;Lockwood M;Snyder JP;Liotta DC;Shim H
C-X-C趋化因子受体4型（CXCR 4）/基质细胞衍生因子-1（SDF-1或CXCL 12）相互作用以及由此产生的细胞信号级联反应在转移和炎症中起关键作用。基于先前发表的CXCR 4拮抗剂5（WZ 811），设计并合成了一系列新型非肽类抗CXCR 4小分子以提高效力。在5左右的结构-活性曲线之后，发现了N，N ′-（1，4-亚苯基双（亚甲基））二嘧啶-2-胺系列中更高级的化合物，并且显示其具有比5更高的CXCR 4结合潜力和特异性。化合物26（508 MCl）是先导化合物，并且在三种体外测定中表现出亚纳摩尔效力，包括竞争性结合、基质胶侵入和Gαi环腺苷一磷酸（cAMP）调节信号传导。此外，化合物26通过在三种小鼠模型中干扰CXCR 4功能而显示出有希望的效果：爪炎症、基质胶栓塞血管生成和葡萄膜黑色素瘤微转移。这些数据表明，二嘧啶胺是具有高效力和特异性的独特CXCR 4拮抗剂。
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. Based on the previously published CXCR4 antagonist 5 (WZ811), a series of novel non-peptidic 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 leading 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.
登录
查看更多内容
影响因子：
56.9
作者：
Feng, Y;Broder, CC;Berger, EA
通讯作者：
Berger, EA
影响因子：
120.1
作者：
De Clercq, E
通讯作者：
De Clercq, E
影响因子：
4.4
作者：
Gupta, SK;Pillarisetti, K;Aiyar, N
通讯作者：
Aiyar, N
影响因子：
3.6
作者：
Kajiyama, Hiroaki;Shibata, Kiyosumi;Kikkawa, Fumitaka
通讯作者：
Kikkawa, Fumitaka
影响因子：
0.9
作者：
Gao, C.;Li, Y.
通讯作者：
Li, Y.